Strains of P. falciparum from different regions ofthe worid have varying capacifies to acquire resistance to new antimalarials. Founder events leading to clinical drug resistance against tradifional antimalarials were rare, yet, when they occurred, they occurred in specific regions ofthe worid such as SoutheastAsia (Thailand), Central America (Columbia), and Papua New Guinea. The Project Director's (PD) lab has shown that the capacity to acquire resistance to new antimalarials in vitro is best related to parasite strains originating in countries with high level of drug resistance. However, these studies were performed with laboratory parasite clones adapted to culture two decades ago. and have long, varied histories in individual research labs. The goal of Project 2 is to determine if parasites in South Asia can acquire resistance to experimental anfimalarials at extraordinary rates, and to establish their genotypes. There is a unique opportunity here to study origins of complex polymorphisms associated with resistance in parasites, both because ofthe proximity of South Asia to Myanmar and Cambodia, and due to some major initiafives to eradicate malaria in defined regions of India. In this project, exisfing and newly isolated P. falciparum from South Asian pafients will be phenotyped for the Accelerated Resistance to Mulfiple Drugs (or ARMD) trait based on their capacities to acquire resistance to novel, well-characterized anfimalarials through in vitro selecfion experiments. The methodologies for in vitro selecfions were developed, and are well established, in the PD's lab. Using 3 different chemical probes, the parasites will be characterized with respect to frequencies of resistance, rates of point mutations, and frequency of amplification/deletion events Similarities and differences in resistance mechanisms will be compared between established lab clones from around the worid and newly culture-adapted field strains from South Asia.
TO OVERALL APPLICATION: Project 1, will provide parasite samples isolated from pafients with recorded clinical presentafions. From work in the present Project 2, we will provide ARMD status of individual isolates and a specific sample collection region of South Asia. This will be useful for Project 1 (Epidemiology of diseases severity). Project 2 (Pathogenesis tracking disease mechanisms), Project 3 (evaluafing breath of Vector preferences) and Project 5 (which could gain improved genome associafions after patients are stratified into those carrying ARMD and non-ARMD parasites.
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