Abstract
The respiratory viruses can concurrently or sequentially infect a host and influence the trajectory of each other. The underlying immune mechanisms are not well understood. Here, we investigated whether respiratory syncytial virus (RSV) infection affects host vulnerability to subsequent SARS-CoV-2 infection in two murine models of SARS-CoV-2 infection. We found that prior RSV infection-induced heterologous protection against subsequent SARS-CoV-2 infection was dose and time dependent. RNA-seq and immunological analyses revealed that RSV triggered the activation of lung antigen presenting cells (APC)s and SARS-CoV-2 reactive mucosal T cells at day 9, which declined at 1 month. RSV also induced the expansion of lung γδ T cells and the upregulation of their cellular metabolic pathways. Furthermore, RSV infection in TCRδ (-/-) mice, which are deficient of γδ T cells, resulted in a reduced SARS-CoV-2 reactive mucosal T cell response and subsequent increased viral loads and higher levels of virus-induced inflammatory responses in the lung upon SARS-CoV-2 challenge compared to the wild-type mice. In summary, our findings suggest that RSV infection provides heterologous protection against the subsequent SARS-CoV-2 infection via induction of γδ T cell-mediated trained immunity in the lung and SARS-CoV-2 reactive mucosal T cell responses.