Ursodeoxycholic Acid Inhibits Porcine Pneumonia Caused by PRCV through Activating the Type Ⅰ Interferon Pathway Mediated by TLR4-IRF3

Porcine respiratory coronavirus (PRCV) is a genetic variant of Porcine transmissible gastroenteritis virus (TGEV). It is tropic exclusively to the respiratory tract and mainly manifests as atypical interstitial pneumonia and mild subclinical symptoms. Additionally, PRCV also serves as a potential animal respiratory coronavirus model for studying human respiratory coronaviruses. Research on effective antagonistic drugs for PRCV is highly important for preventing and controlling this disease. In this study, we found that Ursodeoxycholic acid (UDCA) can significantly inhibit the infection of PRCV in bronchial epithelial cells (NPTR). Further research revealed that UDCA primarily suppresses PRCV through two mechanisms: First, UDCA can directly disrupt the viral envelope components, inducing the disintegration of the viral structure; Second, UDCA can significantly promote the secretion of IFN-β in NPTR cells, enhance the phosphorylation and nuclear translocation of STAT1, and upregulate the expression of the interferon-stimulated genes ISG15 and MX1. Molecular dynamics simulations indicate that UDCA can embed into the hydrophobic pocket of the TLR4 dimerization domain, thereby activating the TLR4-IRF3 signaling pathway to induce IFN-β production and suppress PRCV infection. The TLR4 signaling pathway inhibitor Schaftoside can effectively reverse the anti-PRCV effect of UDCA. Finally, a live lung tissue slice model of piglets was established to verify that UDCA can effectively reduce the viral load and inflammatory response of PRCV in lung tissue. The findings of this study provide a scientific basis for the development of antiviral drugs targeting PRCV and offer insights into research on human respiratory coronaviruses.