Resistance Project

Summary Among our best tools for the control of malaria are effective drugs and insecticides used for treatment and prevention of the disease. However, the value of these tools is limited by drug resistance in malaria parasites and insecticide resistance in anopheline mosquitoes. Alarmingly, partial resistance to artemisinins (ART-R), the backbone of treatment regimens, has emerged in Uganda, as demonstrated by our group. Susceptibility to key artemisinin partner drugs is also in jeopardy, threatening efficacy of artemisinin-based combination therapies to treat malaria. ART-R also decreases activity against early gametocytes and is associated with increased production of transmissible gametocytes. Resistance to multiple classes of insecticides similarly puts vector control strategies at risk, and suboptimal performance of vector control interventions has been demonstrated in Uganda. We already have an understanding of mediators of antimalarial and insecticide resistance. For antimalarials, polymorphisms in drug transporters and folate enzymes are associated with resistance to key components of treatment and chemoprevention regimens, and specific mutations in PfK13 are primary mediators of ART-R. For insecticides, point mutations in insecticide target-sites and altered activity of detoxification enzymes are associated with resistance to pyrethroid, carbamate, organophosphate, and neonicotinoid insecticides. Markers for these polymorphisms are valuable tools for the longitudinal surveillance of drug and insecticide resistance in Uganda. This project will leverage the large PRISM surveillance network and utilize deep sequencing strategies to conduct broad surveys of the prevalence of known resistance markers across Uganda. In addition, we will search for associations between resistance markers and both utilization of specific control interventions and longitudinal measures of malaria metrics. Lastly, we will characterize impacts of resistance on malaria transmission. We hypothesize that malaria treatment and control in Uganda will be challenged by increasing resistance in malaria parasites and anopheline vectors, that the rate of resistance development will vary depending on the extent of implementation of control measures and level of malaria transmission, and that resistance will impact on both human malaria and ongoing transmission. We will test these hypotheses with serial surveys for parasite and mosquito resistance mediators at sites with varied malaria control interventions and transmission intensity and with specific studies of transmission to mosquitoes. Our specific aims will be 1) to characterize antimalarial drug resistance by serial surveillance at diverse sites with varied implementation of control measures across Uganda, 2) to characterize anopheline insecticide resistance by serial surveillance at diverse sites with varied implementation of control measures across Uganda, and 3) to characterize impacts of antimalarial drug resistance on malaria transmission. The results of this study will add important insights regarding drivers of drug and insecticide resistance and be of value to policy-makers working to best control malaria in Uganda.