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Immunopathology of viral infections 1 Characteristics of a virus-induced immune pathology • disease is based on the immune reaction against a viral infection • disease is induced by chronic persistent viral infections • immune response induces symptoms • immunocompromised patients will not develop symptoms Effectors of a virus-induced immune pathology • activated B-cells/plasma cells > auto reactive antibodies • fulminant innate immune response > e.g. cytokine expression • activated T-cells > CD8+ CTL (destruction of chronic infected cells, autoimmune reactions) 2 Immunopathology of viral infections: examples Viral infection Immune response Antibody-dependent enhancement of virus infection (dengue virus) Overreaction of the immune system „cytokine storm“ (influenza virus) Induction of autoimmune reactions „molecular mimicry“ (coxsackievirus) Tissue destruction via the immune response against virus-infected cells (hepatitis B virus) 3 Immunopathology of viral infections Antibody-dependent enhancement (ADE) of viral infections occurs when non-neutralizing antiviral proteins facilitate virus entry into host cells, leading to increased infectivity and fulminant immune responses. http://www.the-scientist.com/images/March2013/dengue_virus.pdf - Disease: - Pathogen: Dengue fever (DF) Dengue hemorrhagic fever (DHF) Dengue hemorrhagic shock syndrome (DHSS) Dengue virus (4 types: DENV1-4) Flaviviridae, single-stranded (+)RNA (ca. 11 kb) enveloped capsid, 40-50 nm in size http://www.stanford.edu/group/virus/flavi/2000/dengue.htm www.guatezona.org 4 Immunopathology of viral infections - Distribution: ca. 2.5 billion people live in endemic areas next to Malaria, DF is the most important tropical disease DF: ca. 50-100 (300) million cases/year DHF/DHSS: ca. 0.5 million cases/year world-wide increase of diseases and fatal casualties due to an increase of distribution of viral strains (multiple infections), endemic in > 110 countries most frequently imported tropical disease in Germany: 656 cases in 2014 „Epidemiologisches Jahrbuch“ of the RKI 2013: 5 http://www.rki.de/DE/Content/Infekt/Jahrbuch/Jahrbuch_2013.pdf?__blob=publicationFile Immunopathology of viral infections Outbreak: Starting October 2012, the most important DENV1 outbreak has been observed in Europe since 1927. Until 18.2.2013: - 2164 cases with 122 hospitalizations - no fatal casualties - Germany: 19 imported cases 6 Immunopathology of viral infections - Transmission: man > mosquitoes > man vector: yellow fever mosquito Stegomyia aegypti (also: blood or organ donations) - Incubation period: 3-14 days - Symptoms: DF: fever, headache, characteristic skin rash (similar to measles), muscle and joint pain (“break bone fever”), vomiting, diarrhea DHF/DHSS: bleeding, fever, low levels of blood platelets, blood plasma leakage, low blood pressure, death - Treatment: supportive, oral and/or intravenous rehydration - Prevention: no approved vaccination, control and prevention from mosquito bites, control of mosquito habitats 7 Immunopathology of viral infections Antibody-dependent enhancement (ADE) of viral infection Induction of virus-specific antibodies Rothman, Nature Review Immunol., 2011, 11, 532-43. Glycoprotein E von DENV 8 Immunopathology of viral infections Antibody-dependent enhancement (ADE) of viral infection Induction of virus-specific antibodies DENV1 infection DENV2 infection Fc receptor > Generation of neutralizing (Y) as well as binding/ non-neutralizing (Y) antibodies against DENV1 > cross reaction Y Y Y Y Y > enhanced viral uptake of DENV2 via viral and Fc receptors of monocytes and macrophages > increased release of inflammatory cytokines > endothelial damage > hemorrhagic fever, shock, death (1-15 % ) 9 Immunopathology of viral infections: examples Viral infection Immune response Antibody-dependent enhancement of virus infection (dengue virus) Overreaction of the immune system „cytokine storm“ (influenza virus) Induction of autoimmune reactions „molecular mimicry“ (coxsackievirus) Tissue destruction via the immune response against virus-infected cells (hepatitis B