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The arsenal of malaria combatants

The arsenal of malaria combatants. Shane Ewalt. Topics. BRIEF HISTORY POPULAR METHODS METHODS IN PROGRESS THE VACCINE. Where it all started.

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The arsenal of malaria combatants

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  1. The arsenal of malaria combatants Shane Ewalt

  2. Topics • BRIEF HISTORY • POPULAR METHODS • METHODS IN PROGRESS • THE VACCINE

  3. Where it all started • “The Ross-Grassi discovery of malaria transmission by the mosquito completed the essential knowledge of the parasite’s life cycle. It was now possible to contemplate, in a rational manner, how malaria might be controlled” (Desowitz)

  4. The popular methods

  5. DDT • Dichlorodiphenyltrichloroethane • Paul Muller found it very effective against potato beetles and cloth moths in the 1930’s • During WWII it showed to be effective, powerful, cheap, and very safe with humans due to its low acute toxicity levels. • “Foresters quickly began to use DDT for aerial sprays against important forest pests, and farmers tried DDT against almost anything that flew, crawled, or walked.” Dunlap, Thomas R. DDT: Scientists, Citizens, and Public Policy. Princeton, New Jersey: Princeton University Press, 1981. Print.

  6. Rise and fall • The Global Eradication of Malaria Program thought DDT could eradicate malaria during the 1950’s and 60’s • Mosquitoes became physiologically and behaviorally resistant to the insecticide. • Developed enzymes to detoxify it and changed they behavior of resting on walls after feeding. Desowitz, Robert S. The Malaria Capers: Tales of Parasites and People. New York: W.W. Norton and Company, 1993. Print.

  7. Negative effects • Soon after its release for public use, the FDA found it could accumulate in the body, primarily in adipose tissue, and could be passed to children through breast milk (Dunlap). • Experimental studies using DDT and its metabolites such as DDE on animals have shown that it is neurotoxic, carcinogenic, immunotoxic, and causes adverse reproductive effects (van den Berg). • It is shown to biomagnify with increasing trophic levels in food chains and causes thinning of egg shells of predatory birds (van den Berg) • It is still used as an indoor residual spray under regulations of the World Health Organization, primarily for its deterrent and irritant effects (van den Berg)

  8. http://actionoutdoors.org/edres/images/DDT.jpg

  9. Insecticide treated bed nets • Most popular method with residual spraying and antimalarial drugs. • WHO adopted mass distribution of free bed nets as main strategy in 2007. • Distributed mainly for pregnant women and children • Some treated with long lasting pyrethroid sprays that can last up to 5 years and cover two children • Each net costs 10 dollars to produce, transport, and distribute (Sachs) • Problems include misuse (wedding veils or fishing aids), uncomfortable to sleep under, and only protects against mosquitoes that bite indoors at night (Kaplan)

  10. http://projectdiaspora.org/wp-content/uploads/2008/02/d00b2603-e7f2-99df-318897535877846a_1.jpghttp://projectdiaspora.org/wp-content/uploads/2008/02/d00b2603-e7f2-99df-318897535877846a_1.jpg

  11. IRS and zooprophylaxis Kawaguchi, Isao, Akira Sasaki, and Motoyoshi Mogi. (2003). Combining zooprophylaxis and insecticide spraying: a malaria-control strategy limiting the development of insecticide resistance in vector mosquitoes. Proceedings: Biological Sciences, 271(1536), 301-309. Strategy to attract vectors to domestic animals that can act as dead end hosts or decoy hosts to limit the amount of bites on humans Cattle is the main host chosen because human malaria parasites cannot amplify in cows IRS and zoophrophylaxis can help control of malaria and the evolution of insecticide resistance by deterring vectors from homes with the insecticides and drawing them to the cattle where the parasite will not reproduce. Habitat separation is key for this method to be effective It is maladaptive for mosquitoes to avoid feeding on the cows if they are closer than the human blood meal

  12. Negative aspects • Introducing more cattle can raise the mosquito density and their fitness by introducing more blood meals • The cattle have to be far enough away to draw attention from the human blood but also have to be close enough to gain attention of the mosquitoes. • A division of populations to both targets will reduce the efficacy of the method. • Not all mosquitoes are zoophilic • Most African vectors are anthropophilic • Kawaguchi, Isao, Akira Sasaki, and Motoyoshi Mogi. (2003). Combining zooprophylaxis and insecticide spraying: a malaria-control strategy limiting the development of insecticide resistance in vector mosquitoes. Proceedings: Biological Sciences, 271(1536), 301-309.

