Respiratory syncytial virus infection induces heterologous protection against SARS-CoV-2 via induction of trained immunity and SARS-CoV-2 reactive mucosal T cells

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 both BALB/c and the K18 hACE-2 transgenic mouse models. We found that RSV infection- induced heterologous protection against subsequent SARS-CoV-2 infection was dose and time dependent. RNA-seq and immunological analyses revealed that RSV infection triggered antigen presenting cell (APC)s and SARS-CoV-2 reactive mucosal T cell activation in the lung at day 9, which declined at 1 month. RSV infection induced the expansion and the upregulation of cellular metabolic pathways of gd T cells. Furthermore, RSV infection in TCRd-/- mice, which are deficient of gd T cells triggered a lower SARS-CoV-2 reactive mucosal T cell response. Following SARS-CoV-2 infection, TCRd-/- mice with prior RSV infection had increased viral loads and higher levels of virus-induced inflammatory responses in the lung compared to the WT group. In summary, our results suggest that RSV infection provides heterologous protection against subsequent SARS-CoV-2 infection via induction gd T cell- mediated trained immunity in the lung and SARS-CoV-2 reactive mucosal T cell responses.