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German Center for Infection Research ANNUAL REPORT 2014 Title: A hepatitis C virus finds its way into a liver cell using different adhesion and receptor molecules. 3 DZIF at a glance The German Center for Infection Research (DZIF) coordinates and oversees the strategic planning of translational infection research within Germany. Its mission is to translate the results from basic biomedical research into clinical research. 35 DZIF research centres work concertedly against the global threat presented by infectious diseases. 4 Table of contents Editorial ..................................................................................................................................................................................................................... 3 About DZIF ............................................................................................................................................................................................................ 4 Science - Translation in focus Emerging infections . ........................................................................................................................................................................... 6 Tuberculosis . ................................................................................................................................................................................................. 8 Malaria . ........................................................................................................................................................................................................... 10 HIV ........................................................................................................................................................................................................................ 12 Hepatitis ......................................................................................................................................................................................................... 14 Gastrointestinal Infections ..................................................................................................................................................... 16 Infections of the immunocompromised Host . ................................................................................................. 18 Healthcare-associated and Antibiotic-resistant bacterial Infections .................................. 20 Novel Antiinfectives . ...................................................................................................................................................................... 22 Research infrastructures Product Development Unit . .................................................................................................................................................. 24 Clinical Trial Unit . ................................................................................................................................................................................ 25 African Partner Institutions ................................................................................................................................................... 26 Natural Compound Library . .................................................................................................................................................. 27 Biobanking .................................................................................................................................................................................................. 28 Bioinformatics ........................................................................................................................................................................................ 29 DZIF Academy .............................................................................................................................................................................................. 30 Collaborations at the DZIF. ........................................................................................................................................................... 31 DZIF Highlights 2014 . ......................................................................................................................................................................... 32 Science and public .................................................................................................................................................................................... 34 External collaborations ..................................................................................................................................................................... 36 German Health Research Centres ...................................................................................................................................... 39 Facts and figures Organisation and bodies ............................................................................................................................................................ 40 Partner sites and member establishments .......................................................................................................... 42 Finance . .......................................................................................................................................................................................................... 46 Personnel and awards . ................................................................................................................................................................. 48 Publications ............................................................................................................................................................................................... 50 Member establishments ............................................................................................................................................................ 53 Imprint .................................................................................................................................................................................................................... 54 3 Last year again demonstrated the kind of global challenges infection research is confronted with. The unusual magnitude and spread of the still ongoing Ebola epidemic in West Africa required concerted international action plans to contain the disease. In September 2014, the WHO declared the Ebola epidemic to be “out of control”. During this crisis, the DZIF was able to prove its strength: in March 2014, our physicians and scientists from Hamburg, Marburg and Munich were already on the ground in Africa to establish viral diagnostics and to help the people affected. Furthermore, a research consortium to tackle Ebola – EBOKON – was established within the shortest time under the leadership of the DZIF research field “Emerging Infections”, and was generously supported with further federal funding. A definite highlight was the DZIF’s participation in clinical trials for a vaccine against the Ebola virus in Hamburg and Lambaréné. Over the last year, antibiotic-resistant pathogenic bacteria returned to the public spotlight, and the DZIF network accomplished internationally acknowledged success here as well. With teixobactin and cystobactamides, DZIF scientists have identified new active agents which have the potential to form a new generation of antibiotics. Product development now needs to be expedited in collaboration with the industry. After longstanding research work, the research goals for HIV and viral hepatitis are on the verge of a change of paradigm: new active agents have made chronic hepatitis C a curable disease. The DZIF partner sites have made significant contributions to this development and testing. This development raises hopes that other chronic infections such as hepatitis B and HIV infection may also be cured. We hope these examples have inspired you to continue reading. The Annual Report illustrates the DZIF’s broad range of translational research approaches, including the latest diagnosis, prevention and treatment approaches of MERS coronavirus, HIV, malaria and tuberculosis. DZIF e.V. Executive Board Prof Dr Martin Krönke Prof Dr Ulrike Protzer Prof Dr Dirk Heinz EDITORIAL Editorial 4 About DZIF ABOUT DZIF A national network for international infection research United against infections: group photo at the DZIF Annual Meeting 2014. Infectious diseases remain a major challenge in medicine, even in the 21st century. How can we stop the spread of pathogens? Which new treatment approaches work? What should we do when pathogens become insensitive to antibiotics? Researchers at the German Center for Infection Research (DZIF) try to answer these questions, and others. They develop new drugs, vaccines, and preventive measures against infectious diseases. The German Center for Infection Research is a research association, organised virtually, with an affiliation of a total of 35 establishments at seven partner sites. Around 250 scientists work together across the different partner sites in Germany. Under the motto “United against infections”, they contribute their expertise to developing new agents against infectious diseases. DZIF research activities are strategically planned and aligned to accomplish this from the start. The DZIF is one of six German Centers for Health Research (DZG) established by the German Federal Ministry of Education and Research (BMBF). The fundamental goal of this initiative is to fight widespread diseases more effectively. The DZIF started its work under the umbrella of this alliance in 2012. Financing is 90 percent from federal funds and 10 percent from participating federal states´ funds. Organised across the sites All researchers have the infrastructures and competencies of the existing establishments at their disposal. DZIF partner sites include: Bonn-Cologne, GießenMarburg-Langen, Hamburg-Lübeck-Borstel, Hannover- 5 Aligning translation The DZIF aims to close existing gaps between basic research and clinical applications. Research is governed by the practical needs of the patient. To this effect, the DZIF promotes a rapid transfer of research results from bench to bedside (translation). Well-structured collaboration between researchers, medical doctors, probands and patients ensures smooth operating procedures. In doing so, patients benefit faster from the improvements made to diagnosis, prophylaxis and treatment of infectious diseases. Structured thematically The DZIF is divided into nine research fields. In each field, specialised scientists at the different partner sites dedicate themselves to working on a pathogen or specific issue in infection research. The research fields are called “Emerging Infections”, “Tuberculosis”, “Malaria”, “HIV”, “Hepatitis”, “Gastrointestinal Infections”, “Infections of the immunocompromised Host”, “Healthcare-associated and Antibiotic-resistant bacterial Infections”, and “Novel Antiinfectives”. Supportive infrastructure Moreover, the DZIF has established its own infrastructures important to its research. These comprise specialised services which are available to all members and provide support. Here, for example, information is collected for subsequent processing, and important patient samples or natural substances are stored for later testing. Advice is provided for difficult processes, and further training for next-generation talents. Also, contacts can be made to establishments all over the world. Collaborating internationally Numerous collaborations with external scientific institutions and the industry strengthen the DZIF’s position as a top-class institution for infection research. In addition, it has international partner sites, for example in Africa and Eastern Europe. In this way, infectious diseases which are rare in Germany, such as malaria, Ebola and tuberculosis, can be researched where they occur frequently. These contacts and collaborations are critical to the DZIF for taking on the global challenges in infection research. DZIF groups its research activities into nine research fields and six research infrastructures – internally called Thematic Translational Units (TTUs) and Translational Infrastructures (TIs): Research fields • Emerging Infections • Tuberculosis • Malaria • HIV • Hepatitis • Gastrointestinal Infections • Infections of the immunocompromised Host • Healthcare-associated and Antibiotic-resistant bacterial Infections • Novel Antiinfectives Research infrastructures • Product Development Unit • Clinical Trial Unit • African Partner Institutions • Natural Compound Library • Biobanking • Bioinformatics • DZIF Academy ABOUT DZIF Braunschweig, Heidelberg, Munich und Tübingen. DZIF research institutes, universities, hospitals and federal research institutes collaborate across the sites. Basic research, epidemiology and clinical research are promoted equally. 