Employing Genetic and Genomic Surveillance to Reveal Mechanisms of Malaria Parasite Persistance

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Abstract With the support of this K01, Dr. Amy Bei will pursue her career goal of conducting cutting-edge tropical diseases research in the United States and overseas, in close collaboration with resident scientists in malaria endemic countries. Dr. Bei's research focuses on applied international public health, and lies at the intersection between population genetics, genomics, epidemiology, molecular genetics, and immunology. She will use a translational systems biology approach to study the impact of antigenic diversity on immune evasion and vector transmission. The mentorship and training proposed here will facilitate her transition to an independent researcher, working towards the goal of an effective, diversity-transcendent vaccine for malaria. As an established member of two scientific communities, Dr. Bei contributes to the activities of the Harvard Malaria Initiative at HTHCSPH and the Broad Institute, which provide the technical innovation and scientific resources needed to augment her growth as a scientist, and to those of the greater malaria research community of Dakar, Senegal, which is represented by the Institute Pasteur Dakar, University Cheikh Anta Diop, National Malaria Control Program, and PATH: MACEPA. While based at Le Dantec Hospital in the laboratories of Drs. Daouda Ndiaye and Souleymane Mboup, Dr. Bei has guided both malaria training and research activities for the past 5 years. Dr. Bei will assess the impact of genetic diversity on the development of immunity and dynamics of vector transmission in malaria endemic West Africa, while gaining expertise in the analytical tools needed to process complex genomic and transcriptomic data. She will conduct these studies under the expert guidance of U.S. mentor Dr. Dyann Wirth, Department Chair of Immunology and Infectious Diseases at the Harvard School of Public Health, a leader in malaria biology with extensive experience in studying parasite genetics, elucidating mechanisms of drug resistance, and developing advanced genomic approaches; Senegal mentor Dr. Daouda Ndiaye, Chief of the Laboratory of Parasitology-Mycology at Le Dantec Hospital, a recognized leader in infectious diseases research on antimalarial drug resistance and malaria parasite diversity; co-mentor Dr. Carole Long, Chief of the Malaria Immunology Section, LMVR, NIAID, NIH and director of the Malaria Vaccine Reference Center; and co-mentor Dr. Rick Fairhurst, Chief of the Malaria Pathogenesis and Human Immunity Unit, LMVR, NIAID, NIH. Both co-mentors have extensive expertise in performing longitudinal cohort studies, standardizing immune and drug resistance assays, and evaluating malaria vaccines. Antigenic diversity plays a major role in immune evasion, potentially compromising the development of natural or vaccine induced protective immunity. In Senegal, parasites with identical genotypes are found to increasingly infect multiple individuals in the population. This unique observation provides an unprecedented opportunity to test if individuals develop variant-specific immunity to the parasite genotypes to which they have been previously exposed. Alternatively or additionally, such persisting parasite genotypes may preferentially transmit to the mosquito vector or may be overrepresented in asymptomatic reservoirs. Such hypotheses can only be tested in a disease endemic setting in which patients can be monitored longitudinally, parasite genotypes can be tracked spatiotemporally in real-time, and robust correlates of immunity and transmission can be measured ex vivo. Dr. Bei will assess the effector function of naturally acquired IgG to specific parasite genotypes in growth inhibition assays (GIAs), variant surface antigen (VSA) recognition assays, and opsonophagocytosis assays, over time in a Senegalese longitudinal cohort, as well as the parasites' transmission potential for Anopheles mosquitoes. The proposed studies require the cohesion of cutting-edge genomic technologies, a well characterized longitudinal cohort to follow infection evolution and immunity development, standardized assays to serve as in vitro correlates of immune protection and transmission, and strong ties to endemic country scientists and institutions. Dr. Bei is uniquely positioned to combine these critical requirements to investigate the implications of parasite diversity on the development of protective immunity. Ultimately, this knowledge will be essential to developing a diversity-transcendent malaria vaccine.