  13. Entomopathogenic Fungi • Fungal spores infect and kill adult mosquitoes and larvae • They can be applied in sprays but take up to 10 or 12 days to kill and may have to be reapplied in a matter of weeks (Enserink). • Bacillus thuringiensis has shown to be effective in controlling larval stages (Blanford et al.) • The sprays are oil based formulas of the entomopathogens and can be used on indoor surfaces or curtains (Blanford et al.) • The mosquito is infected through external contact with the spores germinating and penetrating through their cuticle and then proliferating in the hemocoels (Blanford et al.) Blanford, Simon, Brian H. K. Chan, Nina Jenkins, Derek Sim, Ruth J. Turner, Andrew F. Read, Matt B. Thomas. (2005). Fugal Pathogen Reduces Potential for Malaria Transmission. Science, 308, 1638-1641.

  14. Habitat and Larvae Control

  15. Habitat and larvae control • This method has proved successful in malaria control • Mussolini drained the canals in the 1930’s (Desowitz) • The permanent and temporary alteration of the breeding grounds. • The main emphasis of this method is to target species specific breeding sites to avoid having to attempt to manage all possible areas • A. gambiae is known to lay its eggs in natural and man made habitats close to housing. • A. umbrosus is known to lay its eggs in shaded wooded habitats. • Gu, Weidong, Jurg Utzinger, and Robert J. Novak (2008). Habitat-Based Larval Interventions: A new Persepctive for Malaria Control. The American Society of Tropical Medicine and Hygiene, 78(1), 2-6.

  16. Habitat and Larvae Control • Problems with this method include: • Small habitats such as hoof prints, ground depressions, rice fields, and stone pools can all contain larvae. • However, studies show that anopheline mosquitoes have limited range when seeking hosts so controlling immediate habitats are more cost effective. • Gu, Weidong, Jurg Utzinger, and Robert J. Novak (2008). Habitat-Based Larval Interventions: A new Persepctive for Malaria Control. The American Society of Tropical Medicine and Hygiene, 78(1), 2-6. http://www.arbovirus.health.nsw.gov.au/areas/arbovirus/mosquit/photos/various_larvae.jpg

  17. Larvivorous Fish • Gambusia affinis, mosquito fish, and Gambusia holbrooki have been used for larvae control for more than 100 years • They are very hardy omnivores and can rapidly reproduce in most aquatic environments • Primarily effective in drainage ditches, fish ponds, and other small bodies of water • Can tolerate a wide variety of water temperatures, oxygen levels, pH levels, and salinity levels http://www.ailyns-pond.com/AP/Images/Gambusia_MosquitoEater_Fish.jpg Walton, William E. (2007). Larvivorous fish including Gamusia. Journal of the American Mosquito Control Association, 23(2), 184-220.

  18. Drawbacks • Non native fish are known to have dramatic effects on new habitats. • Not efficient in high nitrogen habitats • Dispersal to all habitats • Adverse food web effects http://www.briancoad.com/species%20accounts/Gholbrooki-m.gif Walton, William E. (2007). Larvivorous fish including Gamusia. Journal of the American Mosquito Control Association, 23(2), 184-220.

