ITGA4 drives pathogenesis of flavivirus and inhibition of it protects mice against Japanese encephalitis virus infection.

Multiple studies have revealed a potential role for integrin α4 (ITGA4) in the pathogenesis of SARS-CoV-2/HIV/SIV infection, but its role in flavivirus infection remains elusive. Here, we used Japanese encephalitis virus (JEV) as a model, aiming to dissect the regulatory role of ITGA4 in flavivirus infection. We found that JEV infection activates vitamin A metabolism, which in turn induces the upregulation and activation of ITGA4. ITGA4 triggers cytoskeletal reorganization enhancing early viral replication in monocytes via the ITGA4-HSP70-pFAK-Rac1 signaling axis, and reinforces interactions between immune cells and brain microvascular endothelial cells, reducing the expression of tight junction proteins (ZO-1 and Occludin) and increasing blood-brain barrier permeability, thereby enabling viral neuroinvasion and inflammatory cell infiltration. Genetic knockdown of ITGA4 markedly reduces viral load, mitigates neuronal damage, and improves survival in JEV-infected mice. Moreover, ITGA4 enhances the replication of multiple flaviviruses (JEV, dengue virus serotype 2, Zika virus) in monocytes, highlighting a conserved pro-viral function. Collectively, this is the first report demonstrating that ITGA4 as a pivotal host factor orchestrating flavivirus pathogenesis, uncovering the novel dual mechanism through which ITGA4 links vitamin A metabolism, cytoskeletal remodeling, and blood-brain barrier (BBB) disruption to promote flaviviral neuroinvasion.