6 Emerging Infections SCIENCE – TRANSLATION IN FOCUS Reacting rapidly to unexpected strangers “We have survived”: An impressive thank you to all Ebola helpers on the ground, including those from the DZIF. Numerous new pathogens have emerged over the last 40 years, causing diseases such as AIDS, avian influenza and Ebola. In the era of global mobility, viruses and bacteria also know no boundaries. For this reason, DZIF researchers in the field “Emerging Infections” often have to react swiftly to stop the spread of unknown pathogens. In order to achieve this, scientists from research institutes, hospitals and public health services work closely together. DZIF researchers focus on characterising pathogens rapidly, developing new drugs and vaccines, as well as epidemiological investigations. The reason for this is that emerging infectious diseases, like Ebola, can be curbed more effectively, the earlier the pathogen and its routes of spread are identified. On several occasions, DZIF researchers discovered that some pathogens are transmitted from animals to humans. Avian influenza and Ebola belong to this group of pathogens. They cause diseases termed zoonoses and are responsible for around three quarters of all emerging infections. They often originate from viruses that have been transmitted from wild animals to humans. Better prepared for unexpected outbreaks In this context, DZIF scientists investigated the evolutionary biology of the hepatitis C virus which causes severe inflammation of the liver in humans. “We want to understand where the hepatitis C virus comes from,” explains Prof Jan Felix Drexler from the Institute of Virology of the University of Bonn. Together with colleagues from Hamburg, Hannover, Ghana and Moscow, his team recently discovered novel viruses that are distantly related to the hepatitis C virus. The researchers found them in cattle which they investigated at the DZIF partner institution in in Switzerland, Gabon and Kenya, researchers concurrently tested a vaccine called “rVSV-ZEBOV” in a total of 158 healthy adults. “The preliminary results on tolerability and safety, as well as the immune response, are promising,” explains DZIF researcher Prof Marylyn Addo, who is leading the trial at the UKE. “The data from this trial are very helpful for further clinical trials, for example on people who have been in contact with Ebola in Guinea, and they have also helped determine the dosage.” Other projects in the research field include epidemioIn Ghanaian cattle, researchers discovered new viruses that are logical studies on origin, transmission and spread of distantly related to hepatitis C viruses. the MERS coronavirus. The virus, which up to now has been predominantly transmitted to humans from camels, leads to severe respiratory illness, the so-called Ghana. Just like the hepatitis C virus, these newly discovMiddle East Respiratory Syndrome (MERS). Virologists ered novel viruses belong to the group of hepaciviruses. fear that the virus may alter and subsequently transmit However, Drexler is certain, more easily from humans to “The Ebola trial was a networking success. humans—which could result no person with hepatitis C infection contracted the viin larger epidemics. For this We would not have made it without rus from cows—the genetic reason, DZIF researchers the other colleagues, the DZIF and differences are too large. are working intensively on international networking.” Nevertheless, this discovery further investigating and Prof Dr Marylyn Addo, Head of Infectiology Section, Department of allows for important insights introducing a vaccine. Internal Medicine I, at the University Medical Center Hamburg-Eppendorf into the evolution of hepaciviruses. In general: “Only when you know whether a human virus actually originaCoordinator: ted from animals, can you react to future outbreaks and Prof Dr Stephan Becker work towards eradicating certain viruses,” says Drexler. Marburg Ebola virus epidemic: rapid reaction in emergencies The Ebola virus, first described in 1976, could be contained quickly with quarantine measures in all previous outbreaks. However, the 2014 epidemic in West Africa, reached unforeseen dimensions of cases and deaths. Researchers worldwide searched for ways to fight the epidemic, in which patients presented symptoms of fever, vomiting, diarrhoea and internal bleeding, often ending in death. An international expert consortium, led by the WHO, selected a promising candidate vaccine on which to conduct further trials. DZIF researchers were also involved with the first clinical trial in humans. At the University Medical Center Hamburg-Eppendorf (UKE), SCIENCE – TRANSLATION IN FOCUS 7 8 Tuberculosis SCIENCE – TRANSLATION IN FOCUS Modern approaches to f ighting an ancient epidemic Tuberculosis (TB) has become rare in Germany. However, it is a major global public health problem: nine million people contract TB every year; 1.5 million die from the disease. The TB pathogen, the socalled tubercle bacillus, typically infects the lungs and spreads to other organs. DZIF scientists in the research field “Tuberculosis” investigate new methods for prevention and diagnosis. Furthermore, they participate in developing and testing new active substances against TB. resistant (MDR) clones of this particular strain. The Beijing strains originated over six thousand years ago. The strains probably spread from Eastern China to Europe via the Silk Road, and by ship. Towards the end of the 19th century, they spread into Russian Republics and into the Pacific region during surges of migration. Soldiers, refugees and famine during the First World War accelerated the spread. One remarkable finding was that current high rates of MDR TB in Eastern Europe are mainly due to two main outbreak strains. Beneficial genetic mutations in the bacteria are most At the partner sites Hamburg-Lübeck-Borstel, likely the reason for their efficient transmission and Hannover-Braunschweig, Munich and Tübingen, DZIF extreme spread over the last 20 years. “Amongst scientists link basic research with clinical applications other things, this study also highlights the imporin Germany. Beyond this, together with 600 colleagues tance of efficient tuberculosis surveillance and rapid from the European research identification of antibiotic “The DZIF bridges the gap between network TBNET, they are resistance with molecular challenged with a global methods,” explains Prof research and patient care.” problem: there is no effecStefan Niemann, Head of Prof Dr Christoph Lange, Head of Clinical Infectious Diseases tive vaccine against tuberthe study at the Research at the Medical Clinic of the Research Center Borstel culosis. Treatment consists Center Borstel. “Outof several antibiotics and often takes many months. Side breaks and spread of multidrug-resistant tuberculosis effects, high treatment costs and a lack of compliance could then be identified and contained in time.” often lead to abandonment of treatment. Co-infections and antibiotic-resistant tubercle bacilli complicate Reliable diagnostics and tailored the situation. Researchers are particularly concerned therapy required about the rapid increase of multidrug-resistant and Countries with high TB rates often do not have the reextensively drug-resistant TB strains (M/XDR tubersources to treat their patients. “It is our human duty to culosis), for which patients seldomly receive effective take care of the patients in these countries,” says Prof treatment. Christoph Lange, Head of Clinical Infectious Diseases in Borstel. In a TBNET trial, DZIF researchers concenTracing and tracking multidrug-resistant pathogens trated on TB infected patients who had weak immune around the world systems due to pre-existing illnesses. These patients Multidrug-resistant TB strains are spreading, esperun a high risk of developing tuberculosis disease. Here, cially in Eastern Europe, Africa and Asia. DZIF scienthe researchers tested the reliability of TB tests: they tists are doing genuine detective work to stop their compared two, WHO-recommended rapid molecular spread and to trace the evolutionary history of tudiagnostic tests to the conventional tuberculin test. bercle bacilli. In a consortium consisting of 55 TB reEspecially patients with HIV infections developed TB searchers, they analysed genetic fingerprints of almost symptoms whereby the rapid molecular tests did not 5,000 tuberculosis strains of the so-called Beijing confirm all cases. Patients with weak immune systems lineage, from 99 countries. With this study, they could, who received preventive antibiotic treatment during for the first time, show the global spread of multidrugthe study did not develop symptoms. “This result shows 9 SCIENCE – TRANSLATION IN FOCUS Tuberculosis strains of the Beijing genotype have spread globally along historical trade routes. Photo: courtesy of: Merker et al, NatGen 47, 242–249 (2015); doi: 10.1038/ng.3195 Not without a face mask: tuberculosis bacteria are transmitted by coughing and sneezing. that we have to redefine risk groups and use preventive therapy to contain the spread,” says Lange. Overall, the DZIF scientists are therefore increasingly focussing on concepts of tailoring treatment to adjust it to antimicrobial resistance and pre-existing illness. Beyond this, the DZIF is also active in endemic areas. For example, it is funding the establishment of a new trial centre in Bucharest, Romania. Here, new drugs are to be tested in the largest EU tuberculosis hospital. Additionally, a consultation service for doctors has been established, where DZIF infectious diseases specialists are available around the clock to give competent advice. In a national online teleconference, the doctors and scientists discuss best case management of MDRTB patients with competent colleagues from other sites in Germany. In a national TB cohort, DZIF researchers are investigating biomarkers for individualising therapy. Coordinator: Prof Dr Stefan Niemann Borstel 10 Malaria SCIENCE – TRANSLATION IN FOCUS Fighting against intermittent fever The DZIF is working closely with African partner institutions to fight malaria. Every year, there are approximately 200 million cases Despite extensive research, the fight against malaria of malaria and 600,000 malaria deaths; 90 percent of has been challenging scientists all over the world: rewhich occur in Africa. Children under five years are gional genetic differences in the pathogen and in particularly vulnerable, where the infection is one of populations complicate treatment. Further obstacles the major causes of death. are co-infections with other Parasites, so-called plas- “The DZIF’s collaborations and support have pathogens and resistance modia, cause this tropical made it possible to bridge the gap between to conventional treatment. disease which is transmitConsequently, researchers basic research and clinical research.” ted through mosquitos. have to constantly adTypically, the disease prejust their interventions to PD Dr Benjamin Mordmüller, Institute for Tropical Medicine at the University of Tübingen sents with intermittent fight this highly adaptable phases of fever. DZIF repathogen. The DZIF scisearchers in Tübingen, Heidelberg and Hamburg foentists are therefore also looking for alternative pathcus on developing new methods of prevention and ways. The main areas of focus in the research field therapy, as well as epidemiological measures to fight “Malaria” are to test and optimise alternative methods the spread of malaria. of vaccination, and to develop parasite inhibitors. Furthermore, scientists are investigating the regional A mosquito-bite can be dangerous if the insect is carrying the malaria parasite. spread of the pathogens, in order to effectively plan malaria interventions in the affected areas. To this effect, the DZIF is working together closely with African partner institutions in Ghana, Burkina Faso and Gabon. Protection against dangerous parasites Although the quest for a vaccine has been ongoing for years, only a moderately effective vaccine, at best, will be available in the near future. At the Institute for Tropical Medicine of the University of Tübingen, DZIF researchers are testing a new vaccination method in a clinical trial. They intravenously inject live plasmodia and simultaneously administer a drug for malaria to weaken them. This method has been shown to fundamentally work in animal models, as well as in a clinical trial that used infected mosquitoes instead of the purified plasmodia. It results in effective vaccine protection. “By using the entire pathogen, we obtain a strong and broad immune response,” says Dr Benjamin Mordmüller at the DZIF partner site Tübingen. “This vaccination method stands good chances of being approved,” Mordmüller believes. “Then it can also be used to prevent malaria in children in Africa.” Fever does not necessarily mean malaria Especially children are in urgent need of protection against malaria. In African countries, they frequently suffer from fever of unclear origin. “Differentiating between malaria and other infections is hardly possible, given the available facilities,” explains Prof Jürgen May, Head of the Research Group on Infectious Disease Epidemiology at the Bernhard Nocht Institute for Tropical Diseases in Hamburg. In one trial conducted at the African partner institutions, the DZIF team led by May investigated children with severe febrile illnesses in hospitals. With the help of conventional methods and molecular diagnostics, they determined the frequency, risk and treatment options of malaria coinfections. In doing so, they could confirm that the degree of severity of the illness was higher in cases of coinfection. Conversely, malaria also facilitates simultaneous infection with other pathogens, particularly salmonella, as the team from Hamburg observed. “We therefore want to develop a rapid bedside test,” May explains. Further projects In other projects, DZIF researchers are developing novel parasite inhibitors. Moreover, scientists in Hamburg are developing mathematical models to describe the regional spread of the parasites. Models can also help determine the parasites’ life cycles in infected people’s blood. Coordinator: Prof Dr Peter Kremsner Tübingen SCIENCE – TRANSLATION IN FOCUS 11 12 HIV SCIENCE – TRANSLATION IN FOCUS Luring retroviruses out of hiding At the DZIF, Dr Marina Lusic researches HIV’s game of hide-and-seek. Since its discovery in the year 1983, the human immunodeficiency virus (HIV) has spread worldwide: 35 million people are HIV positive, 1.5 million die every year from the consequences of HIV infection—the immune deficiency syndrome AIDS. As yet, there has been no effective vaccine and no prospect of cure. In view of this situation, the DZIF research field “HIV” has set itself the ambitious goal of developing new treatment methods, with the particular aim of curing the disease. HIV belongs to the family of retroviruses: they insert their genetic information into the host’s genome before becoming active. Of all cells, HIV chooses human immune system cells as its host. Once integrated into the host genome of these immune cells, the virus’s genes become insusceptible to attack—by both the human immune defence system and by drugs, as these only target the free viruses in the blood. As soon as treatment is omitted, the virus’s genetic material is reactivated, and the body gets flooded with viruses once again. Virologists describe this hide-and-seek game as latency, and consider this to be the reason why HIV has so far remained incurable. Discovered in its hiding place In Heidelberg, DZIF scientist Dr Marina Lusic investigates HIV latency, in collaboration with colleagues from Cologne and Hamburg. The virologist is convinced, “Only by understanding the mechanisms of HIV latency will we be able to develop therapeutic countermeasures.” In 2014, the young scientist received a tenure-track position funded by the DZIF, for