Role of post-sepsis exercise therapy in regulating CD4 T cell immunity against secondary Pseudomonas aeruginosa infection - Summary Sepsis survivors often develop persistent immunosuppression predisposing them to recurrent infections, which are the primary cause of rehospitalization and death. There is currently no effective approach to reverse post-sepsis immunosuppression. Emerging studies have shown that physical exercise therapy modulates the immune response to improve the outcomes of various diseases, suggesting physical exercise therapy may regulate post-sepsis immune recovery. Although the benefits of physical exercise therapy in sepsis recovery are recognized, there is a knowledge gap in the cellular and molecular mechanisms underlying the benefits of physical exercise therapy in the recovery of post-sepsis immunosuppression. With the increase in the early survival rate of sepsis, the implications of post-sepsis care in healthcare are growing. There is a critical need to understand the mechanisms underlying the effect of exercise on post-sepsis immunosuppression to develop and standardize exercise-based strategies for sepsis patients to prevent and treat recurrent infections and thus improve the life quality of sepsis survivors and alleviate the healthcare burden. Furthermore, sepsis survivors often have impairment in exercise capacities and cannot meet the minimum requirement for achieving the benefits of physical exercise therapies. Lacking mechanistic insights into the exercise-induced beneficial effects impedes developing exercise-mimicking strategies to translate the benefit of exercise therapy into exercise- intolerant sepsis survivors. Our preliminary data suggested that four-week post-sepsis exercise therapy (PSET) protected mice surviving after polymicrobial sepsis from secondary pseudomonas aeruginosa (PA) infection- induced lung injury via enhancing CD4 T cell immunity. Therefore, we hypothesize that PSET reverses immunosuppression via modulating CD4 T cell immunity against secondary PA infection. Here, in Aim 1, we will determine the impact of PSET on CD4 T cell immunity against secondary PA infection. Exercise is known to modulate immune response across tissues via releasing humoral immunoregulator factors called exerkines. Therefore, in Aim 2, we will delineate the association between exerkines and PSET-induced protection (survival, lung injury, CD4 T cell immunity) against PA infection. Furthermore, we will validate our mouse findings from both aims with human circulating CD4 T cells and plasma attained from sepsis survivors with and without PSET in our clinical trial (NCT05784740). The proposed studies represent essential first steps toward completing our long-term goal, which is to understand mechanisms underlying the regulation of PSET in immunosuppression and thus to standardize exercise therapies and devise exercise-mimicking strategies, so-called “exercise in a pill”, for sepsis patients, especially exercise-intolerance patients, to prevent and treat recurrent infections. Successfully completing this application will open a new research direction on PSET in post-sepsis immune recovery. Results from these studies will guide the development of exercise analytics in clinical practice and help us to identify targets for designing PSET-mimic to reverse immunosuppression.
