Abstract
Patients with femur fractures who are concurrently infected with COVID-19 face a threefold increase in mortality, likely due to a compounded inflammatory response. Furthermore, sex-specific differences in immune responses to COVID-19 are well documented, implicating biological sex as a factor that can modulate disease severity in these comorbid conditions. Understanding the inflammatory interplay underlying this association is critical for the development of effective, targeted therapies to mitigate mortality. In this study, we investigated the systemic, sex-specific inflammatory response in mice that sustain a fracture while infected with a murine coronavirus (MHV), which belongs to the same genus as SARS-CoV-2. The combined inflammatory insults of MHV infection and fracture (MHV + FX) disrupted systemic immunity in both females and males, producing immune dysregulation characterized by altered cell recruitment and a perturbed inflammatory cascade. In the MHV + FX group, females showed recovery toward a cytotoxic T cell dominant profile by Day 7, whereas males exhibited persistent cytotoxic T cell suppression with relatively higher T helper cells. Cytokine patterns were also sexually dimorphic: females displayed sustained increases in IL-18 and TNF-α in the MHV + FX group alone, whereas males showed distinct modulation of IL-2/IL-2R and transient changes in chemokines such as CCL7 and IL-4 in both the MHV and MHV + FX groups. Notably, these differences were minimal or moderate in control or fracture alone groups. Our findings indicate that sex-divergent immune programs under a dual viral-trauma insult, marked by cytotoxic vs helper T-cell biases and distinct cytokine signatures, help explain the heightened risk when COVID-19 and fractures coincide. These insights support sex-aware immunomodulatory strategies to improve outcomes for COVID-19 patients with musculoskeletal trauma.