preclinical HIV research at the University of Heidelberg. This exemplifies that furthering careers at the DZIF also plays an important role. The scientist View of the most delicate structures in the HIV Photo: courtesy of Macmillan Publishers LTD: from Nature 517, 505–508 hiding place and activated with drugs to subsequently be destroyed in the blood.” Together with researchers from the Rockefeller University in New York (USA), DZIF physicians from the University Hospital of Cologne are investigating a new treatment approach. The international team has tested a new generation of antibodies in humans for the first time. The trial, also funded by the DZIF, showed: the antibodies can effectively neutralise a large number of different HIV viruses and significantly reduce infected people’s viral loads. “The antibody´s effect proved to be comparable to the current drugs being used for treatment,” says Fätkenheuer. “This method opens up a new field of HIV treatment and could, in future, possibly also be used as a preventive measure after fresh infections. Its principle is similar to that of a passive vaccination.” investigated how the virus alters the nucleus and genome A further DZIF team, led by Prof Joachim Hauber at the structure of infected cells to suit its purpose. Together Heinrich-Pette Institute in Hamburg builds on a gene therwith her team in the Department of Infectious Diseases apy approach: developing new specific enzymes that are at the Heidelberg University inserted into the host cells, Hospital, Lusic discovered which can detect the viral “The DZIF creates structures that the viruses frequently genome in the nucleus and that make Germany attractive insert their genetic material specifically excise it from the for elite researchers.” into specific regions of the human DNA. Subsequently, cell nucleus. Especially often, Prof Dr Gerd Fätkenheuer, Head of the Division of Infectious Diseases, this should prevent a later Department I of Internal Medicine of the University Hospital Cologne the viral genome is found activation of the “dormant” directly behind the nuclear virus. Other projects invespores—the entry channels to the nucleus. “Imagine you are tigate early HIV infection and their long-term effects, a visitor to an event and you are late. You will come through also focussing on patients in Africa in addition to those in the door and take the first available seat,” Lusic explains. Germany. A new approach to treatment and prophylaxis Antiviral drugs keep HIV under control and delay the onset of AIDS (Acquired Immune Deficiency Syndrome). However, they have to be taken over a lifetime and frequently have side-effects. They are often too expensive for patients living in developing countries. Additionally, the virus easily develops resistance. “We therefore need new therapies,” explains Prof Gerd Fätkenheuer, Head of the Division of Infectious Diseases at the University Hospital of Cologne. “Currently, intensive research is ongoing which investigates how the pathogen can be lured from its Coordinator: Prof Dr Hans-Georg Kräusslich Heidelberg SCIENCE – TRANSLATION IN FOCUS 13 14 Hepatitis SCIENCE – TRANSLATION IN FOCUS Real hope for cure A hepatitis C virus finds its way into a liver cell using different adhesion and receptor molecules. The inflammatory liver disease (hepatitis), caused by infections with hepatitis virus types A to E, is globally widespread. More than half a billion people suffer from chronic hepatitis B, C and/or D infections worldwide. In the DZIF research field “Hepatitis”, researchers develop and test new antiviral drugs. They investigate their mechanisms of action and their effective combinations. Additionally, they conduct epidemiological studies to improve patient access to treatment. Patients suffering from chronic hepatitis B, C and/or D infections often have complications and chronic courses of disease. They have a high risk of developing secondary diseases such as liver cirrhosis and liver cancer. A vaccine against the hepatitis B virus (HBV) exists, which simultaneously prevents hepatitis D virus (HDV) infection. Anti- viral drugs for HBV are also available; they curb viral replication but do not actually cure the disease. There is no vaccine available against hepatitis C (HCV). Up to now, the usual treatment of chronic hepatitis C infection has consisted of a combination of three drugs, one of which has to be injected regularly. A cure for hepatitis C New active agents have changed the treatment of chronic hepatitis C tremendously. “Hepatitis C is the first chronic viral infection that has become curable. This is an enormous success story. It will change medicine,” says DZIF Professor Michael Manns, Director of the Department of Gastroenterology, Hepatology and Endocrinology at the Hannover Medical School (MHH). “Treatment now only consists of a combination of several tablets, can be significantly shortened, causes less side effects The global hepatitis D registry helps research into new therapies. and resistance, and is also effective against difficult-toaccess information about their condition to obtain the optreat forms of hepatitis C,” explains Prof Manns. The new timal treatment. Furthermore, it enables the participating drugs, for example, inhibit the enzymes RNA polymecentres to get a rapid overview of their patients’ symprase and protease, which the virus needs for both reptoms and therapies. Patients undergo regular follow-up lication and maturation, thereby suppressing both. The examinations in which their symptoms, liver and kidney mechanism of action of the function, hepatitis serology “The DZIF pools expertise in molecular new substance “daclatasand other blood values are biological processes all the way through to ascertained. Dr Hardtke is vir” was unknown for a long time. DZIF Professor Ralf happy, “In November 2014, clinical development and launching new Bartenschlager, virologist at we registered far over 600 drugs into market.” the University of Heidelberg, patients and twelve particiPD Dr Thomas von Hahn, Senior Physician at the Department of has now deciphered its pating centres worldwide. Gastroenterology, Hepatology and Endocrinology at the mode of action: it binds to The virus blocker “Myrcludex Hannover Medical School the viral protein NS5A. The B”, developed at the DZIF virus needs this protein both for replicating its RNA and partner site Heidelberg, has successfully completed the assembling new virus particles. However, therapy with first clinical trial phase and is considered to be an effective the new active substances is very expensive. candidate for treating, and possibly even curing, hepatitis B and D. Furthermore, researchers at the DZIF partner Hepatitis D: Improving investigations site Hannover-Braunschweig are looking for biomarkers and cure rate that give an indication of the course of disease and effiHDV infection only occurs as a co-infection with hepatitis cacy of treatment, which subsequently enables individuB, and causes the most aggressive form of viral inflamalised treatment. mation of the liver. Conventional therapy with interferon alpha has considerable side-effects and only cures Coordinator: less than twenty percent of treated patients. Therefore, Prof Dr Michael Manns there is an urgent need for new trials to investigate new Hannover treatment approaches. The required number of patients for such trials can only be achieved through international multicentre trials. A DZIF project at the MHH (HepNet Study-House of the German Liver Foundation) therefore established a global registry for patients suffering from chronic HBV/HDV infection. “The hepatitis D registry is to enable scientists to investigate the disease,” explains project coordinator Dr Svenja Hardtke. Patients can better SCIENCE – TRANSLATION IN FOCUS 15 16 Gastrointestinal Infections SCIENCE – TRANSLATION IN FOCUS Targeted treatment instead of broad spectrum antibiotics At the DZIF, scientists develop a vaccine to treat Helicobacter pylori. Gastrointestinal infections are globally widespread and are not only unpleasant, but also underestimated: according to the WHO, about 1.5 million people die each year from diarrhoeal disease caused by pathogens like Salmonella, E. coli and rotaviruses. DZIF scientists in the research field “Gastrointestinal Infections” develop active substances and vaccines directed at specific pathogens. Moreover, they investigate measures for diagnosing and maintaining the natural gut flora which helps to protect against infections and chronic diseases. Conventional antibiotic therapy often damages both the pathogens and the natural gut flora to the same degree. Using antibiotics can cause a shift in composition of the gut flora which may facilitate the development of chronic diseases such as asthma and diabetes. Additionally, antibiotic resistance may develop, consequently leading to infections with difficult-to-treat bacteria. Newer treatment approaches are therefore not directed at the pathogens themselves, but against the characteristics of bacteria that cause illness, so-called virulence factors. Inhibiting instead of damaging DZIF researchers at the partner sites Tübingen and Hannover-Braunschweig, as well as at the University of Münster, are following the approach of inhibiting bacteria’s pathogenic characteristics instead of damaging the actual pathogens themselves. Active agents working on this principle are called pathoblockers. “They basically prevent the pathogen from penetrating the gut wall, or inhibit their toxins in the gut,” explains Prof Ingo Autenrieth, Medical Director of the Institute of Medical Microbiology and Hygiene at the University Hospital Tübingen. On a research platform together with DZIF colleagues, Autenrieth and his team are systematically searching compound libraries for such substances. A potential target with DZIF scientists in Hannover, are developing a therapeutic vaccine: “We want to vaccinate adults infected with Helicobacter pylori who have not yet developed gastric ulcers or gastric cancer, so as to protect them from developing these conditions,” Gerhard explains. “In 2014, vaccine production was initiated in a spin-off company and preclinical tests were completed successfully. First clinical studies are pending.” Microbiome research A further focus of the research field is microbiome research. In January 2014, DZIF scientists at the partner sites HanAn electron microscope portrait of the dreaded gastric pathogen Helicobacter pylori. nover, Munich and Tübingen founded the Center for Gastrointestinal Microbiome Research (CEGIMIR) under the umbrella of the DZIF. This new research platform will more structure for future antiinfectives could be a type III intensively investigate the microbial diversity of the gastrosecretion system, commonly found in bacteria which, for intestinal tract and its role in infections. The alliance aims to example, salmonella use like discover diagnostic biomar“The pharmaceutical industry focuses a needle to inject toxins into kers that give an indication of host cells. On their quest for individual sensitivities to speon high profits—the DZIF on substances that inhibit this cific gut pathogens. Based on high clinical relevance.” mechanism, the researchers these, therapies will be detested around 5,000 active veloped that protect the gut Prof Dr Ingo Autenrieth, Medical Director of the Institute of substances, and were suc- Medical Microbiology and Hygiene at the University Hospital Tübingen flora and/or fortify the imcessful: “We have found a mune system. “For medicine, handful of effective substances which could be potential enormous potential lies in gaining a better understanding candidates,” Autenrieth says happily. of the microbiome’s role in health and disease, and the diverse interactions between gut pathogens and gut flora. The Helicobacter pylori: vaccine instead of antibiotics DZIF has made it possible for us to pool our research caHelicobacter pylori is also an important gut pathogen. The pacities in this field and to move forward together quickly,” bacteria cause gastric infection in half of the world’s popsays Prof Sebastian Suerbaum, Director of the Institute of ulation. It is the main cause of gastric ulcers and gastric Medical Microbiology and Hospital Epidemiology at the cancer. About ten percent of the world’s population deHannover Medical School, and Coordinator of the DZIF revelop a gastric ulcer once in their lifetime; 750,000 peosearch field “Gastrointestinal Infections”. ple worldwide die of malignant gastric cancer every year. Antibiotics that are effective against Helicobacter pylori Coordinator: exist and therefore also protect against the secondary Prof Dr Sebastian Suerbaum complications of infection. However, “Many patients have Hannover become untreatable due to antibiotic resistance, and the rates of resistance are increasing steadily,” adds Prof Markus Gerhard from the Technische Universität München (TUM). For this reason, the TUM scientists, in collaboration SCIENCE – TRANSLATION IN FOCUS 17 18 Infections of the immunocompromised Host SCIENCE – TRANSLATION IN FOCUS Decoding the immune system’s mechanisms Biological samples are safely cryopreserved in nitrogen tanks. Pathogens, harmless to healthy people, can become a life-threatening danger to people with impaired immune systems. These include transplant and cancer patients, chronically ill people, people with inherited or acquired immune deficiencies, and elderly patients. These people are difficult to treat with conventional antibiotics. The DZIF research field “Infections of the immunocompromised Host” therefore focuses on investigating immune defects, identifying biomarkers for infection control, as well as developing new approaches to prevention and immunotherapy. The prevention and treatment of infections in immunocompromised patients is playing an ever growing role— especially in the day-to-day life of hospitals. Better knowledge of the causes and mechanisms of immune deficiencies form a basis for developing new therapies. More knowledge about immune deficiencies “We learn a lot from patients with rare, inherited diseases of the immune system,” emphasizes DZIF Prof Christoph Klein, Director of LMU Munich’s Dr. von Hauner Children‘s Hospital. In order to understand these immune defects, Klein and his team look for the gene loci and gene products of impaired functions. In doing so, they have found a defective gene which codes for “Jagunal 1” (JAGN1), an important transport protein. It regulates the function of neutrophil granulocytes, cells