About 3 billion individuals around the world are at risk for malaria, there are about 250 million cases per year, with about 1 million deaths. While deployment of insecticide impregnated bed nets, new drug combinations, and possibly new vaccines may help control malaria, we hypothesize that shrinking parasite population sizes would place greater burdens on the pathogens to change at faster rates, possibly contributing to higher virulence. Initially, such evolution could be to overcome drugs and cause resistance. However, once the capacity for faster genetic change is in place, the traits may favor acquisition of new niches, within vectors (to favor propagation of the disease) and within human hosts (possibly presenting new disease presentations). This multicenter Program Project application will study the evolution of malaria parasites in South Asia. Malaria is not uniform across South Asia. One sees large variation in species-dominance from NE to Southern states, one sees frequent epidemics of severe malaria, sometimes for unexplained reasons. We hypothesize that South Asia harbors virulent forms of P. falciparum from SE Asia that display the Accelerated Resistance to Multiple Drugs (ARMD) phenotype. This may help ARMD P. falciparum over run traditional P. vivax. In addition to drug resistance, the transmission and virulence properties of sites harboring ARMD parasites, are expected to be different. The Program Director proposes a 5 project Center that touches on epidemiology, parasite plasticity, pathogenesis, transmission, and human genetics in South Asia. Research will be facilitated by scientific partnerships between physicians and academic researchers in India and the US, and by Administration, Data Management, and Statistical support from partners in Delhi and Kolkata. Parasites and their interactions with humans, and mosquitoes, will be studied in Assam and Tripura (near Myanmar), in Ranchi (proximal forested sites with highly endemic malaria), in Wardha in Central India, and finally in the Western cities of Mumbai and Goa (with urban malaria, low endemicity, and high human genetic diversity). The results will teach us about propagation of malaria across subcontinents, and about the possible barriers and breakdown of barriers against the spread of virulent malaria parasites.
Understanding the genetic plasticity of malaria parasites in South Asia, and their relationship to Drug resistance, virulence, transmission, and human immunity, should greatly assist assessment of malaria threat levels in South Asia. Such information may also have predictive value in understanding new, unexpected outbreaks of severe malaria.
|Deng, Xiaoyi; Kokkonda, Sreekanth; El Mazouni, Farah et al. (2014) Fluorine modulates species selectivity in the triazolopyrimidine class of Plasmodium falciparum dihydroorotate dehydrogenase inhibitors. J Med Chem 57:5381-94|
|Rice, Benjamin L; Acosta, Mónica M; Pacheco, M Andreína et al. (2014) The origin and diversification of the merozoite surface protein 3 (msp3) multi-gene family in Plasmodium vivax and related parasites. Mol Phylogenet Evol 78:172-84|
|Turner, Louise; Lavstsen, Thomas; Berger, Sanne S et al. (2013) Severe malaria is associated with parasite binding to endothelial protein C receptor. Nature 498:502-5|
|Herricks, Thurston; Avril, Marion; Janes, Joel et al. (2013) Clonal variants of Plasmodium falciparum exhibit a narrow range of rolling velocities to host receptor CD36 under dynamic flow conditions. Eukaryot Cell 12:1490-8|
|Guler, Jennifer L; Freeman, Daniel L; Ahyong, Vida et al. (2013) Asexual populations of the human malaria parasite, Plasmodium falciparum, use a two-step genomic strategy to acquire accurate, beneficial DNA amplifications. PLoS Pathog 9:e1003375|
|Kumar, Ashwani; Chery, Laura; Biswas, Chinmoy et al. (2012) Malaria in South Asia: prevalence and control. Acta Trop 121:246-55|
|Tutterrow, Yeung L; Avril, Marion; Singh, Kavita et al. (2012) High levels of antibodies to multiple domains and strains of VAR2CSA correlate with the absence of placental malaria in Cameroonian women living in an area of high Plasmodium falciparum transmission. Infect Immun 80:1479-90|
|Narayanasamy, Krishnamoorthy; Chery, Laura; Basu, Analabha et al. (2012) Malaria evolution in South Asia: knowledge for control and elimination. Acta Trop 121:256-66|
|Herricks, Thurston; Seydel, Karl B; Turner, George et al. (2011) A microfluidic system to study cytoadhesion of Plasmodium falciparum infected erythrocytes to primary brain microvascularendothelial cells. Lab Chip 11:2994-3000|
|Gujjar, Ramesh; El Mazouni, Farah; White, Karen L et al. (2011) Lead optimization of aryl and aralkyl amine-based triazolopyrimidine inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with antimalarial activity in mice. J Med Chem 54:3935-49|