In vivo investigation of PEDV transmission via nasal infection: mechanisms of CD4 + T-cell-mediated intestinal infection

ABSTRACT The porcine epidemic diarrhea virus (PEDV), a highly pathogenic coronavirus, poses significant challenges to global swine agriculture with severe economic consequences. Our research reveals that in addition to known transmission routes, PEDV can be airborne, initially invading the nasal mucosa and subsequently being transported by dendritic cells and peripheral blood T cells, ultimately leading to intestinal disease in piglets. This study elucidates the cellular mechanisms behind the process, demonstrating how PEDV is internalized by CD4 + T cells after being transferred by dendritic cells, where it establishes a latent infection. Crucially, PEDV induces the upregulation of the integrin α4β7 homing receptor, facilitating the migration of these infected CD4 + T cells to the small intestine. Furthermore, our findings reveal that the activation of the α4β7-Rho-GTPases-Cofilin signaling pathway by PEDV reorganizes the actin cytoskeleton, enabling CD4 + T-cell transmigration through high endothelial venules into the intestinal mucosa, resulting in the infection of intestinal epithelial cells. These insights not only illuminate the molecular mechanisms PEDV employs to hijack CD4 + T cells for transmission from the respiratory tract to the intestine but also identify novel targets for therapeutic intervention, providing new perspectives for effectively preventing and managing PEDV infection with broader implications for controlling similar pathogens in diverse hosts. IMPORTANCE Porcine epidemic diarrhea virus (PEDV), characterized by rapid transmission and widespread prevalence, poses a significant long-term threat to the global pig farming industry. Our previous research revealed that, in addition to the classic fecal-oral infection route, PEDV can invade through the nasal mucosa, leading to intestinal infection. This study further investigated the molecular mechanisms by which the virus is transported by T lymphocytes from the respiratory tract to the intestines. We found that PEDV establishes a latent infection in CD4 + T cells and promotes their intestinal homing by upregulating the homing receptor integrin α4β7. Additionally, we elucidated the activation of the integrin α4β7-mediated Rho-GTPase-Cofilin signaling axis by PEDV, which regulates pseudopod formation and facilitates CD4 + T-cell migration to the intestinal mucosal lamina propria post-homing. This study elucidates the mechanism underlying the lymphocyte-dependent dissemination of PEDV following nasal infection, providing new insights into strategies for preventing PEDV invasion.