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I never found the order I searched for But always a sinister And well-planned disorder That increases in the hands Of those who hold power While the others who clamor for A more kindly world A world with less hunger and more hopefulness Die of torture in the prisons Claribel Alegria, Nicaraguan poet How can we defeat this disease? Leading causes of death in Sub-Saharan Africa, South Asia, and Southeast Asia for persons age 0-44 (World Health Organization) First, how does your body strike back? Can you say antibodies and T cells? Antibodies work at all stages but T cells are only effective when the parasite is in the liver Why? Red blood cells do NOT express MHC proteins and thus infected cells cannot generate a T cell response! In adults the immune system does a pretty good job, but in kids it’s a different story Young kids are hit much harder by malaria Because of differences in their immune response www.columbia.edu/itc/hs/medical/pathophys/parasitology/2006/PAR-05Color .pdf How does the malaria parasite respond to the natural selection produced by immune attack? www.columbia.edu/itc/hs/medical/pathophys/parasitology/2006/PAR-05Color .pdf One comes fromdo theNOT fact that malaria makes Redclue blood cells express MHC Red blood cells “sticky” so they lodge in capillaries and thus infected cells cannot generate a T cell response proteins This them to prevent theirexpress host cells MHC from Redallows blood cells do NOT Going through the spleen where they can be killed and thus infected cells cannot generate a T cell response proteins Infected red blood cells can be recognized by a change Red blood cells do NOT express MHC proteins In shape--the cells get “knobs” and thus infected cells cannot generate a T cell response parasite www3.niaid.nih.gov/.../ malariaGeneticsSection/ The “knobs” and the stickiness from Red blood cells do NOTresult express MHC proteins Plasmodium proteins that are put on the plasma membrane and thus infected cells cannot of the red blood cell including the PfEMP proteins generate a T cell response www3.niaid.nih.gov/.../ malariaGeneticsSection/ Red blood cells NOTbyexpress MHC proteins PfEMP-1 proteins aredo encoded the var (for variable) genes. individual parasite genomes containcells 50-150 var genes and thus infected cannot but only one is expressed at any one time. generate a T cell response PfEMP-1 proteins are very antigenic and thus we mount a strong and effective response Parasites fight back: theyNOT switchexpress on different var genes Red blood cells do MHC proteins during asexual reproduction allowing them and thus infected cells cannot to evade the initial immune response! generate a T cell response Nature 415: 673 (2002) Variation also allows the parasite to re-infect previously exposed hosts Nature 415: 673 (2002) Despite this, as we have seen, most adults fight off the infection over time www.columbia.edu/itc/hs/medical/pathophys/parasitology/2006/PAR-05Color .pdf How can we speed up this process, protect children and the elderly, and reduce the death rate? www.columbia.edu/itc/hs/medical/pathophys/parasitology/2006/PAR-05Color .pdf How can we speed up this process, protect children and the elderly, and reduce the death rate? We need drugs www.columbia.edu/itc/hs/medical/pathophys/parasitology/2006/PAR-05Color .pdf We’ll focus on the deadliest parasite But there is a problem that takes us back to the family tree mushrooms You and me Plasmodium plants http://drnelson.utmem.edu/Woods.Hole/slide5.png We seem like distant relatives but this is only part of the tree of life mushrooms You and me Plasmodium plants http://drnelson.utmem.edu/Woods.Hole/slide5.png Here’s the bigger picture--we are actually relatively closely related to Plasmodium Staph. aureus TB bug E. coli Plasmodium and me! Genome Research 12, 1080-1090 (2002) We share much more of our cellular machinery Than we do with bacteria. Staph. aureus TB bug E. coli Plasmodium and me! Genome Research 12, 1080-1090 (2002) We need to find drug targets that Plasmodium have And people do not share The first insight goes back >400 years Following their arrival in the New World, Spanish Jesuit missionaries in Peru learned of a medicinal bark That the native Quechua used to treat “fever”. web1.caryacademy.org/.../ Quinine/history.htm Legend suggests that the Countess of Chinchón, wife of the Viceroy of Peru, was cured of her fever with the bark. The tree was named Cinchona after the countess. The Quechua