Protection Against Nosocomial Infections After Severe Burn Injury Through Trained Immunity

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PROJECT SUMMARY Nosocomial infections remain the leading cause of death in severely burned patients due to barrier loss, im- paired immunity, and high prevalence of antibiotic resistant pathogens. Immunomodulatory strategies aimed at augmenting the host response are greatly needed. Evidence suggests that Toll-like receptor (TLR) agonists hold strong promise as immunotherapeutic agents to achieve that goal. Priming with TLR4 agonists enhances resistance against a variety of clinically relevant infections associated with severe burn injury in mice via induc- tion of “trained immunity” whereby innate immune cells become more responsive to subsequent infectious stimuli. TLR4-mediated trained immunity is characterized by metabolic reprogramming and mitochondrial ex- pansion in macrophages which boost antimicrobial responses. Cellular signaling mechanisms responsible for TLR-mediated trained immunity and the effect of burn injury on metabolic and mitochondrial function in innate leukocytes remains to be elucidated. Our research program aims to investigate immunomodulatory therapies for prevention of infection following severe burn by elucidating burn-induced immunometabolic dysfunction and the potential for triggering trained immunity for protection after burn. To achieve these goals, we will pursue three integrated projects: Project 1 will investigate the impact of severe burn and post-burn infection on myeloid cell immunometabolism and mitochondrial function. We will assess metabolic, mitochondrial, and antimicrobial function using a variety of techniques including glycolytic and oxidative stress capacity, mitochon- drial content and function analyses, and differential gene expression in mouse and human leukocytes after burn. This project will expand our understanding of molecular mechanisms behind burn-induced leukocyte dys- function. Project 2 will evaluate mechanisms by which TLR agonists induce trained immunity in leuko- cytes after burn. We will use genetic modification, TLR signaling pathway-selective agonism, and signaling pathway blockade to investigate the molecular mechanisms involved in TLR-mediated induction of trained im- munity after burn. We will examine the ability of TLR agonists to induce trained immunity in leukocytes from burn patients. This project will fill critical gaps in our understanding of mechanisms by which we can improve resistance to infections in burn patients. Project 3 will elucidate the potential of targeting TLR-signaling pathways for therapeutic benefit in clinically relevant models of burn-associated infection. We will de- termine the efficacy of clinically applicable TLR agonists in conferring protection against a variety of pathogens prevalent in burn patients. We will evaluate protection duration, extension of protection upon repeated therapy, and whether TLR agonists can promote infection clearance after infection onset. This project will reveal poten- tial drug targets that should be considered for clinical development for mediating protection against nosocomial infections in burn patients. These projects will enhance our understanding of burn-induced innate immune dys- function and identify therapeutic targets to improve immunity and protect against burn-related infections.