The Multifactorial Roles of Platelets in Uncomplicated Malaria Infection

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Project Summary/Abstract The malaria causing Plasmodium parasite continues to be a major public health threat, with at least 230 million annual cases worldwide. Plasmodium vivax (P vivax) is the cause of uncomplicated malaria (UCM), which while typically not deadly, is the cause of significant global morbidity and economic cost. Despite great efforts, vaccine development has proven challenging and due to growing resistance to anti-malarial drugs, complications also persist. While platelets are the cellular mediators of thrombosis, platelets are also the most numerous immune cells in the blood, and a first responder to infections. Thrombocytopenia is a frequent complication of malaria, and a decrease in platelet count is a negative predictor of disease outcome. Malaria infection elicits a strong interferon gamma (IFN) response. IFN is a potent inducer of indoleamine 2,3-dioxygenase (IDO1) the rate- limiting enzyme that catalyzes the first step in Tryptophan (Trp) metabolism in the kynurenine (Kyn) pathway. Trp metabolism may be altered in malaria infection as a means to regulate immunometabolic responses, but the mechanisms remain unknown. Our platelet RNA-sequencing data from humans infected with P vivax and from mice infected with Plasmodium yoelii showed increased expression of genes related to Trp metabolism, including IDO1. Furthermore, the role for platelets in metabolic pathway regulation is poorly explored in general, but particularly in infectious diseases. The PI introduces a novel idea that platelets participate in immunometabolism to infection. The PI has assembled a mentoring team with complementary expertise in platelets and immunology (C Morrell; primary, M Rondina), infectious diseases (C Morrell, M Rondina, L Steiner) and metabolomics (J Munger, M Rondina) to guide her research and career development (all members). The environment at the University of Rochester excels in resources, has a collegial faculty, and is noted for research achievements in infectious diseases, platelet biology and immunology. Using complementary experimental approaches such as liquid chromatography-mass spectrometry, ELISA, PCR, western blot, and flow cytometry, the PI will test the hypothesis that platelets are a source of IDO1 in UCM malaria, and thrombocytopenia results in IDO1 depletion and immune dysregulation. The PI will determine the role of platelets in Trp metabolic pathway regulation (Aim 1) and explore whether platelet regulated immune responses to malaria infection are in part dependent on the Trp metabolic pathway (Aim 2). Further understanding this interplay between platelets and biochemical pathways may provide an understanding of the impact of thrombocytopenia in diseases beyond malaria, and provide a means to improve malaria infection responses as well as improved platelet-derived therapeutics in many hematological, metabolic, and immune diseases. The research proposal contains novelty that could open new avenues for integrative research in the fields of immunology, pathology, and biochemistry at both clinical and basic science levels. The completion of the mentored activities and career development as described in the PI’s training plan will facilitate the PI’s long-term goal of becoming an independent researcher.