On the contribution of the rodent model Plasmodium chabaudi for understanding the genetics of drug resistance in malaria |
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| Affiliation: | 1. School of Science, Mae Fah Luang University, Chiang Rai, Thailand;2. Gut Microbiome Research Group, Mae Fah Luang University, Chiang Rai, Thailand;3. Laboratory of Molecular and Evolutionary Parasitology, RAPID Group, School of Biosciences, University of Kent, Canterbury, United Kingdom;1. Institute of Parasitology, Biology Centre, Czech Academy of Sciences, Branišovská 31, 370 05 České Budějovice, Czech Republic;2. I. I. Schmalhausen Institute of Zoology NAS of Ukraine, B. Khmelnytsky Street, 15, Kyiv 01030, Ukraine;1. Department of Veterinary Parasitology, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar, Haryana 125004, India;2. Parasitology Lab, ICAR-National Research Centre on Equines, Hisar, Haryana 125001, India;3. Department of Veterinary Physiology and Biochemistry, Lala Lajpat Rai University of Veterinary and Animal Sciences, Hisar, Haryana 125004, India;1. Department of Ecology and Evolutionary Biology, Federal University of São Paulo (UNIFESP), Diadema, SP 09972-270, Brazil;2. Department of Veterinary Medicine, School of Animal Husbandry and Food Engineering, São Paulo University (FZEA/USP), Pirassununga, SP 13635-900, Brazil;3. Department of Animal Biology, Institute of Biology, State University of Campinas (UNICAMP), 13083-970 Campinas, SP, Brazil;1. Aquatic Parasitology Laboratory, School of Fisheries, Aquaculture, and Aquatic Sciences, College of Agriculture, Auburn University, 203 Swingle Hall, Auburn, AL 36849, USA;2. North Carolina Wildlife Resources Commission, 645 Fish Hatchery Road, Marion, NC 28752, USA;1. Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510542, China;2. Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt |
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| Abstract: | Malaria is a devastating disease that still claims over half a million lives every year, mostly in sub–Saharan Africa. One of the main barriers to malaria control is the evolution and propagation of drug-resistant mutant parasites. Knowing the genes and respective mutations responsible for drug resistance facilitates the design of drugs with novel modes of action and allows predicting and monitoring drug resistance in natural parasite populations in real-time. The best way to identify these mutations is to experimentally evolve resistance to the drug in question and then comparing the genomes of the drug-resistant mutants to that of the sensitive progenitor parasites. This simple evolutive concept was the starting point for the development of a paradigm over the years, based on the use of the rodent malaria parasite Plasmodium chabaudi to unravel the genetics of drug resistance in malaria. It involves the use of a cloned parasite isolate (P. chabaudi AS) whose genome is well characterized, to artificially select resistance to given drugs through serial passages in mice under slowly increasing drug pressure. The end resulting parasites are cloned and the genetic mutations are then discovered through Linkage Group Selection, a technique conceived by Prof. Richard Carter and his group, and/or Whole Genome Sequencing. The precise role of these mutations can then be interrogated in malaria parasites of humans through allelic replacement experiments and/or genotype-phenotype association studies in natural parasite populations. Using this paradigm, all the mutations underlying resistance to the most important antimalarial drugs were identified, most of which were pioneering and later shown to also play a role in drug resistance in natural infections of human malaria parasites. This supports the use of P. chabaudi a fast-track predictive model to identify candidate genetic markers of resistance to present and future antimalarial drugs and improving our understanding of the biology of resistance. |
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