Cmss1 limits FMDV infection by enhancing antigen presentation and CD8⁺ T cell responses

The foot and mouth disease virus (FMDV) poses a heavy burden on the global swine industry, underscoring the urgent need for long-term protective vaccines to control FMDV infection. Dendritic cells (DCs) are critical in activating innate immune cells and initiating adaptive immune responses. However, the role of DCs in FMDV infection remains poorly understood. In this study, we developed a mouse model lacking the type I interferon receptor for infection, followed by single-cell RNA sequencing to generate a high-resolution map of DCs in the spleens of FMDV-infected mice. Next, we established an evaluation system to investigate the antigen-presenting capacities of gene-edited DCs and mice. The results reveal that FMDV infection alters the proportions of DC subsets and significantly suppresses antigen processing and presentation. Additionally, we identified Cmss1 as a novel host factor that antagonizes the inhibition of the antigen-presenting process caused by FMDV infection, thereby limiting FMDV pathogenicity in mice. These findings provide valuable insights into potential antiviral strategies against FMDV infection.IMPORTANCEIn this study, we first developed C57BL/6 mice lacking the type I interferon receptor as an infectious model, which was subjected to single-cell RNA sequencing analysis of DC features in response to FMDV infection. We identified VP41_9-30 as an immunodominant CD8⁺ T cell epitope of FMDV and established an in vitro system to evaluate the antigen-presenting capacities. Based on these findings, we validate Cmss1 as a novel host factor in antigen processing and presentation during FMDV infection. Since DCs play critical roles in mediating immune responses, our findings comprehensively characterize the immune features of dendritic cells for the first time and present a new mechanism through which the host defends against FMDV infection, suggesting Cmss1 as a novel potential target for antiviral therapies.