called it Quinquina = “bark of barks” In 1820 J.B. Caventou and P.J. Pelletier isolated the active chemical and named it quinine A synthesis approach was discovered in the 1940s But most is still purified From Cinchona bark Quinine remains an effective drug and was dominant through 1950. But chemists sought more effective derivatives that had less side effects Hans Andersag at Bayer discovered chloroquine in 1934 and by the 1950’s it became the drug of choice How do quinine And its derivatives kill Plasmodium? Most current drugs target the red blood cell stage Plasmodium eats blood! (actually really hemoglobin) Plasmodium eats blood! When living in red blood cells It survives by digesting Hemoglobin in its food vacuole (the parasite lysosome). However, the leftover “heme”, the metal complex that actually carries oxygen, Is quite toxic. Wikipedia.com Plasmodium eats blood! The parasite’s heme polymerase converts the toxic heme into non-toxic hemazoin Which then crystalizes Chloroquine accumulates in the food vacoule Where it inhibits conversion of heme to hemazoin Either by directly binding heme and/or By inhibiting heme polymerase http://www.tulane.edu/~wiser/protozoology/notes/drugs.html Chloroquine accumulates in the food vacoule Where it inhibits conversion of heme to hemazoin Either by directly binding heme and/or By inhibiting heme polymerase No, not chloroquine! Ahhhhhhhhh….. http://www.tulane.edu/~wiser/protozoology/notes/drugs.html Chloroquine allowed major progress against malaria-What do you think happened next? No, not chloroquine! Ahhhhhhhhh….. http://www.tulane.edu/~wiser/protozoology/notes/drugs.html www.columbia.edu/itc/hs/medical/pathophys/parasitology/2006/PAR-05Color .pdf What cellular changes underline resistance? www.columbia.edu/itc/hs/medical/pathophys/parasitology/2006/PAR-05Color .pdf Chloroquine is linked to a mutation in a Red bloodresistance cells do NOT express MHC proteins membrane-located food vacuolar drug-metabolite transporter protein and thus infected cells cannot T move cell response Mutant PfCRTgenerate is thoughtato Chloroquine out of the food vacuole www3.niaid.nih.gov/.../ malariaGeneticsSection/ Choroquine resistance set back the fight against malaria www.uhhg.org/mcrh/resources/video/malariappt.pdf www.uhhg.org/mcrh/resources/video/malariappt.pdf Option 1: make more derivatives of quinine or use quinine again www.columbia.edu/itc/hs/medical/pathophys/parasitology/2006/PAR-05Color .pdf Option 2: new drug targets http://www.tulane.edu/~wiser/protozoology/notes/drugs.html Pyrimethamine (DHFR) + sulfadoxine or dapsone (DHPS) attack enzymes involved in making nucleotides (we can take in folate from our diet- they cannot) www.columbia.edu/itc/hs/medical/pathophys/parasitology/2006/PAR-05Color .pdf One of the newest medicines has one of the longest histories Artemisia has been used by Chinese herbalists for >1000years to treat many illnesses including malaria Med Trop (Mars). 1998;58(3 Suppl):13-7. Int J Parasitol. 2002 Dec 4;32(13):1655-60. The active compound was found to be Artemisinin Med Trop (Mars). 1998;58(3 Suppl):13-7. Int J Parasitol. 2002 Dec 4;32(13):1655-60. Artemisinin is not toxic until it is cleaved inside the parasite by exposure to heme-iron A resulting free radical intermediate may kill the parasite by poisoning one or more essential malarial protein(s). Med Trop (Mars). 1998;58(3 Suppl):13-7. Int J Parasitol. 2002 Dec 4;32(13):1655-60. What’s another rule to prevent resistance we learned from treating TB? When you use new drugs, use them in combination! Current CDC guidelines are: If malaria was acquired in areas without chloroquine resistance Then Treat with chloroquine Current CDC guidelines are: If from area with resistance : 1. quinine plus doxycycline or tetracycline or 2. Atovaquone + proguanil (Malarone) Current CDC guidelines are: If P. vivax or P. Ovale Chloroquine plus PRIMAQUINE to hit liver stage Plasmodium is also evolving resistance to other drugs http://www.tulane.edu/~wiser/protozoology/notes/drugs.html Research continues to identify new drugs Nature 415: 686 (2002) Scientists also sequenced the genome of P. falciparum In 2002 looking for new drug targets 23 million base pairs 5,300 proteins encoded 60% are not similar to known proteins! Nature 415: 686 (2002) The genome of P. vivax was completed this past month (October 2008) More similar to P. falciparum than expected Only 150 unique proteins Hey wait a minute, aren’t you forgetting something? pathmicro.med.sc.edu/ppt-vir/vaccine.ppt