application abstract): Drug-resistant malaria is an important emerging disease and new strategies to control this problem are urgently needed. This project will involve the study of in vivo and in vitro antimalarial drug resistance in Uganda. It will be used as a pilot for subsequent larger studies designed to identify molecular markers of drug-resistant malaria. In this study, a series of patients presenting with falciparum malaria at Mulago Hospital, Kampala, Uganda will be studied. The clinical responses of patients to standard therapy with chloroquine will be correlated with measurements of the in vitro sensitivity of their malarial isolates, with the presence of mutations in critical genes in infecting parasites, and with the presence of host genetic polymorphisms that may impact on responses to drug-resistant malaria.
The specific aims of the project are designed to test the hypotheses that in vitro antimalarial drug resistance patterns can predict clinical drug resistance in a heterogeneous African population, that specific parasite mutations can predict drug resistance, and that certain host mutations may alter the clinical course of drug-resistant malaria.
These specific aims are (1) to correlate in vitro drug resistance with clinical responses to antimalarial therapy, (2) to correlate drug resistance with mutations in Plasmodium genes that may mediate resistance, and (3) to correlate clinical outcomes during drug-sensitive and drug-resistant malaria infections with host genetic polymorphisms. These studies should help define the extent of in vitro and clinical resistance to antimalarial drugs in Kampala, a previously under-studied site, allow the evaluation of resistance progression over time, provide information on our ability to use in vitro data to predict clinical responses in a heterogeneous population, and test the contributions of parasite and host genetic polymorphisms in antimalarial drug resistance. The long-term goals of the study are to develop a mechanism for tracking antimalarial drug resistance in Uganda and to identify molecular markers of clinically relevant drug resistance. Such markers should significantly aid in the study, and eventually the therapy and control of drug-resistant malaria in Africa.
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