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Simple Summary  Mouse polyomavirus (MPyV) is widely used as a model for cancer development studies. In many preceding studies, its tumorigenic potential was attributed to a virus protein called middle T antigen (MT), which possesses a transforming ability through activation of cell-associated tyrosine kinases, resulting in increased cell growth. Here, we studied the effects of the innate immune responses triggered by MPyV in mouse fibroblasts. We found that recognition of MPyV by Toll-like receptor 4 (TLR4), a sensor of the innate immunity system, induces the production of interleukin 6 (IL-6) and other cytokines without inhibiting virus multiplication. The cytokine microenvironment changed the phenotype of adjacent noninfected fibroblasts toward the cancer-associated fibroblast (CAF)-like phenotype associated with increased chemokine production and invasiveness. Thus, our data indicate that MPyV contributes to the CAF-like phenotype in mouse fibroblasts via a TLR4-driven inflammatory response.    Abstract  The tumorigenic potential of mouse polyomavirus (MPyV) has been studied for decades in cell culture models and has been mainly attributed to nonstructural middle T antigen (MT), which acts as a scaffold signal adaptor, activates Src tyrosine kinases, and possesses transforming ability. We hypothesized that MPyV could also transform mouse cells independent of MT via a Toll-like receptor 4 (TLR4)-mediated inflammatory mechanism. To this end, we investigated the interaction of MPyV with TLR4 in mouse embryonic fibroblasts (MEFs) and 3T6 cells, resulting in secretion of interleukin 6 (IL-6), independent of active viral replication. TLR4 colocalized with MPyV capsid protein VP1 in MEFs. Neither TLR4 activation nor recombinant IL-6 inhibited MPyV replication in MEFs and 3T6 cells. MPyV induced STAT3 phosphorylation through both direct and MT-dependent and indirect and TLR4/IL-6-dependent mechanisms. We demonstrate that uninfected mouse fibroblasts exposed to the cytokine environment from MPyV-infected fibroblasts upregulated the expressions of MCP-1, CCL-5, and α-SMA. Moreover, the cytokine microenvironment increased the invasiveness of MEFs and CT26 carcinoma cells. Collectively, TLR4 recognition of MPyV induces a cytokine environment that promotes the cancer-associated fibroblast (CAF)-like phenotype in noninfected fibroblasts and increases cell invasiveness.

TLR4-Mediated Recognition of Mouse Polyomavirus Promotes Cancer-Associated Fibroblast-Like Phenotype and Cell Invasiveness