What about a vaccine against malaria? pathmicro.med.sc.edu/ppt-vir/vaccine.ppt (Program for Appropriate Technology in Health) Genetically attenuated P. falciparum sporozoites. Developmentally arrested at an early stage following liver cell invasion, or Radiation attenuated sporozoite Of all malaria vaccines, GlaxoSmithKline’s RTS,S/AS02A is the furthest along in clinical testing, "at least by four to five years," Zarifah Reed at the WHO Initiative for Vaccine Research RTS,S/AS02A is generated against CSP, the most abundant cell surface protein during the malaria parasite's infectious sporozoite stage The RTS,S/AS02A antigen is a fusion of CSP with a surface protein from hepatitis B, to stimulate a more effective immune response CS is attached to the plasma membrane and contains a large immunodominant domain that consists of repeats of a short, species-specific peptide. It is important for invasion of liver cells Membrane anchor Since RTS,S incorporates a hepatitis B antigen, it "will also be a hepatitis B vaccine," she adds. An estimated one million people die annually worldwide from hepatitis B and ensuing liver complications. After Phase I trials demonstrated safety, the vaccine entered Phase II trials in children in Africa Here’s the data--did it work? It continues to look good after a longer follow up The Lancet 366 10 December 2005, pp. 2012-2018 Other vaccines are following this though trials are less far along That’s high tech—how about low tech Reduce Contact Between Humans And Mosquitoes Personal protective measures – DEET – PERMETHRIN – Bed nets Insecticide treated bednets can reduce infection by 63% For example, 20 million Bednets have been distributed in Ethiopia Legend: PSI - Population Services International; WB -World Bank. GFATM 2, 5 - Global Fund for AIDS, TB and Malaria Cum nets: Cumulative number of nets distributed. UNICEF Ethiopia WHO, UNICEF, the World Bank and the UN Development Program formed a new partnership in 1998 It’s goal: eliminate malaria as a major disease by 2015 Accessible drugs Nets and Insecticide Rapid diagnostic tests More Artemesia A U.S. government initiative designed to cut malaria deaths in half in sub-Saharan Africa. Announced by President Bush on June 30, 2005. Pledges to increase U.S. funding of malaria prevention and treatment in sub-Saharan Africa by > $1.2 billion over 5 years. Before we end, let’s consider one other cool aspect of malaria This brings us back to blood and how it carries oxygen J. Mol. Biol., 235, 657 Hemoglobin is a finely tuned machine crafted by natural selection to deliver oxygen and remove CO2 J. Mol. Biol., 235, 657 A single amino acid change alters hemoglobin structure And allows the protein to form long “rods” A single amino acid change alters hemoglobin structure And allows the protein to form long “rods” These protein “rods” change the shape of the Red blood cell and this change occurs when hemoglobin is not bound to oxygen Sickled cell block capillaries and trigger lower oxygen and more “sickling” The disease is treatable in the developed world But still shortens life expectancy Untreated, as in much of the developing world, the disease is fatal in childhood The mutation responsible for sickle cell anemia is surprisingly common in parts of the world anthro.palomar.edu/synthetic/synth_4.htm Why hasn’t natural selection eliminated this allele? anthro.palomar.edu/synthetic/synth_4.htm Does this map look familiar? anthro.palomar.edu/synthetic/synth_4.htm Does this map look familiar? Malaria distribution Heterozygotes have an advantage! While red blood cells from heterozygotes are usually normal, they are prone to sickle and be destroyed if infected by Plasmodium, eliminating the blood stage of the parasite before it can reproduce And this is not the only such example! Glucose-6-phosphate dehydrogenase plays a key role in glucose metabolism but also generates glutathione Protects red blood cells Against oxidative stress 200 million people are deficient in this process Protects red blood cells Against oxidative stress Complete loss of function can lead to episodes of anemia Protects red blood cells Against oxidative stress Milder reductions can provide partial resistance to malaria as malaria-infected red cells are susceptible to more rapid death Protects red blood cells Against oxidative stress However, these individuals are also hypersensitive to certain antimalarials like primaquine that affect oxidative stress Protects red blood cells Against oxidative stress