Sexual Dimorphism in Systemic Inflammatory Responses to Femur Fracture in Mice Infected with SARS-CoV-2-Like Virus

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 have been documented, implicating gender as a potential modulator of 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. Our findings reveal that the combined inflammatory incidents of MHV infection and fracture disrupt the systemic immune response in both female and male mice, leading to immune dysregulation characterized by altered cell recruitment and disruption of the normal inflammatory cascade. Notably, the study identifies sex-specific differences in immune response, with female subjects exhibiting significantly elevated levels of inflammatory cytokines, including IL-18 and TNF, while males exhibit a diminished response. These sexually dimorphic differences are also reflected in the systemic immune cell populations, suggesting that the quantity of immune factors released may contribute to the observed discrepancies. Notably, these differences were minimal or moderate in animals that either got an MHV infection or fracture alone. Our findings indicate that the overproduction of proinflammatory cytokines, such as IFN{gamma}, IL-18, and TNF--reminiscent of cytokine storm syndrome--drives immune dysregulation, exacerbating outcomes in patients with these comorbidities. The observed sex-specific responses may be influenced by factors such as sex hormones, including estrogen, highlighting the importance of considering gender in therapeutic approaches. These insights provide a foundation for the development of tailored interventions to improve outcomes for COVID-19 patients with musculoskeletal trauma, including fractures.