Impact of Antimalarials on Parasite Selection Through the Mosquito Vector

Malaria remains a significant global infectious disease burden. Common prevention strategies include vector control measures and long-acting chemoprevention for the most at-risk populations. Recently, World Health Organization guidelines for use of preventative antimalarials have expanded, both for demographic groups and regions where chemoprevention is acceptable. Data suggest mosquitoes refeed frequently in their lifespan. More population-wide drug use thus raises questions about mosquito antimalarial ingestion via human bloodmeals, and whether this could affect mosquitoes and/or parasites developing within them – a largely unexplored topic. Plausibly, antimalarials could affect parasite development and drug resistance selection within the mosquito, with critical drug resistance transmission implications. I have developed an experimental model for mosquito antimalarial exposure and have found detectable drug levels in mosquito circulatory fluid (hemolymph) several days post drug exposure, highlighting this phenomenon as an important and innovative area of study that I now propose to expand into P. falciparum-infected mosquitoes. Here, I will investigate the effect of antimalarials on parasite development, strain complexity, and drug resistance propagation within the vector. My overarching hypothesis is that antimalarials taken by humans can exert selective pressure on parasites progressing through vector stages. Broadly, my aims include assessing the impact of commonly deployed long-acting antimalarials on 1) basic mosquito fitness and vector-stage parasite development and 2) parasite genomic strain complexity and drug-resistant allele selection within mosquitoes. Combining use of controlled lab parasite and mosquito strains, as well as previously collected field samples from Burkina Faso and Senegal, will allow comprehensive analysis of mosquito antimalarial uptake and its consequences. My work will help inform mass treatment strategies and drivers of resistance, with research contributing to future work on malaria transmission-blocking strategies. I am a physician-scientist with a background in infectious disease bench research and global health. My career goal is to become an independently funded project leader researching infectious diseases affecting resource- limited settings, focusing on malaria. The proposed training will build expertise necessary to carry out the proposed project, including skills in bioinformatics and genomic analysis, malaria vector-stage pathogenesis and entomology research, and leadership and professional skills to run clinical studies and foster a successful academic career. My mentors support me with their expertise in malaria pharmacology, genomic epidemiology, and vector biology. I have a unique access to world-class lab resources at Yale and previously collected field samples from Burkina Faso and Senegal which will allow me to answer my research questions. My PhD background in blood-stage malaria pathogenesis is strong, but further training in vector and genomics research will further shape me into a well-rounded malariologist with an important niche and potential for R01 success.