CAREER: Genetic and Molecular Mechanisms of Parasite Infection in Insects

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Many parasites require obligatory insect hosts as part of their life cycle. Understanding the biology of host-parasite interactions, particularly at the genetic and molecular levels of analysis, is an important area of basic research because we lack an understanding of the principles of these interactions. Parasites with insect hosts must overcome insect innate immune defenses to be able to complete their life cycles, including development in the host and transmission. The molecular mechanisms underlying these interactions, and the genetic basis for variation in these interactions, are not fully understood. This project focuses on understanding host-parasite interactions in the mosquito Anopheles gambiae and the malaria-causing parasite Plasmodium falciparum to gain improved understanding of fundamental host-parasite interactions. The investigator has linked some host genetic variation with variation in the number of parasite life stages in the host, indicating variable immunity among individual insect hosts and therefore potentially differential ability to transmit the parasite. This researcher has developed a novel, computational approach to identify additional host genes associated with parasite infection, which enables the investigation of such genetic variation in immunity to parasites in natural populations of An. Gambiae, which can be more informative than studies in laboratory populations. The investigator will employ modern genomic, biochemical and computational methods in this study. This project will improve our knowledge base about the genetic basis of, and the molecular mechanisms of insect innate immunity against parasites, and more generally host-parasite interactions. An important broader scientific and societal impact of this study is improved understanding of the specific mosquito-parasite system that causes the disease malaria, which causes suffering and death in millions of people each year.Genetic analyses have demonstrated that genetic variation in Anopheles gambiae is associated with the number of Plasmodium oocysts in mosquitoes. Identifying the genes associated with variation in infection intensity and understanding how they function are important in decoding the genetic and molecular basis of insect-parasite interaction. Targeting these genes will lead to novel approaches in controlling parasite transmission. However, it is difficult to determine causative mutations from ~300 million base pairs and ~15,000 genes in the mosquito genome using traditional approaches. In a recent, significant finding, the Principal Investigator and co-workers used a novel computational approach and identified approximately 1% of the An. gambiae genome that is enriched with genes related to P. falciparum infection in mosquitoes. This research project is aimed at analysis of these newly identified genomic regions to elucidate molecular mechanisms of insect-parasite interaction using the well-characterized An. gambiae populations and P. falciparum parasites from western Kenya. Direct association studies will be systematically conducted to detect genetic variations associated with P. falciparum infection intensity in wild A. gambiae populations from Africa. Then the relative role of the candidate mosquito genes on parasite invasion will be determined under laboratory conditions and in the wild in Africa. Finally, the molecular mechanisms of candidate genes will be investigated. The combination of computational approaches, molecular functional analyses in the laboratory, and field entomology studies is a very powerful set of tools to address insect-parasite interactions. This CAREER project will integrate research and education from K-12 to graduate students, locally, nationally and internationally. K-12 students and teachers will have opportunities to learn and participate in genomics research with the investigators in this study. Seminars on insect-parasite interactions will be provided in local schools and universities. The educational seminars will also be given to the communities in Kenya where P. falciparum infection is endemic. While undergraduate and graduate students play important roles in the research, the research program also provides materials and resources for education in classrooms. Ultimately, an outstanding research program coupled with an excellent genomics curriculum will be established.