Respiratory syncytial virus infection induces heterologous protection against SARS-CoV-2 through γδ T cell-mediated trained immunity and the activation of SARS-CoV-2–reactive mucosal T cells

Respiratory viruses can infect hosts concurrently or sequentially, potentially influencing each other’s pathogenic trajectory. However, the underlying immune mechanisms governing these interactions remain poorly understood. In this study, we examined whether respiratory syncytial virus (RSV) infection modulates host susceptibility to subsequent SARS-CoV-2 infection using two murine models. We found that prior RSV infection conferred dose- and time-dependent heterologous protection against SARS-CoV-2. Transcriptomic and immunological analyses revealed that RSV activated lung antigen-presenting cells (APCs) and SARS-CoV-2–reactive mucosal T cells by day 9 post-infection, with responses waning by 1 month. RSV also promoted expansion of pulmonary γδ T cells and upregulation of their metabolic pathways. Notably, RSV-infected TCRδ^-/- mice, which lack γδ T cells, exhibited diminished SARS-CoV-2–reactive mucosal T cell responses, elevated viral loads, and exacerbated lung inflammation following SARS-CoV-2 challenge compared to wild-type controls. These findings suggest that RSV infection induces γδ T cell-mediated trained immunity and primes mucosal T cell responses, thereby providing heterologous protection against SARS-CoV-2.