virus) 10 Immunopathology of viral infections Overreaction of the innate immune system „cytokine storm“ (influenza virus) „cytokine storm“: - over boarding reaction of the immune system based on enhanced production and release of inflammatory mediators (>150 cytokines, chemokines etc. etc.) - positive feedback increases reaction - live-threatening shock conditions including massive inflammations - observed by influenza, smallpox, Ebola, sepsis etc. Osterholm. New England Journal of Medicine, 352 (18): 1839, 2005 11 Immunopathology of viral infections Overreaction of the innate immune system „cytokine storm“ (influenza virus) Influenza pandemia 1918 • March-June 1918 (1th wave): – • August-December 1918 (2.nd wave): – – – – – – – • extreme contagious and extreme lethal esp. among young adults maximum: September-November 1918 up to 70 % mortality induced by secondary bacterial pneumonia decreased average life span in the US more than 10 years probably contributed to the end of WW I in the US: one third of the population was infected in Germany: ca. 10 mill. people were infected 1919-1920 (3. rd wave) – • extreme contagious but less lethal global situation: 10-20 mill. fatalities (?) Analysis: – tissue material of victims, 2005: complete sequence > virus reconstruction (H1N1) – only a few sequence differences – Host transmission: bird > man/pig or pig only > man (?) 12 Immunopathology of viral infections Overreaction of the innate immune system „cytokine storm“ (influenza virus) death Emerging Infectious Diseases, 18, 2012 disease High fatality rate by: - new virus variant - changes in the HA, NA and polymerase - overreaction of the immune system of young immunocompetend adults - damage of the lung epithelium - secondary bacterial infections with Haemophilus influenzae, Streptococcus pneumonia, Streptococcus pyogenes, Staphylococcus aureus - social aspects (war, hunger etc.) 13 Immunopathology of viral infections Overreaction of the innate immune system „cytokine storm“ (influenza virus) Aim: Is it possible to reduce the severity of influenza virus infection via the application of immune modulators? „Player“: PNAS, 2011, 108(29), 12018-12023 Virus: FLUAV H1N1 2009 pandemic Drugs: modulation via sphingosine-1-phosphate-(S1P) agonists AAL-R (synthetic sphingosine analogue) sphingosine (C18H37NO2) (R-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol) part of sphingomyeline in cell membranes phosphorylation via sphingosine kinase 2 AFD-R (R-2-amino-4-(4-heptyloxyphenyl)-2methylbutyldihydrogenphosphate) Finglimod/Fingolimod (Gilenya®, FTY720, Novartis) drug against multiple sclerosis S1P receptor binding: > lymphocytes remain in lymph nodes > suppression of the immune response 14 Immunopathology of viral infections Overreaction of the innate immune system „cytokine storm“ (influenza virus) Sphingosine-1-phosphate: synthesis and function - cell proliferation - cell migration - angiogenesis - apoptosis www.caymanchem.com/images/currents/017/Sphingosine.jpg 15 Immunopathology of viral infections Overreaction of the innate immune system „cytokine storm“ (influenza virus) Function: sphingosine-1-phosphate/sphingosine-1-phosphate receptor Involvement of S1P receptors in the regulation of physiological and pathophysiological phenomena. S1P receptor agonists: > endothelial barrier > release of pro-inflammatory cytokines/chemokines > cellular viability 16 Nature Reviews Drug Discovery, 8, 2009, 297-307 Immunopathology of viral infections Overreaction of the innate immune system „cytokine storm“ (influenza virus) AAL-R administration leads to significant increase of the survival rate. AAL-R administration decreases inflammatory reactions. AAL-R and/or oseltamivir administrations do not influence the formation of neutralizing antibodies. 