Uncovering the Role of Platelets in Anti-Aspergillus Immune Defense

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PROJECT SUMMARY/ABSTRACT. This proposal describes a mentored two-year training plan that will provide the applicant with broad training in fungal pathogenesis, platelet biology, cellular immunology, and microscopy to develop a career as an investigator in infectious disease research. The sponsor’s and co-sponsor’s broad clinical and laboratory expertise in modeling and analyzing immune responses to microbial pathogens, the inclusion of a training committee with expertise in platelet biology, the dedicated training plan, and institutional strengths in immunology and microbial pathogenesis all contribute to an outstanding training environment and high likelihood of success. Aspergillus fumigatus is a filamentous mold and opportunistic human pathogen. Every day, humans inhale hundreds of airborne A. fumigatus conidia or vegetative spores. In immune competent hosts, innate immune cells, such as neutrophils, are recruited to the lungs, and clear the infection. In immune compromised hosts, conidia can escape inactivation, germinate into tissue-invasive hyphae and cause invasive aspergillosis (IA). Because standard of care treatment still results in high mortality, there is an unmet medical need to understand the host response to infection. Beyond the established roles of neutrophils, thrombocytopenia has recently been identified as a risk factor for IA. The in vivo role of platelets in the context of the antifungal immune response remains an open question. The Hohl lab is particularly well equipped for me to train in this area and to address this question. My preliminary data suggests that thrombocytopenia impairs host survival in two independent mouse models. In addition, thrombocytopenia increases tissue damage and impacts the antifungal activities of neutrophils by reducing conidial uptake. My training and research objective is to integrate the role of platelets in the context of the pulmonary antifungal immune response and to acquire training in the technical disciplines needed for these studies. I hypothesize that platelets are necessary for murine survival due to their functions in maintaining hemostasis, tissue integrity, and regulating phagocyte function and microbicidal activity. Specific Aim 1 of the proposed research will define the roles of platelets in anti-Aspergillus host defence at a cellular level. By using complementary models of thrombocytopenia and fluorescent labeling of platelets, I will uncover the relative contributions of platelet interactions, platelet cross-talk with immune effector cells, and platelet-mediated tissue integrity to host survival. Specific Aim 2 of the proposed will identify molecular mechanisms of platelet-mediated host defence. Using candidate-gene and unbiased approaches, I will uncover novel regulators of platelet-driven anti-Aspergillus immunity. The implications of these studies will lead to novel therapeutic approaches for invasive aspergillosis.