of the immune system important for the defence against fungal infections. The researchers investigated JAGN1 gene defects in mice, and discovered that administering them with a certain granulocyte stimulating factor had a protective effect against infections with Candida albicans, a type of yeast which is responsible for many fungal infections in humans. Clinical trials now need to be conducted to investigate whether this is a treatment 19 can be used: their infection is controlled by T lymphocytes, in short T cells, that specifically target EBV. In the same manner, immunocompromised lymphoma patients can be cured with infusions of EBV-specific T cells. In order to develop these treatment approaches More immunotherapy for cancer patients further, Behrends and her team investigated the effect of DZIF scientist Prof Uta Behrends, from the university different EBV-specific T cells in mouse models. The result hospital of the Technische Universität München, found was surprising: “Lymphoma growth was inhibited by some a piece of the puzzle which helps understand the conT cells, promoted by some and unaffected by others,” nections between infections, says Behrends. Treatment “Physicians and scientists from the most the immune system and canwith solely tumour inhibiting cer. It involves the EpsteinEBV-specific T cells could varied disciplines come together at the Barr virus (EBV). Most people therefore further improve interfaces of DZIF projects – in this lies the in Europe contract this virus, efficacy of current immunogreatest potential for innovation.” but the infection goes untherapy approaches. noticed in most cases. The Prof Dr Christoph Klein, Director of the Dr. von Hauner pathogen remains “hidden” Another important project Children‘s Hospital, Ludwig-Maximilians-Universität (LMU) München in infected cells over many in the research field is to years. It often only becomes noticeable when the incontinuously develop the Transplant Cohort. Here, fected person develops a weak immune system, as transplant patients are examined before and after procehappens with blood stem cell and organ transplants. dures, medical data and samples are collected and anaThese patients then suffer more frequently from cancer lysed. In doing so, researchers want to find out why some of the white blood cells, so–called lymphomas. EBV patients are more susceptible to infection than others. is an important stimulus for developing lymphoma in patients who have had a transplant. To treat these Coordinator: patients, the same defence mechanism that protects Prof Dr Dirk Busch EBV-infected people with healthy immune systems München The Epstein-Barr virus can “hide” in infected cells over many years. SCIENCE – TRANSLATION IN FOCUS option transferable to humans. “Each defect we identify is like part of a puzzle. The more of these we find, the better we can understand the immune system’s mechanisms and can also treat other patients,” Klein stresses. 20 Healthcare-associated and Antibiotic-resistant bacterial Infections SCIENCE – TRANSLATION IN FOCUS Getting hospital pathogens under control The emergence of resistance is monitored in hospitals, as is antibiotic use. Hospital pathogens are one of the biggest challenges in healthcare. According to the German Society for Hospital Hygiene, approximately 900,000 hospital-acquired infections occur in Germany every year. The threat of falling back into a “pre-antibiotic era” is growing, especially because of the increase in antibiotic-resistant pathogens. In order to better control the pathogens, DZIF scientists in the research field “Healthcare-associated and Antibiotic-resistant bacterial Infections” are concentrating on several issues simultaneously: they are encouraging a more targeted use of antibiotics, looking for new active substances, and developing improved hospital hygiene management. In particular, intensive care units run a high risk of developing and spreading multidrug-resistant pathogens. Especially the inappropriate use of broad spectrum antibiotics is promoting an increase in resistance. This results in longer and more severe courses of disease, along with higher treatment costs. Methicillin-resistant Staphylococcus aureus (MRSA) strains and multidrug-resistant gramnegative Enterobacteriaceae are especially dreaded in hospitals. Some pathogens have even become insensitive to the “last resort” antibiotics that are reserved for emergencies only. Mobile resistances identified and stopped At the University Hospital of Gießen, Dr Can Imirzalioglu and his team also encountered this problem. During a routine examination in a hospital in Hessen, they identified various bacteria that produced carbapenemase. This enzyme renders carbapenem, a “last resort” antibiotic, ineffective. “As very different bacteria produce this enzyme, we suspected that its genetic information may not be located on a bacterial chromosome, but on a plasmid,” says Imirzalioglu. These plasmids, or mobile experts recommend using “antibiotic stewardship” programs, ABS for short. Here, a multidisciplinary team advises hospital colleagues on selection, dose and administration of an optimal antibiotic. It recommends specific antibiotics for certain diseases and excludes others. ABS experts also compile lists of recommended drugs for hospitals, and monitor antibiotic usage, as well as the emergence of resistance. First results, including those from DZIF studies, show: 10-40 percent of the administered drugs can be omitted, the duration of treatment can be shortened, and resistance can be reduced in the long-term. Keeping an eye on the pathogens: controlling growth In collaboration with an international team, Prof Evelina in a petri dish. Tacconelli, Head of the Division of Infectious Diseases at the University Hospital Tübingen also developed genetic elements, consist of short ring-shaped DNA European guidelines for controlling multidrug-resistant and can easily transfer resistance between bacteria. gram-negative bacteria. In view of the increasing spread And indeed, in each sample, the DZIF bioinformaticiof pathogens across all borders, the DZIF researcher ans in Gießen localised a underlines the importance “The DZIF is a pioneer in translational resistance-gene encoded in of Europe-wide recomresearch in Europe, particularly a plasmid. For the first time mendations. “This is partiin the world, they successcularly important for counin the field of multidrug-resistant fully identified and charactries which do not have hospital pathogens.” terised the mobile genetic national guidelines of their Prof Dr Evelina Tacconelli, Head of the Division of Infectious Diseases, element as responsible for own,” Tacconelli thinks. She Department for Internal Medicine I at the University of Tübingen transferring the carbapebrings expertise in infection nem resistance while the outbreak was still ongoing. In research, which she gained in other European countries, doing so, they could rapidly identify the source of infecto the DZIF. Further projects in this research field focus tion and the routes of spread, and therefore contain the on developing new substances that inhibit colonisation outbreak. of multidrug-resistant Staphylococcus, as well as measures against multidrug-resistant Enterobacteriaceae in Antibiotic stewardship: reducing resistance in the cancer patients. long-term Together with other scientists, Prof Winfried Kern, Head Coordinator: of the Division of Infectious Diseases at the University Prof Dr Andreas Peschel Medical Center Freiburg, developed guidelines for antiTübingen biotic use in hospitals, as a prevention measure against hospital pathogens. “Treatment has become so complicated that a surgeon will almost be unable to select a correct antibiotic without consulting an infectious diseases specialist,” is how the DZIF researcher describes the situation. In the national guidelines, issued in 2014, SCIENCE – TRANSLATION IN FOCUS 21 22 Novel Antiinfectives SCIENCE – TRANSLATION IN FOCUS Finding valuable natural treasures They co-discovered a novel antibiotic: Anna Müller, Ina Engels, Prof Tanja Schneider and Dr Till Schäberle. Medicine without antibiotics is no longer imaginable. They are the most important agents against infectious diseases. However, more and more pathogens are developing resistance, making the former “silver bullets” less and less effective. Although there is a great need for antibiotics, the pharmaceutical industry has hardly introduced any new ones to market – they are not lucrative enough. The research field “Novel Antiinfectives” is counteracting this development: it identifies new target structures for antibiotics, develops candidate agents and strategies for fortifying the body’s immune defence. Fungi and bacteria produce active substances to protect themselves against other microorganisms, amongst which new antibiotics could potentially be found. Scientists comb through natural substances in marine sediments, soil and animal excrements in pursuit of such organisms. DZIF researchers see a particularly high potential in soil bacteria. However, less than one percent of all bacteria and fungi are cultivatable in conventional culture media. The quest for antibiotics is painstaking and has a low rate of success. Valuable resource against gram-positive bacteria Together with DZIF members, an international team of researchers from the USA, took the trouble of searching and was rewarded: thanks to a special culturing method, the scientists were able to isolate previously uncultured ground bacteria, and subsequently discovered an untapped source of new antibiotics. By means of a new screening method, they discovered “teixobactin”. Prof Tanja Schneider, leader of a DZIF junior research group at the University of Bonn, is happy, “It is a highly interesting active substance and the first member of a new class of antibiotics.” The biologist and her team deciphered its The newly discovered cystobactamides could be effective against gram-negative bacteria (here: EHEC pathogens). Bacteria of the species Pseudomonas aeruginosa (in the photo) can cause infections if the immune system is weakened. “We have discovered a completely new substance class, and have christened it ‘cystobactamides’.” In tests, they have been effective against the gram-negative bacteria Escherichia coli and Acinetobacter baumannii. The active substance works by preventing bacterial DNA from being compacted like a twisted garden hose. Interfering with this process, results in the bacteria’s metabolism becoming impaired. By chemically modifying the active substance, the researchers hope to enhance this effect and broaden the spectrum of targetable bacteria. “If we succeed in doing this,” says Müller, “cystobactamides will be a real beacon of hope in the fight against hospital pathogens.” Furthermore, the DZIF scientists analyse microbial genomes at the partner site Tübingen. With new techniques, such as genome mining, they looked for “silent” mechanism of action: “Teixobactin simultaneously targene segments which could code for potential active gets many different important sites in bacterial cell wall substance syntheses. After activating these gene clussynthesis, and makes it almost impossible for bacteria ters, the scientists discovered promising active substanto use their adaptation strategies,” Schneider emphaces in the glycopeptide class. In 2014 alone, the DZIF sises. In first tests in mice, research field “Novel Antithe substance was effective “Thanks to the DZIF interactions, we focus infectives” discovered a toagainst numerous probletal of three new classes of our basic research a lot more on what is matic gram-positive bacteria antibiotics. The chemists now important for hospitals.” and did not cause resistance. need to work at optimising Prof Dr Rolf Müller, Managing Director of the Helmholtz Institute The scientists consider it to the candidate active subsfor Pharmaceutical Research Saarland (HIPS) be a promising new drug tances, for good tolerability, candidate against bacteria such as Staphylococcus aureus effectiveness against a broad spectrum of pathogens and Mycobacterium tuberculosis. and to prevent the development of resistance as far as possible. Beacon of hope in the fight against hospital pathogens Coordinator: Gram-negative bacteria are even more challenging: “They Prof Dr Hans-Georg Sahl have two cell membranes. Potential agents have to Bonn penetrate through both to be effective,” explains Prof Rolf Müller, Director of the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS). Despite complex requirements, Müller and his colleagues from Saarbrücken succeeded in isolating an active substance from myxobacteria at the Helmholtz Centre for Infection Research (HZI) in Braunschweig. Müller is happy, SCIENCE – TRANSLATION IN FOCUS 23 24 Product Development Unit RESEARCH INFRASTRUCTURES Well-supported, from the target molecule to approval to identify promising approaches for potential products and assess the prospects of their further development. Conrad emphasizes the benefit of contacting the office early on: “Researchers are welcome to get in touch from the moment they have a good idea for a potential product.” This is how the utilisation of scientific insights and the subsequent realisation of medicinal products can be improved. Once the pilots are on board, they provide advice and support for developing trial designs, planning and managing product development, for questions about clinical testing as well as for marketing approval. With the help of the “Product Development Unit” at the DZIF, a phase I trial for an Ebola vaccine candidate was initiated. The journey from discovering a new target molecule in the body to the approval of a suitable drug takes years. 