The Mechanism of PEDV-Induced Exosomes from Intestinal Epithelial Cells Inhibiting Macrophage Migration and Phagocytic Function

Virus-induced inflammation has long served as a canonical hallmark of host immune activation. Paradoxically, the same pathogen can sculpt an immunosuppressive milieu that accelerates its own dissemination. Here we show that, although porcine epidemic diarrhea virus (PEDV) rapidly triggers intestinal epithelial cells to secrete pro-inflammatory cytokines and chemokines—thereby amplifying epithelial–macrophage crosstalk and engaging RIG-I and Toll-like receptor signaling in macrophages—the cells’ phagocytic, endocytic, and lysosomal effector pathways are markedly repressed. Mechanistic dissection revealed that PEDV-infected epithelial cells release exosomes that potently inhibit macrophage migration and phagocytosis. Exosomal miR-190a, induced by PEDV, targets tropomodulin-3 (TMOD3), disrupting actin capping, reducing cellular stiffness and adhesion, and consequently impairing macrophage motility. Concomitantly, PEDV-induced exosomal lncRNA TS-2083 binds ANXA2, facilitating its ubiquitin-dependent degradation and disrupting phagocytic-cup formation, thereby attenuating macrophage engulfment. Notably, after oral PEDV challenge, piglet serum contains circulating exosomes enriched in miR-190a and lncRNA TS-2083 that recapitulate the same inhibitory effects on macrophage migration and phagocytosis. Our findings reposition PEDV immune evasion from “interferon antagonism” to “cross-cell communication reprogramming,” providing a new theoretical framework and translational roadmap for dissecting pathogenesis and designing host-directed interventions against porcine coronaviruses and other mucosa-tropic viruses.