RESISTANCE PROJECT SUMMARY Our best available tools for the control and eventual elimination of malaria are effective antimalarial drugs and insecticides. Prompt therapy prevents progression to severe disease and limits transmission to others. Intermittent preventive therapies (IPTs) decrease the incidence of malaria in high-risk groups, in particular infants and pregnant women. Appropriate use of insecticides in indoor residual spraying (IRS) and insecticide- treated bednet (ITN) programs decreases malaria transmission. However, the value of all of these interventions is limited by the development of resistance in malaria parasites to available drugs and in anopheline mosquitoes to available insecticides. Therefore, consideration of the resistance and transmission implications of antimalarial drugs and insecticides is required to optimize control policies. This project will perform surveillance for markers of antimalarial drug and insecticide resistance in Uganda, utilizing a network of established surveillance sites. These sites have undergone different interventions over time, with dramatic impacts on malaria. In addition to offering insights into the prevalence of resistance to different agents across time and space, we will assess the impacts of malaria control interventions and the epidemiology of malaria on resistance progression. We hypothesize that benefits of current malaria control measures, including effective therapies, IPT, IRS, and ITNs, will be challenged by increasing resistance in malaria parasites and anopheline vectors; that the rate of resistance development will vary depending on the degree of implementation of control measures, level of malaria transmission, and other measurable factors at different locations; that novel contributors to resistance will be identified by interrogating samples with deep sequencing approaches; and that some resistance mediators will impact upon malaria transmission. We will test these hypotheses with serial surveillance for resistance mediators in parasites and mosquitoes across Uganda; searches for associations between control interventions and factors specific to parasites and vectors; deep sequencing to identify novel resistance mediators; and measures of impacts of polymorphisms on malaria transmission. Our specific aims will be (1) to assess impacts of malaria control interventions on drug resistance, (2) to assess impacts of malaria control interventions on insecticide resistance, and (3) to characterize impacts of drug and insecticide resistance on malaria transmission. These studies will offer insights into the evolution of drug and insecticide resistance across Uganda over time, the impacts of specific malaria interventions on this evolution, and the impacts of specific resistance mediators on malaria transmission. Overall, the program will offer novel insights regarding mechanisms of resistance and inform on optimal interventions to achieve malaria elimination.