  19. Antimalarial Drugs

  20. Antimalarials • There are only a limited number of drugs which can be used to treat or prevent malaria (Bloland) • Three general categories of clinical needs are used for the requirements of antimalarials • Treatment of severe and complicated malaria • Treatment of uncomplicated malaria • Chemoprophylxis and intermittent preventive treatment (Mordmuller) • Combination therapy is used to treat resistant parasites and prevent further resistance from emerging (Bloland)

  21. Therapies • Quinine is used in the treatment of severe malaria, multi drug resistant P. falciparum, and during the first trimester of pregnancy. • Targets the heme metabolism of the parasite. • Chloroquine is used in the treatment of non falciparum infections because its increase in drug resistance. Also used for chemoprophylaxis where it remains effective and cheap. • Targets the heme metabolism and is able to selectively enter the lysosomes of the parasite. Bloland, Peter B. (2001). Drug resistance in malaria. World Health Organization, 1-24.

  22. Artemisinin and derivatives • Flowering plant that is widespread in China and Vietnam but is cultivated in Africa, the U.S., Russia, India, Brazil, and there is a large breeding program in Switzerland • Considered the best current treatment for uncomplicated P. falciparum malaria • Inhibits PfATP6, calcium ATP-ase, outside the food vacuole • Very rapid reduction of parasites almost immediately after administration with a good safety profile • Not expected to be affected by widespread resistance in the future de Ridder, Sanne, Frank van der Kooy, and Robert Verpoorte. (2008). Artemisia annua as a self-reliant treatment for malaria in developing countries. Journal of Ethnopharmacology, 120, 302-314.

  23. Artemisinin drawbacks • Short half life in the body causes the elimination of parasites below a detectable level but can continue to reproduce after the drug has been eliminated from the body • 18 month production cycle to grow, harvest, and process • 10 to 20 times higher price than available but less effective drugs in Africa • Best used with a combination of long acting drugs http://www.biocis.u-psud.fr/IMG/jpg/artemisia.jpg de Ridder, Sanne, Frank van der Kooy, and Robert Verpoorte. (2008). Artemisia annua as a self-reliant treatment for malaria in developing countries. Journal of Ethnopharmacology, 120, 302-314.

  24. Marine Antimalarials • With 70% of antimalarials in Africa coming from informal private sectors such as roadside vendors there needs to be a push for more affordable and effective drugs (Dunavan) • Progress has been shown in antimalarials from seven extracts from different marine species of • Chordata • Echinodermata • Cnidaria • Porifera (Gardemann) 3 Main Compounds http://www.mdpi.com/1660-3397/7/2/130/ag

  25. Gin and tonic method • Tonic water includes a small amount of quinine • Considerable amounts of tonic water, for a short period of time can suppress malaria parasites • However, prophylaxis effects cannot be achieved by drinking tonic water Meyer, Christian G., Florian Marks, and Jurgen May (2004). Gin tonic revisited. Tropical Medicine and International Health, 9(12), 1239-1240.

  26. In progress

  27. Sterile mosquito method • Radiation technology sterilizes male mosquitoes which are introduced into natural populations • Effective because female mosquitoes only breed once in their two week lifespan. • The sterile males can be targeted to specific species. • Anopheles gambiae was the first species of mosquito to have its DNA altered but other species can be altered in the same way Williams, N. (2005). Hopes for sterile males. Current Biology, 15(23), R941 http://www.nature.com/nbt/journal/v23/n11/covers/largecover.gif

  28. Targeting males • Since only females transmit malaria, releasing them would only make the problem worse • A team from the department of biology in Imperial College added a gene that makes the testicles of the male mosquitoes fluorescent • A sorting machine based on laser light separated the males and females in their larvae forms at 180,000 larvae in 10 hours • Main drawback is determining whether the sterile males will be as fit as the wild males in order to be chosen as a mate http://www.imperial.ac.uk/pictures/people/scan_mosq.jpg Williams, N. (2005). Hopes for sterile males. Current Biology, 15(23), R941

  29. Gene Introgression • Engineering mosquitoes with a genetic trait that makes them resistant to malaria or causes population suppression • Drive this trait through natural populations • First proposed in 1968 and in 1982 the fruit fly became the first insect to be stably transformed with a transposable element http://www.uci.edu/uci/features/2008/11/images/malariasymp_p081117_02a_.jpg Christophides, George K. (2005) Transgenic mosquitoes and malaria transmission. Cellular Microbiology, 7(3), 325-333.

