Dendritic Cells Undergo Cytoskeletal, Adhesive, and Inflammatory Remodeling During Productive Infection with Vaccinia Virus Western Reserve

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that regulate key aspects of innate and adaptive immunity. Their functions rely on dynamic cytoskeletal remodeling and specialized adhesive structures, including podosomes and focal adhesions (FAs), which coordinate cell–matrix interactions, antigen sampling, and migration to lymphoid organs, where DCs initiate T-cell responses. Non-pathogenic or attenuated vaccinia virus (VACV) strains can modulate DC functions despite undergoing abortive infection in these cells. However, the capacity of VACV Western Reserve (VACV-WR), a pathogenic and highly mouse-adapted strain with pronounced virulence in murine models, to productively infect DCs and its effects on their cytoskeletal organization, adhesive properties, and immune functions remain poorly characterized. Here, we demonstrate that VACV-WR completes its replication cycle and produces infectious progeny virions in murine GM-CSF-derived bone marrow DCs (BMDCs). Such productive infection promotes the phenotypic maturation of BMDCs with a limited pro-inflammatory response and induces rapid podosome disassembly accompanied by increased FA number and length. Consequently, podosome-dependent extracellular matrix (ECM) degradation was abolished in infected cells. Despite pronounced morphological and adhesive remodeling, VACV-WR infection did not significantly alter mean BMDC migration distance or speed in the two-dimensional assay, although time-lapse analysis revealed a significantly increased proportion of stationary cells. These findings indicate that VACV-WR induces the coordinated cytoskeletal, adhesive, and immunological reprogramming of BMDCs, with functional consequences for ECM remodeling but not basal motility.