Grant: Discovery Grants Program - Individual

<p>While we have extensive knowledge of the lifecycle of Plasmodium parasites, and comprehensive genomic resources for host and pathogen alike, one area of need is a better understanding of why individuals vary in their response to malaria infection. Little is known about natural variation in dynamic feedback between the host and the parasite. The long-term goals of this research program are to establish a better understanding of co-evolution of the primate immune system and malaria response. Population genetic studies of whole genome sequences of the parasite have highlighted important roles for selection on genetic variation in helping to shape the pathogen's evolution. Numerous genes contributing to the evolution of host resistance are also known, including those associated with globinopathies (Hb, beta-thalassemia), metabolism, and blood groups. Much less is known about how the host and parasite influence each other's function.</p> <p>My team, with long standing collaborations at the NIAID/NIH and McGill, has been instrumental in developing the first genomic maps of malaria (P. falciparum). Here we propose to document the covariance of host and Plasmodium gene expression profiles in a large sample. An important step in this process is identifying inter-species differences in host response to different Plasmodium spp. We propose a set of parallel experiments that interrogate the gene expression of malaria hosts, and their parasites in vivo. In this proposed research we are developing a novel paradigm for analysis of the ""genomic response"" of infection in both the host and the pathogen that is applicable to studies of not just malaria but any infectious agent. Parasites genes and associated pathways differentially regulated by the host genetic background and associated with virulence will be identified. Contrasting host and parasite transcriptomes simultaneously allows us to move beyond mere documentation of clinical severity and genomic variation (in either the host or the pathogen), to generating hypotheses about how gene expression co-varies with infection types and rates as well as parasitemia, within and among populations. </p>