  30. Techniques • The genetic trait must linked to mechanisms for selection to make the population replacement a faster process • Meiotic drive and fitness advantages are attempted to be incorporated into drive mechanisms such as mobile DNA elements • There must be a “tight” linkage between the drive mechanism and the trait http://puesoccurrences.files.wordpress.com/2009/07/dna_500.jpg Christophides, George K. (2005) Transgenic mosquitoes and malaria transmission. Cellular Microbiology, 7(3), 325-333.

  31. Promising • Marcelo Jacobs-Lorena, microbiologist from John Hopkins University performed an experiment in which after 9 generations the transgenic mosquitoes made up 70% of the population • Done with rodent malaria • Not only could survive but out competed natural species http://malaria.jhsph.edu/bin/n/v/jacobs_lorena_marcelo.jpg Fischetti, Mark. (2007) Mosquitoes Enlisted to Beat Malaria. Scientific American, 316, 47.

  32. Wolbachia pipientis • Intracellular parasitic bacterial symbiont microbe that can be injected into mosquitoes. • The infection causes mating between uninfected females and infected males to have reduced egg hatch due to cytoplasmic incompatibility (Jin et al.) • Mating with any infected female causes the offspring to be infected (Jin et al.) • The bacterial strain is estimated to be able to be spread at rates as high as 100 kilometers per year by refractory transgenes (Christophides) http://en.wikipedia.org/wiki/File:Wolbachia.png

  33. Possible scenarios • 1. use the bacterial strain to drive refractory transgenes into populations to stop the transmission of the parasites • 2. release infected males into populations to cause cytoplasmic incompatibility throughout • 3. release infected mosquitoes with the virulent pathogenic form to shorten life span Jin, Chaoyang, Xiaoxia Ren, and Jason L. Rasgon. (2009). The Virulent Wlbachia Strain wMelPop Efficiently Establishes Somatic Infections in the Malaria Vector Anopheles gambiae. Applied and Environmental Microbiology, 75(10), 3373-3376.

  34. Obstructions • No infections have been identified in natural Anopheles populations which supports that some species may be naturally resistant • Certain strains have been shown to be able to colonize Anopheles gambiae and reduce its life span up to 50% but it is uncertain whether the infection will be transmitted to offspring Jin, Chaoyang, Xiaoxia Ren, and Jason L. Rasgon. (2009). The Virulent Wlbachia Strain wMelPop Efficiently Establishes Somatic Infections in the Malaria Vector Anopheles gambiae. Applied and Environmental Microbiology, 75(10), 3373-3376.

  35. Selfish Genes - Medea • Naturally occuring gene in the flour beetle that kills competitive genotypes • One gene is a toxin that poisons every egg cell • The other is like an antidote that allows the offspring to live only if the whole set is carried • A transgene set has been produced that codes for RNA sequences that silence the expression of a gene that is essential for normal development in flies. This gene was linked to an antidote gene that saves the embryo Levy, Sharon. (2007). Mosquito Modifications: New Approaches to Controlling Malaria. BioScience, 57(10), 816-821.

  36. The Vaccine

  37. Approaches • The production of all stages of the malaria parasite in rodent malaria allowed the vaccine to be feasible • A successful approach of P. falciparum into human volunteers was carried out by inducing a sterile immunity after using weakened sporozoites • Generated protective anti-CSP ( circumsporozoite protein) antibodies and CD4 and CD8 T cells that act against sporozoites that infect liver cells • Another approach attempted sub unit vaccines which are based on immunogenic components of sporozoites Vanderberg, Jerome P. (2009). Reflections on early vaccine studies, the first successful human malaria vaccination, and beyond. Vaccine, 27, 2-9.

  38. RTS,S • Considered the world’s most promising vaccine that shows an acceptable safety profile, immuogenicity, and partial protection against malaria in adults, children, and infants in endemic areas • Recombinant protein that binds a circumsporozoite protein with the hepatitis B surface antigen molecule • Combined with a GlaxoSmithKline adjuvant system • Induces production of antibodies and WBC’s that target the parasite in the liver RTS,S Malaria Vaccine Clinical Trials. Malaria vaccine initiative.

