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

Area of Science:

• Immunology
• Virology
• Trauma Research

Background:

• COVID-19 patients with femur fractures face a threefold mortality increase, linked to compounded inflammatory responses.
• Sex-specific immune variations in COVID-19 suggest biological sex influences disease severity in comorbid conditions.
• Understanding the inflammatory interplay is crucial for targeted therapies.

Purpose of the Study:

• To investigate the systemic, sex-specific inflammatory response in mice with concurrent fracture and murine coronavirus (MHV) infection.
• To elucidate the immune dysregulation and sex-divergent responses under dual viral-trauma insult.

Main Methods:

• Mice were subjected to fracture and/or MHV infection (a SARS-CoV-2 relative).
• Systemic immune responses, including cell recruitment and cytokine profiles, were analyzed.
• Sex-specific differences in T-cell populations (cytotoxic vs. helper) and cytokine patterns (IL-18, TNF-α, IL-2/IL-2R, CCL7, IL-4) were assessed.

Main Results:

• Combined MHV infection and fracture (MHV+FX) disrupted systemic immunity in both sexes.
• Females showed T-cell recovery towards a cytotoxic profile by Day 7, while males had persistent cytotoxic T-cell suppression.
• Sexually dimorphic cytokine patterns were observed, with females showing sustained IL-18 and TNF-α increases, and males exhibiting distinct IL-2/IL-2R modulation.

Conclusions:

• Sex-divergent immune programs, including T-cell biases and cytokine signatures, contribute to the heightened mortality risk in patients with coinciding COVID-19 and fractures.
• These findings support the development of sex-aware immunomodulatory strategies for improved outcomes in COVID-19 patients with trauma.