# 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

## TL;DR

This study shows that a prior infection with respiratory syncytial virus (RSV) can protect mice from a later SARS-CoV-2 infection by boosting immune responses in the lungs.

## Contribution

The study identifies γδ T cell-mediated trained immunity and mucosal T cell activation as novel mechanisms for RSV-induced protection against SARS-CoV-2.

## Key findings

- Prior RSV infection provides dose- and time-dependent protection against SARS-CoV-2 in mice.
- RSV activates lung antigen-presenting cells and SARS-CoV-2–reactive mucosal T cells.
- γδ T cells are essential for the protective immune response against SARS-CoV-2 following RSV infection.

## Abstract

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.

The mechanisms by which prior respiratory viral infections confer heterologous protection remain largely undefined. In this study, we investigated whether respiratory syncytial virus (RSV) infection influences host susceptibility to subsequent SARS-CoV-2 infection in mice. We found that prior RSV exposure conferred dose- and time-dependent heterologous protection against SARS-CoV-2. Mechanistically, RSV infection induces γδ T cell-mediated trained immunity, enhances antigen-presenting cell activation, and promotes the generation of SARS-CoV-2–reactive mucosal T cells. Together, these immune responses contribute to cross-protective immunity against SARS-CoV-2. Our findings offer new insights into the immunological interplay between co-circulating respiratory viruses and SARS-CoV-2, with implications for future vaccine design and pandemic preparedness.