95 percent of all active agent candidates fail before the clinical trial stage. Developing a new drug requires knowledge of the regulatory requirements, production and patents. Here, the DZIF’s “Product Development Unit” advises and supports its colleagues. The DZIF infrastructure consists of two offices. The Translational Project Management Office (TPMO) at the Helmholtz Centre for Infection Research in Braunschweig develops plans for drug development, assists with their implementation, and advises on commercial matters. The Office for Scientific and Regulatory Advice (OSRA) at the Paul-Ehrlich-Institut in Langen advises on the approval of clinical trials, therapeutic agents and vaccines. OSRA also analyses typical obstacles in drug development and ways of avoiding them. From idea to product “We are like pilots guiding the way through the thicket of regulations and product development,” is how Dr Christoph Conrad from the Paul-Ehrlich-Institut describes OSRA and TPMO’s responsibilities. He, along with his colleagues, join the DZIF research fields’ work meetings From the Ebola emergency to a successful vaccine The DZIF activities during the Ebola outbreak in 2014 exemplify how the infrastructure successfully manages complex and critical translational projects. With the help of the “Product Development Unit”, important stakeholders were brought together to promptly initiate a clinical phase I trial for the candidate vaccine “rVSV-ZEBOV” in Germany. The DZIF infrastructure played a decisive role in this as a point of contact with the WHO, the Canadian health authority Health Canada, which developed the vaccine, the licensee NewLink, sponsors, the trial centre and the applicants as well as the authorities concerned. This enabled the development of a promising candidate vaccine within a few months, which was subsequently available for further trials. Coordinator: Prof Dr Klaus Cichutek Langen Clinical Trial Unit 25 Human trials for humans Consistently high quality standards are implemented across the DZIF’s clinical trial units. New drugs have to be tested thoroughly in clinical trials before they can be brought onto the market. The DZIF “Clinical Trial Unit” (CTU) consists of clinical trial units specialised in infectious diseases. Here, active substances are medically tested under the highest quality standards. Good internal collaboration paves the way to external collaboration The networking infrastructure between the partner sites, consistently high quality standards, efficient operating procedures, and experience in collaborating between academic partners and companies make the units suitable for clinically testing active substances, and this is true not only for substances developed within the DZIF. “A network that maintains quality standards like these is highly valuable to the industry,” explains Angela Steinbach, the CTU project manager. One major advantage of the CTU is that one central contact person enables access to many trial units. Furthermore, this expertise strengthens the DZIF’s position as a partner in international infectious disease networks. Coordinator: These clinical trials test tolerability, efficacy and dosages of drugs and vaccines. In Germany, strict regulations and standardised operating procedures must be adhered to. Research on humans demands competency, precision and utmost attention. In order to ensure reliable results, clinical trials have to be planned thoroughly in advance, conducted in a controlled environment, tested systematically and evaluated carefully. DZIF quality objectives are external signs of quality Currently, eleven clinical trial units are working together within the DZIF infrastructure. The “Coordinating Office” in Cologne has longstanding experience with which it coordinates the alliance, manages feasibility requests and the central management system. In 2014, its main focus was to implement a comprehensive strategy for conducting clinical trials in all participating DZIF clinical trial units. “We have established a joint quality management system,” Prof Dr Oliver Cornely Köln RESEARCH INFRASTRUCTURES explains Prof Oliver Cornely, Coordinator of the DZIF infrastructure. This system is based on so-called Standard Operating Procedures (SOPs), as has been recommended by the Federal Ministry of Education and Research (BMBF). 26 African Partner Institutions RESEARCH INFRASTRUCTURES Reliable alliances in areas of risk Tracking pathogens locally Together with their African colleagues, DZIF researchers conduct epidemiological surveys to better understand the temporal and spatial distribution of pathogens in the affected areas. In one trial, conducted at all four partner institutions, the teams collected samples from children with severe febrile illnesses. The samples were initially analysed on-site with rapid tests and microbiological investigations, and later in Germany with special molecular diagnostic tests. Besides malaria parasites, other pathogens were often found to be the cause of life-threatening febrile illness in children. Trial participants were also recruited from the Agogo Presbyterian Hospital in Ghana. Like many other infectious diseases, AIDS, tuberculosis and malaria occur rarely in Germany. They are, however, widespread in many parts of Africa. In order to better investigate these diseases, the DZIF institutes foster partnerships with research establishments on the African continent. The DZIF promotes collaborations between its partner sites and renowned research establishments in Ghana, Gabon, Burkina Faso and Tanzania. “The DZIF institutions have been working together with these partners for over a decade,” says Prof Jürgen May, Coordinator of the infrastructure “African Partner Institutions”. Thanks to longstanding relationships, contacts and agreements in these reliable alliances have existed for years. They offer DZIF researchers excellent administrative and logistic conditions on the ground: from the provision of accommodation and modern laboratories to infrastructures for clinical trials all the way through to facilitated import and export arrangements for research projects. The Ebola virus vaccine efficacy trial conducted in Gabon, once again demonstrated the potential in these partnerships. Improving on-site diagnostics “We therefore want to improve bedside testing,” says May, “and aim to find simple methods, particularly for regions with limited access to health care.” Together with the Fraunhofer Institute for Silicon Technology, DZIF researchers are developing a new diagnostic testing kit which rapidly analyses blood samples using microchips. The chips will analyse a choice of eight biomarkers in a convenient device with a modular design. The biomarkers can be selected according to the needs in the respective areas. Coordinator: Prof Dr Jürgen May Hamburg Natural Compound Library 27 From gene sequences of bacterial strains, Nübel can read the course of infectious disease outbreaks or the spread of resistance, and can identify the potential in new active substances. Prof Mark Brönstrup, who heads the Department of “Chemical Biology” at the HZI, paves the way to new drugs. Under a DZIF professorship, he is looking for new testing systems and contributing to developing and optimising active substances. In doing so, he draws on his experience from the pharmaceutical industry. The DZIF’s “Natural Compound Library” provides researchers with sufficient substances to “fuel” investigations. Microorganisms not only cause infections, they also produce substances that can fight other pathogens. Most antibiotics have been developed from such natural substances. However, up to now, only a few substances have been investigated for their medicinal effects. In the “Natural Compound Library”, the DZIF has collected compounds from bacteria, fungi and plants. They are available for research to all DZIF establishments. Ordering substances from the library In the long term, an extensive chemical substance library is to be established and made available to the DZIF research fields for screenings. “We have resources for both functional genomics and fermentation, as well as for developing active substance screenings,” emphasises Prof Rolf Müller, Coordinator of the infrastructure “Natural Compound Library”. “In this way, at the request of DZIF colleagues, we can identify substances, reproduce them in a milligram to gram range and send them in minimal amounts on microarray plates along with thousands of other substances.” This testing system permits researchers in the different research fields to conduct rapid, parallel analysis in their quest for active substances. Coordinator: DZIF researchers can draw on collections from the Helmholtz Centre for Infection Research (HZI), the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), the Hans Knöll Institute in Jena as well as the University of Tübingen. These establishments isolate and characterise microorganisms and fungi that produce potential active substances, and subsequently analyse them with methods from system biology, biotechnology and functional genomics. New experts from research and industry Prof Ulrich Nübel brings his expertise in gene function research to the DZIF. He has been Professor of “Microbial Genome Research” at the German Collection of Microorganisms and Cell Cultures (DSMZ) since June 2014. Prof Dr Rolf Müller Braunschweig/Saarbrücken RESEARCH INFRASTRUCTURES Collected works of nature 28 Biobanking RESEARCH INFRASTRUCTURES Reserved for future eventualities provide safe, high-quality, precisely characterised and standardised biomaterials. “Besides this, we advise researchers on selection, transport and condition of the samples, and provide support for project design,” says Schirmacher. Supported by a laboratory information management system (LIMS), the biobanking platform is establishing a data and sample collection from transplant patients, for the National Transplant Cohort, an initiative of the research field “Infections of the immunocompromised Host”. This future project will broadly investigate the influence of infections on immunocompromised patients. From 2015, approximately 800 patients per year will be enrolled in the trial and registered in the biobank. DZIF biobank samples are stored in large nitrogen tanks. Biological samples constitute important materials for infection research. The infrastructure “Biobanking” provides DZIF researchers with samples of body fluids, tissues and microorganisms. On this account, the DZIF has established a biobanking platform with respective technologies. “The infrastructure ‘Biobanking’ has already supported over 70 projects in different research fields,” summarises Coordinator Prof Peter Schirmacher. Here, all samples important to infection research are collected and documented: the Helmholtz Zentrum München archives fluid samples such as serum, plasma and urine while the German Collection of Microorganisms and Cell Cultures in Braunschweig stores pathogens and other microorganisms. The DZIF tissue bank at the Heidelberg University Hospital collects infected tissue samples and coordinates the entire biobanking infrastructure. Long-term use for everyone Equipped with a bar code, the samples are computerdocumented and stored at temperatures down to -196° C. The samples are rapidly found electronically and, in part, even withdrawn under robot control. Thanks to these latest technologies, the DZIF biobanking platform can Accessible to everyone In order to make materials available to as many researchers as possible, the existing collections important for research will be integrated into the DZIF Platform. Additionally, other biobank stocks will be registered and linked throughout Europe. Furthermore, the DZIF biobanking platform coordinates and organises the meetings for the IT and biobanking working group within the German Health Research Centres (DZG). Coordinator: Prof Dr Peter Schirmacher Heidelberg Bioinformatics 29 colleagues at “www.bioinformatics-platform.dzif.de”. It includes a databank with thousands of sequenced common pathogen genomes and current outbreak strains. Besides this, registered users can have access to specifically tailored software, with which they can, for example, rapidly compare typical virulence genes to strains in the databank and identify epidemiological connections. In future, this will enable calculations of risk potentials – using methods similar to those used for weather forecasts. A huge databank with sequenced pathogen genomes is made available to all DZIF researchers. Biotechnological advances have revolutionised the diagnosis of infectious diseases: nowadays, genetic decoding of microorganisms is possible in a matter of days, at decreasing costs and with increasing quality. However, the challenge of processing the obtained data remains. The DZIF infrastructure “Bioinformatics” helps researchers make use of these data. Making bioinformatics easier to understand The infrastructure holds workshops to enable as many scientists as possible to handle the service’s software independently. In these popular, hands-on workshops, DZIF researchers learn how to manage the different functions, and how to programme on their own. “We want to make bioinformatics less daunting and make it a simple, userfriendly technology for everyone,” Chakraborty hopes. The workshops have been in high demand, also attracting external researchers. This is why the range of courses offered is being expanded and also being made available to scholarship holders at the DZIF Academy. Coordinators: Participants in this infrastructure include Gießen University and the Helmholtz Centre for Infection Research (HZI) in Braunschweig. Together, they have established three service areas: “Information transfer”, which advises and informs DZIF colleagues on specific questions; the “Bioinformatics Resource Center” (BRC), which provides analysis software tailored to the specific problems of the researchers; and “Training activities”, where bioinformaticians offer workshops to familiarise researchers with tools for managing the technologies. Making information and software accessible “We have a data explosion,” says Prof Trinad Chakraborty, Coordinator of the infrastructure, “and we need systems that not only store data, but also make it interpretable for everyone.” For this reason, the bioinformaticians established a platform in 2014, which offers its services to DZIF Prof Dr Alice McHardy Braunschweig Prof Dr Trinad Chakraborty Gießen RESEARCH INFRASTRUCTURES Harnessing information on infections 30 DZIF Academy PROMOTION OF YOUNG RESEARCHERS Investing in future infection researchers time, and also the DZIF Prize for Translational Infection Research. Prof Ulrike Protzer, Coordinator of the DZIF Academy is happy, “We had excellent stipend holders in 2014, as the awarded national and European research prizes show – an example being the highly competitive ‘Young Investigator Award from the European Association for the Study of the Liver’.” With this, she especially highlights the scientific accomplishments of women at the DZIF. “Maternity leave stipends are very supportive as they give young mothers the freedom to combine having children with having a career.” The DZIF Academy makes young physicians and scientists enthusiastic about infection research. The best investment into infectious disease research is to further the