Role of extracellular vesicles in assaying and regulating immune dysfunction after burn injury

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ABSTRACT The research and training plan put forth in this NRSA Individual Predoctoral Fellowships to Promote Diversity in Health-Related Research (F31) Award will support our pre-doctoral candidate Micah LaTrell Willis, a current third year graduate student at the University of North Carolina at Chapel Hill. We received a Diversity Supplement for a NIGMS R01 Award (R01GM131124) which enabled Mr Willis to receive continued support, and he has performed excellently. This Research Plan and the Training Plan submitted will provide Mr. Willis with opportunities to not only build an intellectual and technical toolbox to propel him towards the next phase of his trainee/development but provide him the career development opportunities to ensure he obtains his short and long-term career goals. Thus, support from this this F31 will empower Mr. Willis to own and drive his research, training, and career development plans. Burn injury is one of the most devastating forms of trauma, with high mortality rates up to 12% due to complications such as organ failure, pneumonia, and infections of other organs. Burn injury results in biphasic systemic immune dysfunction. First, an early (0-72 hours) hyper-inflammatory state, with increased release of immunostimulatory Damage Associated Molecular Patterns (DAMPs) and pro-inflammatory cytokines which can lead to barrier dysfunction and multiple organ failure. Following this is an immunosuppressive phase (weeks / months after injury) associated with widespread increased susceptibility to infection. This immunosuppressed phase is associated with anti-inflammatory cytokines and increased frequency of peripheral myeloid-derived suppressive cells (MDSC) from the bone marrow, which have been shown to play key immunoregulatory roles after traumatic injury by suppressing T cell responses and regulating cytokine production. There is a critical need to characterize this cell type further in burn injury and define the mechanism of their generation after burn injury. Extracellular vesicles have emerged as novel mediators of immune dysfunction across several immune pathologies. Extracellular vesicles (EV) carry DAMPs, cytokines, and miRNAs, to regulate functions of recipient cells. We have found that EVs are a key reservoir for DAMPs, cytokines, and potent immune complexes after burn injury in humans and mice. Given our findings, and the key role of EVs in multiple immune conditions, we hypothesize that EVs drive the immune dysfunction associated with poor clinical outcomes in severe burn injury. Using same patient and mouse tissue (utilizing our established pre-clinical model of burn injury, and repository of collected human burn patient samples) that we have collected we aim to further characterize the payload, to determine their use as biomarkers of immune dysfunction, and immune function (Aim 1) and effect of cellular homeostasis (Aim 2) of EVs isolated from plasma after injury.