  39. Final Thought • An estimated 30 children died from malaria during this 15 minute presentation regarding all the possible ways of controlling it http://www.who.int/mediacentre/news/releases/2003/pr33/en/

  40. Sources • Jin, Chaoyang, Xiaoxia Ren, and Jason L. Rasgon. (2009). The Virulent Wlbachia Strain wMelPop Efficiently Establishes Somatic Infections in the Malaria Vector Anopheles gambiae. Applied and Environmental Microbiology, 75(10), 3373-3376. • Dunlap, Thomas R. DDT: Scientists, Citizens, and Public Policy. Princeton, New Jersey: Princeton University Press, 1981. Print. • Desowitz, Robert S. The Malaria Capers: Tales of Parasites and People. New York: W.W. Norton and Company, 1993. Print. • Blanford, Simon, Brian H. K. Chan, Nina Jenkins, Derek Sim, Ruth J. Turner, Andrew F. Read, Matt B. Thomas. (2005). Fugal Pathogen Reduces Potential for Malaria Transmission. Science, 308, 1638-1641. • Kawaguchi, Isao, Akira Sasaki, and Motoyoshi Mogi. (2003). Combining zooprophylaxis and insecticide spraying: a malaria-control strategy limiting the development of insecticide resistance in vector mosquitoes. Proceedings: Biological Sciences, 271(1536), 301-309. • Gu, Weidong, Jurg Utzinger, and Robert J. Novak (2008). Habitat-Based Larval Interventions: A new Persepctive for Malaria Control. The American Society of Tropical Medicine and Hygiene, 78(1), 2-6. • Walton, William E. (2007). Larvivorous fish including Gamusia. Journal of the American Mosquito Control Association, 23(2), 184-220. • Bloland, Peter B. (2001) Drug resistance in malaria. World Health Organization, 1-24. • Mordmuller, Benjamin. (2010).New medicines for malaria. The Middle European Journal of Medicine, 122(1), 19-22. • de Ridder, Sanne, Frank van der Kooy, and Robert Verpoorte. (2008). Artemisia annua as a self-reliant treatment for malaria in developing countries. Journal of Ethnopharmacology, 120, 302-314. • Gademann, Karl, and Joanna Kobylinska. (2009). Antimalarial Natural Products of Marine and Freshwater Origin. The Chemical Record, 9, 187-198.

  41. Dunavan, Claire Panosian. (2005). Tackling Malaria. Scientific American, 77-83. • Meyer, Christian G., Florian Marks, and Jurgen May (2004). Gin tonic revisited. Tropical Medicine and International Health, 9(12), 1239-1240. • Williams, N. (2005). Hopes for sterile males. Current Biology, 15(23), R941. • Christophides, George K. (2005) Transgenic mosquitoes and malaria transmission. Cellular Microbiology, 7(3), 325-333. • Fischetti, Mark. (2007) Mosquitoes Enlisted to Beat Malaria. Scientific American, 316, 47. • Jin, Chaoyang, Xiaoxia Ren, and Jason L. Rasgon. (2009). The Virulent Wlbachia Strain wMelPop Efficiently Establishes Somatic Infections in the Malaria Vector Anopheles gambiae. Applied and Environmental Microbiology, 75(10), 3373-3376. • Levy, Sharon. (2007). Mosquito Modifications: New Approaches to Controlling Malaria. BioScience, 57(10), 816-821. • Levy, Sharon. (2007). Mosquito Modifications: New Approaches to Controlling Malaria. BioScience, 57(10), 816-821. • RTS,S Malaria Vaccine Clinical Trials. Malaria vaccine initiative. • van den Berg, Henk.(2009) Global Status of DDT and Its Alternatives for Use in Vector Control to Prevent Disease. Environmental Health Perspectives, 117.11, 1656-1661 • Sachs, Jeffrey D. (2009). Good news on malaria control. Scientific American, 21.

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