talents of the next generation. Promoting junior researchers is therefore of major importance to the DZIF. The DZIF Academy offers physicians and scientists career opportunities in the fields of clinical infectology, microbiology, virology, immunology and molecular medicine. The virtually organised Academy promotes talents across the DZIF partner sites. To this effect, it offers stipends to medical students, for structured doctoral programmes. It also has a clinical leave programme, to support young hospital doctors who are interested in infectious disease research. Additionally, an exchange programme enables participants to gain insights into other DZIF establishments, and maternity leave stipends assist female scientists to return to their professions after having children. Stipend holders can deepen their knowledge at the spring and autumn school seminars – in both basic research and clinical topics. Excellent support for excellent researchers In 2014 alone, the Academy supported 52 junior talents. Furthermore, together with the scientific societies, it awarded prizes to successful doctorates for the first Clinic, Child and Career Dr Sandra Ciesek is also delighted with the support. The DZIF is funding half of her salary during her two-year-long maternity leave stipend. “This enabled me to start again earlier,” the doctor says. Ciesek started working at the Hannover Medical School when her daughter was four months old: she now works mornings in the outpatient clinic. In the afternoons, she has time for her hepatitis C virus research, writes applications for new projects, and instructs scientific staff. At around 4.00 pm, she picks up her daughter from the crèche, and when the little one is asleep in the evenings, Ciesek writes her publications. “This work model is ideal, because I can divide my time,” she says with a smile. “Another advantage is that it enables me to stay connected with research.” And this paid off well for Sandra Ciesek: as a young mother she was offered a professorship. Coordinator: Prof Dr Ulrike Protzer München Collaborations at the DZIF 31 to call on thousands of people, often in very remote areas. In one of the EBOKON projects, DZIF researchers at the Helmholtz Centre for Infection Research (HZI), together with partners in Nigeria, the Hasso Plattner Institute and the software producer SAP, are currently jointly developing an innovative IT system to monitor contact persons: thanks to a new app, Nigerian health authority staff could interview affected people via mobile phone, and record and follow up the results in a central registry. “We tailored our system to the needs of the local authorities and the WHO,” says project leader Prof Gérard Krause from the HZI. Inconspicuous, but dangerous: Ebola viruses caused the 2014 Ebola epidemic in West Africa. Scientists from research establishments, university hospitals and federal research institutes collaborate at the DZIF. During the most recent Ebola epidemic in West Africa, DZIF colleagues experienced how important this collaboration is and how much more can be achieved when you are “united against infections”. “DZIF members were on the ground from the start of the Ebola epidemic in April 2014,” emphasizes Prof Martin Krönke, Chairman of the DZIF Executive Board. The epidemic spread so rapidly, that the WHO declared it an international public health emergency in August. The DZIF thereupon initiated a research consortium called ‘EBOKON’, now being funded by the German Federal Ministry of Education and Research with 2.3 million Euros. Ten research projects are being conducted – with topics spanning from developing new vaccines against Ebola to analysing the process of infection all the way through to epidemiological questions. Mobile telephones for monitoring contact persons Up to then, Ebola outbreaks could be well-contained by isolating ill people and the people they had come into contact with. However, in the most recent epidemic, monitoring and looking after these people meant having International collaboration for vaccine trials Another project clinically tested the vaccine candidate “VSV- ZEBOV”. “We were in contact with the WHO, which provided the vaccine and coordinated the preparations, almost on a daily basis,” says Marylyn Addo, DZIF professor at the University Medical Center Hamburg-Eppendorf (UKE). She led the first clinical trials on healthy adults there. The same vaccine trial was simultaneously conducted in Gabon. DZIF colleagues from the Paul-Ehrlich-Institut provided advice to the researchers for the approval process. EBOKON Coordinator Prof Stephan Becker and his team from the high-security laboratory at the PhilippsUniversität Marburg investigated whether test persons’ immune responses to the vaccine were sufficiently high to be effective against live Ebola viruses. The results are good: “The vaccine can potentially be used to protect against Ebola,” says Becker. COLLABORATIONS AT THE DZIF United against Ebola 32 DZIF Highlights 2014 DZIF Highlights 2014 DZIF HIGHLIGHTS 2014 January DZIF researchers in Hannover, Munich and Tübingen sign a cooperation agreement for the new Center for Gastrointestinal Microbiome Research (CEGIMIR). This new research platform enables more intensive investigations on the gastrointestinal tract’s microbial diversity and its role in infections. On 28 January, the DZIF’s Transplant Cohort is founded at its first General Assembly in Frankfurt am Main. May A model project at the University Medical Center Freiburg proves that targeted reduction of the use of antibiotics in hospitals is possible. The intelligent use of antibiotics is an important strategy in the fight against multi-drug resistant bacteria. The Universität zu Lübeck and the Research Center Borstel jointly establish a new Professorship for Molecular and Experimental Mycobacteriology at the German Center for Infection Research (DZIF), to which Dr Stefan Niemann is appointed. April A phase I clinical trial is initiated at the Institute for Tropical Medicine of the University Hospital Tübingen, to test the efficacy and safety of a promising vaccination method against malaria. February An international research team led by Prof Mathias Heikenwälder and Prof Ulrike Protzer, Institute of Virology at the Helmholtz Zentrum München and the Technische Universität München discover a way of specifically targeting and eliminating hepatitis B viruses’ genetic information “hidden” in the cell nuclei of liver cells. The scientists publish their results in the journal Science. March Marina Lusic takes up a professorship in Heidelberg in the research field “HIV”. 33 The microbiologist and population geneticist Prof Ulrich Nübel was appointed to a DZIF professorship, at the Leibniz Institute DSMZ (German Collection of Microorganisms and Cell Cultures) in Braunschweig. On 1 July 2014, Prof Christoph Lange takes up the professorship “International Health/Infectious Diseases”, which was established in a collaboration between the Research Center Borstel, the Universität zu Lübeck and the DZIF. Start of preclinical trials for a potential vaccine against the “Middle East Respiratory Syndrome coronavirus”, MERS-CoV for short, led by DZIF researcher Prof Gerd Sutter from the Ludwig-MaximiliansUniversität München. September October The DZIF initiates a consortium to strengthen Ebola research: “EBOKON” will be supported by the Federal Ministry of Education and Research with 2.3 million Euros until the end of 2015. At the ICAAC in Washington, the world’s largest conference on antimicrobial agents and infectious diseases, the DZIF contributes with scientific presentations and is represented by its own exhibition stand. November A clinical phase 1 trial for a potential vaccine against the dreaded Ebola virus is ready to begin. The trial is supported by the DZIF and led by two DZIF professors at two locations – in Hamburg und Lambaréné, Gabon. December The virologist Prof Stephan Urban from the Heidelberg University is awarded the DZIF Prize for Translational Infection Research worth 5,000 Euros. It is awarded at the DZIF Annual Meeting for the first time. DZIF HIGHLIGHTS 2014 July June 34 Science and public SCIENCE AND PUBLIC Increasing DZIF visibility, nationally and internationally The brochure “Translation City” explains the DZIF’s research activities. Looking back on the year 2014, the first thing we, in the communication department, think about is Ebola. The epidemic, which became apparent in spring 2014, took up a large segment of our media work, and rightly so. Over and over again, experts from the DZIF made themselves available to journalists for questions and interviews. They also provided further information about Ebola research work, including the development of an Ebola vaccine, which was of great public interest. Classic media work is essential In 2014, the DZIF published two to three press releases per month. Besides Ebola, the MERS coronavirus was also a central issue, which the research field “Emerging Infections” is also investigating intensively. Furthermore, there were research reports on tuberculosis, novel antibiotics and antibiotic resistance, as well as hepatitis and other infectious diseases – all interesting topics that were taken up by the media. What does the DZIF accomplish? What fields of research does it cover, and what is special about this network that has united 32 (recently increased to 35) member establishments “under one roof” since it was founded? Providing answers to these questions and making the activities externally visible – those are the most important responsibilities of the Press and Public Relations Office. Information accessible at the click of a mouse Besides media work, continuously updating and developing the DZIF website plays a key role in the DZIF’s public presentation. Here, different target groups can obtain relevant information with only a few mouse clicks. Around 42,000 visitors took advantage of the DZIF website’s services in 2014. In addition to presenting itself virtually, the DZIF is attending more and more events and fairs to connect with 35 The German Centres discuss their work with politicians at a dinner debate in Berlin (centre of photo: Prof Winfried Kern). Communicating during breaks was also part of the DZIF Annual Meeting’s programme. Strengthening the network with internal communication An association like the DZIF, which unites around 250 scientists and physicians at different partner sites throughout Germany, can only function with good internal communication. The Press and Public Relations Office supports internal communication with a quarterly newsletter and via the DZIF intranet, an exchange platform equally accessible to everyone. Collecting and channelling information from all parties, and serving as an interface between research and the public is also important for a properly functioning network. Face-to-face contact remains essential, despite the era of Facebook, telephone conferencing and e-mailing. The Annual Meeting 2014 demonstrated this, where around 250 DZIF members came together for three days to present the progresses and objectives of their research activities, as well as for discussions. This lively conference which took place in Braunschweig, the Main Office’s location, impressively highlighted the DZIF’s accomplishments to date. Press and Public Relations: Janna Schmidt Karola Neubert potential partners. Exhibition stands at the Permedicon and the Congress for Infectious Diseases and Tropical Medicine in Cologne, as well as the “Interscience Conference on Antimicrobial Agents and Chemotherapy” in Washington, contribute to making the DZIF known, nationally and internationally. Classic print media continue to play an important role in the DZIF’s public presentation: with a focus on special ideas and quality. To this end, an image brochure was conceptualised at the end of 2014 and published in 2015. It brings DZIF scientists working all over Germany closer together in the so-called “Translation City”. The virtual SCIENCE AND PUBLIC research centre was transformed into a city that accommodates for joint research activities on infectious diseases. Short routes, intensive networking and an infrastructure for everyone – this is what the DZIF offers. 36 Collaborations with scientific institutions and industry COLLABORATIONS External Collaborations Networking with external partners has been on the DZIF‘s agenda from the start. Numerous associated partnerships and other external collaborations reinforce the DZIF’s position as a top-class institution in the field of infection research. and the studies were initiated. Additionally, the Charité held training events for practice-based physicians. Furthermore, the Charité organised a multicentre study on infection prevalence at admission, running under ATHOS. DZIF’s associated partners Friedrich-Loeffler-Institut, Riems (DZIF member since June 2015) The Friedrich-Loeffler-Institut (FLI) is partner in a collaborative project aimed at the early detection of pathogens, particularly those transmitted from animals. The FLI provides the necessary blood and tissue samples, as well as nucleic acid preparations, from both domestic and wild animals. Especially the unique laboratory and animal testing facilities, with biosafety levels 2 to 4, make the FLI an important partner for the DZIF. Charité – Universitätsmedizin Berlin Charité – Universitätsmedizin Berlin is partner in a study on the intelligent use of antibiotics (ATHOS: antibiotic therapy optimisation study). It investigates whether interventions for targeted antibiotic use in hospitals (antibiotic stewardship see University Medical Center Freiburg) and in practices (Charité) influence the number of new cases of infection with certain antibiotic-resistant bacteria. A method which was developed in the new module “ATHOSMRE-Surveillance” at the Charité is being used to monitor the multidrug-resistant organisms. In 2014, hospital staff from six university hospitals were trained to use this tool German Liver Foundation/HepNet Study-House, Hannover The HepNet Study-House networks trial centres for hepatitis research, and provides a platform for conducting clinical trials. The DZIF can use the infrastructures and cohorts for its projects. Current research activities are focussing on hepatitis B, C, D and E. In 2014, a project on hepatic encephalopathy was initiated together with the German Liver Foundation. We report on the establishment of a hepatitis D registry on page 15. Goethe University Frankfurt am Main A project focussing on hepatitis, in