Newcastle disease virus promotes spreading infection through vimentin-dependent tight junction injury mediated by MLC/p-MLC activation

Abstract

Newcastle disease virus (NDV), a widespread poultry pathogen, spreads efficiently via the respiratory tract. However, the precise mechanism governing its spreading infection remains unclear. This study reveals that NDV-induced tight junction (TJ) injury is crucial for viral replication and spread. NDV infection significantly reduced TJ proteins OCLN and ZO-1 through multiple degradation pathways involving viral proteins, disrupting TJ integrity and promoting cell migration. Knockdown of OCLN and ZO-1 further enhanced viral replication and spread, underscoring their importance. Concurrently, NDV altered the distribution of OCLN and ZO-1, accompanied by cytoskeletal rearrangements of vimentin and F-actin. Notably, NDV triggered vimentin and F-actin rearrangement to form cage-like structures, benefiting TJ injury and viral replication. Critically, vimentin rearrangement was essential for the redistribution of OCLN, ZO-1, and F-actin, facilitating viral replication, spread, and inflammation. MLC/p-MLC activation was required for vimentin-mediated TJ injury, thereby promoting NDV replication and spread. Unlike avirulent strains, the virulent NDV promoted replication and spread through vimentin-mediated TJ injury, subsequently worsening lung damage in chickens. These findings elucidate how NDV rapidly disseminates and worsens lung damage, providing insights relevant to the pathogenesis and treatment of viral pneumonias, including those caused by coronaviruses and influenza viruses.