17 Immunopathology of viral infections Overreaction of the innate immune system „cytokine storm“ (influenza virus) Ergebnis: A : IAV infection of lung epithelial tissue > tissue destruction, oseltamivir reduces virus distribution B : IAV infection activates the innate immune response (cytokines, chemokines, inflammation) > inhibition via AAL-R C : activation of DC during IAV infection > inhibition via AAL-R D : DC in lymph nodes: activation and expansion of CD4+ and CD8+ lymphocytes > inhibition via AAL-R E : normally, activated T lymphocytes control IAV infection efficiently 18 Immunopathology of viral infections: examples Viral infection Immune response Antibody-dependent enhancement of virus infection (dengue virus) Overreaction of the immune system „cytokine storm“ (influenza virus) Induction of autoimmune reactions „molecular mimicry“ (coxsackievirus) Tissue destruction via the immune response against virus-infected cells (hepatitis B virus) 19 Immunopathology of viral infections Evidence of a viral involvement during autoimmune diseases • autoimmune diseases occur or increase after viral infections • autoimmune diseases can be induced by viral infection under experimental conditions • e.g. „molecular mimicry“: vial and host cell antigens are similar > cross reaction > immune response directed against own tissue Induction of autoimmune reactions „molecular mimicry“ (type 1 diabetes and viral infections – coxsackieviruses) diabetes mellitus type 1 diabetes Juvenile diabetes: destruction of the insulinproducing beta cell of the islets of Langerhans in the endocrine pancreatic tissue leading to complete insulin deficiency. Genetic predisposition (HLA variants) > MHC molecules on cells and environmental factors like viral infections are important > autoimmune reaction type 2 diabetes „adult-onset diabetes“: multiple factors like e.g. a genetic insulin resistance (insulin is produced but cannot bind to receptors > increased insulin production accompanied by reduced efficacy > increased blood sugar levels > obesity), but obesity itself induces type 2 diabetes as well (metabolic syndrome) 20 Immunopathology of viral infections Induction of autoimmune reactions „molecular mimicry“ (type 1 diabetes and viral infections – coxsackieviruses) Coxsackievirus-induced destruction of murine pancreatic tissue control log TCID50/0.1 g tissue 8 viral load in pancreas 6 4 2 0 2 4 6 8 days p. i. 10 12 14 2 d p. i. 28 d p. i. CVB3 21 Immunopathology of viral infections Induction of autoimmune reactions „molecular mimicry“ (type 1 diabetes and viral infections – coxsackieviruses) type 1 diabetes and detection of viral infections: clinical analyses: 22 Immunopathology of viral infections Induction of autoimmune reactions „molecular mimicry“ (type 1 diabetes and viral infections – coxsackieviruses) Detection of viruses in human insulin-producing cells. Virus insulin glucagon somatostatine beta cells alpha cells delta cells double staining yellow=positive Jaidane et al., Rev. Med. Virol., 2010, 265-280 23 Immunopathology of viral infections Induction of autoimmune reactions „molecular mimicry“ (type 1 diabetes and viral infections – coxsackieviruses) Virus-induced immunopathology: „Molecular mimicry“ between viral proteins and proteins of the inulin-producing beta-cells: GAD65: IAR/IA-2: HSP60: glutamic acid decarboxylase protein tyrosine phosphatases heat shock protein 60 24 Jaidane et al., Rev. Med. Virol., 2010, 265-280 Immunopathology of viral infections Coxsackieviruses type 1 diabetes non-specific viral infection induces a virus-specific immune response in the host with genetic predisposition. cross reaction with proteins of the insulinproducing beta-cells induces an autoimmunebased tissue destruction > insulin deficiency onset of type 1 diabetes pancreatic cancer non-specific viral infection induces acute pancreatitis acute pancreatitis evolves to chronic pancreatitis > activation of oncogenes onset of pancreatic cancer 4 % survival after 5 years 25 Immunopathology of viral infections: examples Viral infection Immune response Antibody-dependent enhancement of virus infection (dengue virus) Overreaction of the immune system „cytokine storm“ (influenza virus) Induction of autoimmune reactions „molecular mimicry“ (coxsackievirus) Tissue destruction via the immune response against virus-infected cells (hepatitis B virus) 26 Immunopathology of viral infections Tissue destruction via the immune response against virus-infected cells (hepatitis B virus) - Characteristics: family: Hepadnaviridae, enveloped, 40-42 nm in size, partially dsDNA circular genome, reverse transcriptase, genetic stabile (1 serotype, 7 genotypes), highly stable in the environment - Distribution: worldwide, one of the most frequent infection, ca. 370 mill. chronicinfected people HBV particles HBsAg filaments HBsAg particles binding of virusspecific antibodies capsid (core protein): secreted form: envelop protein: http://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2014/Ausgaben/30_14.pdf?