which clinical cohorts are being established, is currently ongoing at the Goethe University Frankfurt am Main. Blood samples taken from patients before therapy or after therapy failure are available to all collaborating partners. The clinical data, along with viral and host gene analysis and phenotypic results, are being analysed and recorded in an onlinebased tool. This tool aims at improving the evaluations of courses of disease and treatment responses, and to tailor individual treatment. Gottfried Wilhelm Leibniz Universität Hannover DZIF scientists recently discovered a completely new substance class called cystobactamides, which is effective against difficult-to-treat gram-negative bacteria. A project at the HZI aims to develop these cystobactamides further, so that they can undergo testing as potential antibiotics in preclinical trials. Scientists at the Leibniz Universität Hannover succeeded in conducting the first total synthesis of cystobactamide C, which paves the way to the synthesis of further cystobactamide variations. Hans Knöll Institute, Jena The Hans Knöll Institute (HKI) is a leading institute for natural compound research. As an associated partner, it provides the DZIF with natural compounds, particularly fungi. A project is investigating the pharmacodynamics of corallopyronin A, a natural product that has already been successfully tested against the filariasis pathogen and is undergoing preclinical evaluations. The HKI is largely responsible for its biosynthesis; the production was further optimised in 2014. Max Planck Institute for Informatics, Saarbrücken At the Max Planck Institute for Informatics in Saarbrücken, data on hepatitis C patients who are undergoing treatment with new antiviral agents, is being collected as part of a DZIF project. Sequencing, analysis and interpretation of patient and viral genes, along with other parameters, will be used to evaluate the course of treatment. In Saarbrücken, the analysis results are being used to further develop an online-based tool, the so-called Geno2pheno[HCV]. The analysis results are therefore freely accessible online, and can be used to support decisions for personalised treatment. Robert Koch Institute, Berlin (DZIF member since June 2015) The DZIF and the Robert Koch Institute (RKI) collaborate in many areas. A few examples: In the research field “Emerging Infections”, the RKI is supporting strategic partnerships between research establishments, hospitals and pharmaceutical companies. In clinical trials, they are jointly developing clinical guidelines. The DZIF has access to the RKI’s new databank “HIOBs” for its HIV research; the software has been optimised and is now being implemented at the partner sites. University Medical Center Freiburg In a project with the University Medical Center Freiburg on infections of the immunocompromised host, scientists are looking to find genetic factors associated with increased susceptibility to infection. They intend to find biomarkers that allow better infection control, and are concentrating on fungal infections in immunocompromised patients. A second DZIF project is investigating the more targeted use of antibiotics (see also Charité). In 2014, a pilot project impressively showed that antibiotic stewardship (ABS) strategies can be implemented successfully. In an intensive ABS programme in internal medicine at the University Medical Center Freiburg, the use of important broad spectrum antibiotics was reduced by approximately 30 percent in one year. The programme in Freiburg aimed at reducing the use of cephalosporins and fluoroquinolones while encouraging the use of penicillin derivatives. COLLABORATIONS 37 COLLABORATIONS 38 Collaborations with scientific institutions and industry University of Münster The University of Münster is partner in a project aimed at developing new treatment strategies against gastrointestinal infections. In many cases, the commonly used antibiotics harm the normal gut flora and can lead to complications. In Münster, the scientists are working on preventing the complications associated with EHEC. A second project is working on hospital pathogens, particularly multidrug-resistant Staphylococcus aureus in the nasal region. Here, new lytic phage proteins for targeted treatment are being investigated. Their efficiency and specificity will be analysed in Münster. MMV – Medicines for Malaria Venture, Geneva (Switzerland) An MMV portfolio substance is being clinically tested for chemoprevention of Malaria tropica, using a human malaria infection model developed by DZIF colleagues in Tübingen. Myr GmbH, Burgwedel Together with the University of Heidelberg, an active agent (Myrcludex B) is being developed that can prevent hepatitis B viruses from penetrating into cells, and could potentially be used to prevent hepatitis B and D infections. Myr GmbH is coordinating the entire project and overseeing the clinical trial. Collaborations with industry Hyglos GmbH, Bernried Hyglos GmbH and a consortium funded by the DZIF are collaborating to produce and preclinically develop phage lytic protein HY-133 (see University of Münster). They are planning joint early-stage clinical development for nasal decolonisation of Staphylococcus aureus. ImevaX GmbH, Munich The DZIF is funding a research group led by Prof Markus Gerhard from the Technische Universität München in the field of preclinical and early-stage clinical testing of the Helicobacter pylori vaccine candidate IMX-101. Together with other funders, the group founded a spin-off company from the university, ImevaX GmbH. Juno Therapeutics GmbH, Göttingen Juno Therapeutics, formerly Stage Cell Therapeutics, is collaborating and exploitation partner of the research group led by Prof Dirk Busch, Technische Universität München, working in the field of GMP quality-assured production of central memory T cells for treatment of infections and cancer. The DZIF is funding the group led by Prof Busch. Sanaria Inc., Rockville (USA) At the DZIF partner site Tübingen, scientists are developing a human malaria infection model. Here, the disease is induced under controlled conditions in order to test new active agents. Sanaria Inc. in Rockville, USA, produces malaria parasites in GMP quality for immunisation purposes, which fulfil all the criteria for drug approval. 4SC Discovery GmbH, Martinsried In the DZIF research field “Malaria”, a candidate antimalarial has gone into preclinical development. SC83288 is being tested as an inhibitor in animal models, and is being further developed in close collaboration with the company 4SC, which also produces the active agent. DZG 39 DZG German Health Research Centres In focus at the DZG: combatting widespread diseases more effectively. The main objective of the German government’s health research programme is to develop more effective ways to combat widespread diseases. The groundwork for this has been laid at federal and state levels with the establishment of German Health Research Centres (DZG) as long-term, equal partnerships between non-university research institutes and universities with medical centres. These German Health Research Centres pool all of their existing expertise, thereby greatly helping to close knowledge gaps and improve prevention, diagnosis and therapy of their respective diseases. The research policy ensures close collaboration between basic research and clinical research, always specifically oriented on the indications and the patients’ needs. Close networking and the expansion of existing research structures will allow faster transfer of research results into clinical practice (translation). The strategic cooperation of leading scientists in the German Health Research Centres promotes Germany to a high-ranking scientific location and increases its attractiveness to young scientists in Germany and around the world. 2009 saw the foundation of the “German Centre for Neurodegenerative Diseases” and the “German Centre for Diabetes Research”. Alongside DZIF, the “German Center for Cardiovascular Research”, the “German Consortium for Translational Cancer Research” and the “German Center for Lung Research” were launched in 2012. From the outset, the six German Health Research Centres have collaborated closely in order to share their findings and exploit synergies. 40 Organisation and bodies Structure of DZIF General Assembly FACTS AND FIGURES The General Assembly is the central decision-making organ of DZIF. It comprises representatives of the member research establishments of the DZIF. The General Assembly elects the members of the Executive Board and the Executive Director, and decides on the allocation of funds to the research fields and infrastructures (TTUs and TIs). Commission of Funding Authorities Executive Board Scientific Advisory Board The Commission of Funding Authorities is made up of the Federal Government and respective states (Länder) and decides on important matters of finance, organisation and personnel. The Executive Board and the Managing Director report to the Commission on all funding measures. The Executive Board represents the DZIF externally. It implements the resolutions and tasks assigned by the General Assembly and is responsible for routine administrative affairs. The association is supported by the Scientific Advisory Board consisting of internationally renowned experts from the field of infection research. The Scientific Advisory Board advises the Executive Board and General Assembly on all scientific and programme-related matters. Main Office Internal Advisory Board The members of the Internal Council are DZIF scientists representing all areas and locations of the centre. The council advises the Executive Board on all scientific, programme-related and technical matters and performs representative duties. The Main Office is located in Braunschweig and supports the Executive Board in its work. Its duties include organising research initiatives and coordinating DZIF’s press and public relations activities. Thematic Translational Units (TTUs) Translational Infrastructures (TIs) The Thematic Translational Units bundle the research of the centre. Each unit is dedicated to one pathogen or to one specific problem in infection research. Strategically aligned translational infection research requires modern infrastructures. These are provided in the form of the Translational Infrastructures, and can be used by all DZIF members. Emerging Infections Tuberculosis Product Development Unit Clinical Trial Unit Malaria HIV African Partner Institutions Biobanking Hepatitis Gastrointestinal Infections Infections of the immunocompromised Host Healthcare-associated and Antibiotic-resistant bacterial Infections Natural Compound Library Bioinformatics Novel Antiinfectives DZIF Academy Partner Sites DZIF conducts its research in 35 research establishments at seven locations throughout Germany. For each site, two scientists are appointed to coordinate the collaboration and to advise the Main Office. Various external research partners are also involved in DZIF projects. Bonn-Cologne Gießen-Marburg-Langen Hamburg-Lübeck-Borstel Hannover-Braunschweig Heidelberg Munich Tübingen Associated Partners 41 Central bodies Executive Board > Prof Dr M. Krönke, Universität und Universitäts klinikum Köln (Chair) > Prof Dr U. Protzer, Technische Universität München und Helmholtz Zentrum München (Vice Chair) > Prof Dr D. Heinz, Helmholtz-Zentrum für Infektions forschung, Braunschweig Managing Director > Dr T. Jäger, DZIF e.V. Scientific Advisory Board > Prof Dr P. Alonso, WHO Global Malaria Programme, Switzerland > Prof Dr R. Burger, Robert Koch Institut, Germany > Prof Dr H. Feldmann, National Institute of Allergy and Infectious Diseases, USA > Prof Dr B. B. Finlay, University of British Columbia, Canada > Prof Dr A. Friedrich, Universitair Medisch Centrum Groningen, Netherlands > Prof Dr B. Kampmann (Chair), Imperial College London, United Kingdom > Prof Dr J.-M. Pawlotsky, Université de Paris XII, France > Prof Dr C. Rooney, Baylor College of Medicine, USA > Prof Dr H. J. Schmitt, Johannes Gutenberg-Universität Mainz, Germany, and Pfizer Vaccines, France > Prof Dr A. Telenti, The J. Craig Venter Institute, USA > Prof Dr S. Ward, Liverpool School of Tropical Medicine, United Kingdom > Prof Dr R. G. Werner, Universität Tübingen, Germany Internal Advisory Board > Prof Dr I. Autenrieth, Universität und Universitätsklinikum Tübingen > Prof Dr K. Cichutek, Paul-Ehrlich-Institut, Langen > Prof Dr C. Drosten, Universität und Universitätsklinikum Bonn > Prof Dr M. Hoelscher, Ludwigs-Maximilians Universität München and Klinikum der Universität München > Prof Dr R. Horstmann, Bernhard-Nocht-Institut für Tropenmedizin, Hamburg (Vice Chair) > Prof Dr H.