__blob=publicationFile Constant number of infections HBcAg HBeAg HBsAg 27 Immunopathology of viral infections Tissue destruction via the immune response against virus-infected cells (hepatitis B virus) - Transmission: parenteral via blood transfusion, needle stick injury, i.v. drug abuse, sex, perinatal, asymptomatic HBsAg carrier often with more than 108 HBVparticle/ml blood, but also via shaver, toothbrush, tattooing, body piercing etc. (HBV is 40-100 times more infectious than HIV) - Time of incubation: 75 (45-160) days - Symptoms: 2/3 without any symptoms, 1/3 with symptoms of an acute hepatitis with growing pains, bellyache, nausea, vomiting and diarrhea cirrhosis of the liver or liver cancer reason of ca. 80 % of all liver cancers - Diagnostic: antigen detection via e.g. ELISA, PCR, serology, liver biopsy - Therapy: interferon, nucleoside/tide analogs (e.g. Lamivudin) - Prevention: vaccination, aseptic conditions, control of blood donors, education 28 Immunopathology of viral infections Tissue destruction via the immune response against virus-infected cells (hepatitis B virus) Course: infection marginal replication immune defense inapparent transient infection immunity fulminant replication delayed, intense immune defense acute healing fulminant immune tolerance inapparent, chronic incomplete immune defense HBsAg carrier chronic hepatitis cirrhosis of liver liver cancer 29 Immunopathology of viral infections Tissue destruction via the immune response against virus-infected cells (hepatitis B virus) Cirrhosis of liver: pathological final state of disease; chronic, irreversible disease characterized by replacement of liver tissue by fibrosis (scar tissue) These changes lead to loss of liver function. healthy tissue cirrhotic tissue 30 Immunopathology of viral infections Tissue destruction via the immune response against virus-infected cells (hepatitis B virus) Evidence of immunopathology: - HBV replicates without cytophatic effects - HBV carrier with active viral replication do not have a liver damage - chronic HBV-infected newborns reveal no symptoms - patients with a chronic-active hepatitis B reveal infiltrates of mononuclear cells in the liver - HBV-transgenic mice produce huge amounts of HBV without symptoms - HBV-infected chimpanzees reveal liver damage after the acute phase sALT: serum alanine aminotransferase marker of liver damage experimental infection of chimpanzees 31 Immunopathology of viral infections Tissue destruction via the immune response against virus-infected cells (hepatitis B virus) Hypothesis of the immune-mediated pathogenesis of hepatitis B: HBV infection immune response virus carrier missing T-cell reaction induces conditions of inapparent virus carriers chronic hepatitis healing intense T-cell reaction Induces a fast virus elimination weak T-cell reaction induces viral persistence accompanied by an ongoing destruction of virus-infected cells Chronic forms of hepatitis B are induced by a weak but ongoing immune responses against HBV. 32 Immunopathology of viral infections Summary: Immune responses play a role during pathogenesis of certain viral infections: - humoral immune reactions may increase the pathogenesis of viral infections via ADE reactions (DHSS) - induction of an overwhelming expression of inflammatory immune mediators induces severe forms of diseases (influenza) - immunological cross-reactions following viral infections play a role in the onset of autoimmune reactions (type 1 diabetes) - cellular immune responses against persistent-infected cells may induce ongoing chronic tissue destructions followed by cancer (hepatitis B) 33