-G. Kräusslich, Universität und Universitätsklinikum Heidelberg (Chair) > Prof Dr T. Schulz, Medizinische Hochschule Hannover > Prof Dr T. Welte, Medizinische Hochschule Hannover 42 Partner sites and member establishments Hamburg - Lübeck - Borstel Hannover - Braunschweig Bonn - Cologne Gießen - Marburg - Langen Heidelberg Tübingen Munich 43 Partner sites and member establishments Germany-wide infection research FACTS AND FIGURES Baden-Württemberg Heidelberg is responsible for coordinating the TTU HIV at the DZIF. In order to control HIV infections, DZIF researchers at this location research factors of the innate immune system and identify sites in the DNA into which the viral DNA can become integrated. Alongside HIV, Heidelberg co-coordinates the TTUs Hepatitis, Malaria and Infections of the Immunocompromised Host. The Heidelberg scientists also coordinate the DZIF-wide translational infrastructure Biobanking, with focus on establishing tissue banks. Heidelberg Spokesperson: Klaus Heeg (Heidel- Tübingen has taken over the coordinating role at the DZIF for Malaria and Healthcare-associated and Antibiotic-resistant bacterial Infections, and co-coordinators of Gastrointestinal Infections and Novel Antiinfectives work at this location. The main focus in Tübingen is on translating research results into medicine and vaccine development as well as on infection models and epidemiology. Regarding infections caused by antibiotic-resistant, bacterial pathogens, the focus is on improving diagnosis and therapy of multiresistant pathogens such as methicillinresistant Staphylococci (MRSA) and multiresistant gram-negative pathogens (e.g. so-called ESBLs). berg University Hospital) Establishments: German Cancer Research Center in the Helmholtz Association, Heidelberg University, Heidelberg University Hospital TTU coordination: • Hepatitis (co-coordination) • HIV (coordination) • Infections of the Immunocompromised Host (co-coordination) • Malaria (co-coordination) TI coordination: • Biobanking (coordination) Tübingen Spokesperson: Prof Dr Ingo Autenrieth (University of Tübingen) Establishments: University of Tübingen, Max Planck Institute for Developmental Biology, University Hospital Tübingen TTU coordination: • Gastrointestinal Infections (co-coordination) • Healthcare-associated and Antibiotic-resistant bacterial Infections (coordination) • Malaria (coordination) • Novel Antiinfectives (co-coordination) 44 Bavaria Hamburg/Schleswig-Holstein Hessen The scientists of the Munich DZIF establishments have special focus on immune control of infections and the development of novel therapies. Pathogen-specific immunotherapies (prophylactic or therapeutic) aim at strengthening the body’s natural defence system so that it can control specific infectious diseases more effectively or even avoid them entirely. Other focuses in Munich are Gastrointestinal Infections, HIV, Hepatitis and Tuberculosis. The Hamburg-Lübeck-Borstel site combines a unique collection of expertise and infrastructure for studying infectious diseases and emerging infections of national and worldwide relevance. It is involved in clinical, entomological and virological studies. It is the DZIF base for medical chemistry, for active agent development as well as for the epidemiology of malaria and translational studies on tuberculosis and hepatitis. The TI African Partner Institutions is coordinated from here. Munich Spokesperson: Prof Dr Dirk Busch (Technische Universität München) Establishments: Helmholtz Zentrum München – German Research Center for Environmental Health, Bundeswehr Institute of Microbiology, Klinikum der Universität München, Klinikum rechts der Isar der Technischen Universität München, Ludwig-Maximilians-Universität München, Technische Universität München TTU coordination: •Gastrointestinal Infections (co-coordination) •Hepatitis (co-coordination) •HIV (co-coordination) •Infections of the Immunocom- promised Host (coordination) • Tuberculosis (co-coordination) TI coordination: • Biobanking (co-coordination) • DZIF Academy (coordination) Hamburg - Lübeck - Borstel Spokesperson: Prof Dr Rolf Horstmann (Bernhard Nocht Institute for Tropical Medicine) Establishments: Bernhard Nocht Institute for Tropical Medicine in the Leibniz Association, Research Center Borstel – Leibniz-Center for Medicine and Biosciences, FriedrichLoeffler-Institut (member since June 2015), Heinrich Pette Institute – Leibniz Institute for Experimental Virology, Universität Hamburg, University Medical Center HamburgEppendorf, Universität zu Lübeck TTU coordination: •Emerging Infections (co-coordination) •Malaria (co-coordination) • Tuberculosis (coordination) TI coordination: •African Partner Institutions (coordination) In Gießen-Marburg-Langen, DZIF researchers identify new active agents and vaccines and produce them in quality-assured production processes for scientific and industrial partners. Research activities are concentrated on developing strategies for combatting new or re-emerging infectious diseases in order to contain outbreaks of new pathogens, for example by quick, effective action and rapid vaccine development. Marburg focus on viral pathogens, while Gießen concentrate on bacteria and resistance to antibiotics. Gießen - Marburg - Langen Spokesperson: Prof Dr Trinad Chakraborty (Giessen University) Establishments: Giessen University, Paul Ehrlich Institute Langen, Philipps-Universität Marburg, Mittelhessen University of Applied Sciences TTU coordination: • Emerging Infections (coordination) • Healthcare-associated and Anti- biotic-resistant bacterial Infections (co-coordination) TI coordination: •Bioinformatics (coordination) •Product Development Unit (coordination) 45 Seven partner institutes collaborate within DZIF at the HannoverBraunschweig location. The TTUs Hepatitis and Gastrointestinal Infections are coordinated from here. The scientists here want, among other things, to improve access to hepatitis therapies and are researching on new diagnostic markers for the course of infection and therapy. Also in the researchers’ sights are new pathogen-specific medicines against pathogens such as EHEC, Helicobacter pylori or salmonellae. This location is coordinating the establishment of the Natural Compound Library, which is available to all DZIF researchers in the search for new medicines. Hannover - Braunschweig Spokesperson: Prof Dr Sebastian Suerbaum (Hannover Medical School) Establishments: Helmholtz Centre for Infection Research, Braunschweig, Leibniz Institute DSMZ – German Collection of Microorganisms and Cell Cultures, Hannover Medical School, Robert Koch Institute (Member since June 2015) University of Veterinary Medicine Hannover, Foundation, Technische Universität Braunschweig, TWINCORE – Centre for Experimental and Clinical Infection Research TTU coordination: • Gastrointestinal Infections (coordination) • Hepatitis (coordination) • Infections of the Immunocom promised Host (co-coordination) North Rhine-Westphalia TI coordination: • Natural Compound Library (coordination) • Biobanking (co-coordination) • Bioinformatics (coordination) Bonn-Cologne coordinates the TTU Novel Antiinfectives. The DZIF researchers are also researching into faster and more efficient methods for characterising unknown viral pathogens. Unique in Germany are the patient cohorts for HIV and HCV infections as well as HIV/HCV co-infections. In HIV research, researchers are bringing into translation gene-therapy–based strategies for the control and prophylaxis of these infections. This location coordinates the DZIF Clinical Trial Unit. Bonn - Cologne Spokesperson: Prof Dr Achim Hörauf (University of Bonn) Establishments: Federal Institute for Drugs and Medical Devices (BfArM/ Member since June 2015), University of Bonn, University Hospital Bonn, University of Cologne, University Hospital Cologne TTU coordination: • Emerging Infections (co-coordination) • HIV (co-coordination) • Healthcare-associated and Anti- biotic-resistant bacterial Infections (co-coordination) •Novel Antiinfectives (coordination) TI coordination: • Clinical Trial Units (coordination) FACTS AND FIGURES Lower Saxony 46 Finance DZIF financial data 2014 2014 expenditure in Euros By partner site Associated Partners 949,832 Gießen-Marburg-Langen Hannover-Braunschweig 4,034,046 FACTS AND FIGURES 1,626,759 Heidelberg 2,938,715 Hamburg-Lübeck-Borstel 2,901,904 Munich 2,727,883 Bonn-Cologne Tübingen 2,504,326 2,144,753 By type of expenditure Material Expenses 5,790,516 Investments 375,635 Personnel 13,662,068 47 Field of work Emerging infections Tuberculosis Grants from government and Länder in Euros Euros 1,805,260 775,428 Land Euros Baden-Württemberg 508,347 Bavaria 269,614 Malaria 1,796,459 Hamburg 167,361 HIV 1,362,739 Hessen 110,850 Hepatitis 1,807,037 Lower Saxony 403,405 North Rhine-Westphalia 250,433 Infections in the immunocompromised Host 2,034,029 Schleswig-Holstein 122,829 Healthcare-associated and Antibioticresistant bacterial Infections 1,097,482 Financial Contributions from Associated Partners Novel Antiinfectives 2,233,992 Federal Government 17,908,381 Total 19,828,218 Gastrointestinal Infections 903,178 Product Development Unit 586,627 Clinical Trial Unit 275,461 African Partner Institutions 272,704 Biobanking 727,185 Natural Compound Library 396,074 Bioinformatics 345,801 DZIF Academy 1,630,624 Administration 1,778,137 Total 19,828,218 The German Center for Infection Research expenditure in 2014 was around 19.8 million Euros. 129 collaborative projects and 52 stipends were funded within DZIF in 2014. The majority of funding came from the Federal Government (90 %) and from Länder funds (10 %). Only departmental research projects of the federal R&D institutions were fully funded by Germany’s Federal Ministries. Funding management at the Helmholtz Centre for Infection Research in Braunschweig forwards the federal funds to the DZIF partner institutes to support their projects. Expenditure was reported by the partners in their interim statements for 2014 and audited by Funding Management. 87,000 FACTS AND FIGURES By field of work 48 Personnel and awards Employees of DZIF Full-time equivalent by professional group Professor Junior Group Head 4.5 13.3 Physician Other 25.0 59.1 Total: 266.1 FACTS AND FIGURES Postdoc 74.4 TA/Study Nurse 55.6 PhD/MD Student 34.1 Full-time equivalent corresponds to a full-time position in an entire fiscal year. Number of employees by professional group and gender Professional Groups Men Women Total Professor 6 2 8 Junior Group Head 13 5 18 Physician 17 27 44 Postdoc 52 90 142 PhD/MD Student 47 56 103 TA/Study Nurse 22 80 102 Other 27 49 76 Total 184 309 493 DZIF recruited 2014 six employees from abroad and assisted ten mothers on their return from maternity leave. 49 Laureates Awards Prof Dr Ralf Bartenschlager Heidelberg University Thomson Reuters Selection: Highly Cited Researchers 2014 Prof Dr Jonas Schmidt-Chanasit Bernhard Nocht Institute for Tropical Medicine Wissenschaftspreis „Klinische Virologie“ der Gesellschaft für Virologie und der Deutschen Vereinigung zur Bekämpfung der Viruskrankheiten Prof Dr Christoph Klein Klinikum der Universität München Hector Research Prize Prof Dr Florian Klein University Hospital Cologne/Rockefeller University AIDS-Forschungspreis der Deutschen Gesellschaft für Infektiologie (DGI) Prof Dr Dr h.c. Christoph Lange Research Center Borstel “Society needs Science” Award by the Stifterverband (Donors‘ Association for the Promotion of the Sciences and the Humanities in Germany Dr Clara Lehmann University Hospital Cologne DGI-Förderpreis für Klinische Infektionsforschung Dr Julie Lucifora Helmholtz Zentrum München European Young Investigator Award, EASL Dr Konstantin Neumann Klinikum rechts der Isar, Technische Universität München Gábor-Szász-Prize Prof Dr Sebastian Suerbaum Hannover Medical School Election into the American Academy of Microbiology Prof Dr Stephan Urban Heidelberg University DZIF Prize for Translational Infection Research Dr Christopher Weidenmaier University of Tübingen Förderpreis der DGHM FACTS AND FIGURES Awards and commendations 50 Publications Scientific achievements 2014 In the following you will find a list of selected publications from 2014 (Impact Factor larger than 10). See the complete list of DZIF publications on our website. 1. Alduina R, Gallo G, Renzone G, Weber T, Scaloni A, Puglia AM (2014) Novel Amycolatopsis balhimycina biochemical abilities unveiled by proteomics. FEMS Microbiol Lett, 351(2): 209-215 PUBLICATIONS 2. Allweiss L, Volz T, Lutgehetmann M, Giersch K, Bornscheuer T, Lohse AW, Petersen J, Ma H, Klumpp K, Fletcher SP, Dandri M (2014) Immune cell responses are not required to induce substantial hepatitis B virus antigen decline during pegylated interferon-alpha administration. J Hepatol, 60(3): 500-507 3. Baize S, Pannetier D, Oestereich L, Rieger T, Koivogui L, Magassouba N, Soropogui B, Sow MS, Keita S, De Clerck H, Tiffany A, Dominguez G, Loua M, Traore A, Kolie M, Malano ER, Heleze E, Bocquin A, Mely S, Raoul H, Caro V, Cadar D, Gabriel M, Pahlmann M, Tappe D, Schmidt-Chanasit J, Impouma B, Diallo AK, Formenty P, Van Herp M, Gunther S (2014) Emergence of Zaire Ebola virus disease in Guinea. N Engl J Med, 371(15): 1418-1425 4. Baumann S, Herrmann J, Raju R, Steinmetz H, Mohr KI, Huttel S, Harmrolfs K, Stadler M, Muller R (2014) Cystobactamids: myxobacterial topoisomerase inhibitors exhibiting potent antibacterial activity. Angew Chem Int Ed Engl, 53(52): 14605-14609 5. Berger C, Romero-Brey I, Radujkovic D, Terreux R, Zayas M, Paul D, Harak C, Hoppe S, Gao M, Penin F, Lohmann V, Bartenschlager R (2014) Daclatasvir-like inhibitors of NS5A block early biogenesis of hepatitis C virus-induced membranous replication factories, independent of RNA replication. Gastroenterology, 147(5): 1094-1105.e1025 6. Bos KI, Harkins KM, Herbig A, Coscolla M, Weber N, Comas I, Forrest SA, Bryant JM, Harris SR, Schuenemann VJ, Campbell TJ, Majander K, Wilbur AK, Guichon RA, Wolfe Steadman DL, Cook DC, Niemann S, Behr MA, Zumarraga M, Bastida R, Huson D, Nieselt K, Young D, Parkhill J, Buikstra JE, Gagneux S, Stone AC, Krause J (2014) Pre-Columbian mycobacterial genomes reveal seals as a source of New World human tuberculosis. 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Lancet Infect Dis, 14(4): 327-340 53 Bernhard Nocht Institute for Tropical Medicine Robert Koch Institute* Bundeswehr Institute of Microbiology Technische Universität Braunschweig Federal Institute for Drugs and Medical Devices* Technische Universität München Friedrich-Loeffler–Institut* TWINCORE - Centre for Experimental and Clinical Infection Research German Cancer Research Center Giessen University Hannover Medical School Heidelberg University Heidelberg University Hospital Heinrich Pette Institute–Leibniz Institute for Experimental Virology Universität Hamburg Universität zu Lübeck University of Bonn University of Cologne University of Tübingen University of Veterinary Medicine Hannover, Foundation Helmholtz Centre for Infection Research University Hospital Bonn Helmholtz Zentrum München–German Research Center for Environmental Health University Hospital Cologne Klinikum der Universität München University Hospital Tübingen University Medical Center Hamburg-Eppendorf Klinikum rechts der Isar der Technischen Universität München Leibniz Institute DSMZ–German Collection of Microorganisms and Cell Cultures Ludwig-Maximilians-Universität München Max Planck Institute for Developmental Biology Mittelhessen University of Applied Sciences Paul-Ehrlich-Institut Philipps-Universität Marburg Research Center Borstel–Leibniz-Center for Medicine and Bioscience * Member establishment since June 2015 MEMBER ESTABLISHMENTS Member establishments of the German Center for Infection Research 54 Imprint German Center for Infection Research (DZIF e.V.) Main Office Inhoffenstraße 7 D-38124 Braunschweig T +49 (0)531-61 81-11 52 F +49 (0)531-61 81-11 53 [email protected] www.dzif.de Project coordination: DZIF Press Office Text: Dr Heidrun Riehl-Halen, Medizinkontext, and DZIF Press Office English translation: Julia Kyambi Photos: Title: Alix Poulot, University of Lyon | p. 3: DZIF/scienceRELATIONS | p. 4: Hallbauer IMPRINT + Fioretti | p. 6: Günter Fröschl | p. 7 (above): Robert Wollny | p. 7 (below): DZIF/scienceRELATIONS | p. 9 (above): Reprinted by permission from: Merker et al. 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