H1N1 Influenza Virus Cross-Activates Gli1 to Disrupt the Intercellular Junctions of Alveolar Epithelial Cells

Tao Ruan,Jing Sun,Wei Liu,Richard A Prinz,Daxin Peng,Xiufan Liu,Xiulong Xu

doi:10.1016/j.celrep.2020.107801

Abstract

Influenza A virus (IAV) primarily infects the airway and alveolar epithelial cells and disrupts the intercellular junctions, leading to increased paracellular permeability. Although this pathological change plays a critical role in lung tissue injury and secondary infection, the molecular mechanism of IAV-induced damage to the alveolar barrier remains obscure. Here, we report that Gli1, a transcription factor in the sonic hedgehog (Shh) signaling pathway, is cross-activated by the MAP and PI3 kinase pathways in H1N1 virus (PR8)-infected A549 cells and in the lungs of H1N1 virus-infected mice. Gli1 activation induces Snail expression, which downregulates the expression of intercellular junction proteins, including E-cadherin, ZO-1, and Occludin, and increases paracellular permeability. Inhibition of the Shh pathway restores the levels of Snail and intercellular junction proteins in H1N1-infected cells. Our study suggests that Gli1 activation plays an important role in disrupting the intercellular junctions and in promoting the pathogenesis of H1N1 virus infections.

Highlights

Alveolar epithelial and vascular endothelial cells form a natural barrier to prevent protein and other substances from infiltrating into the alveoli and developing edema (Short et al, 2016)
We evaluated the ability of Influenza A virus (IAV) to regulate the expression of these two transcription factors and their downstream target genes
We further showed that CA09, a pandemic H1N1 strain, increased the levels of Gli1 and Snail proteins but decreased the levels of E-cadherin, Occludin, and ZO-1 proteins in A549 cells (Figure S2)

Summary

Introduction

Alveolar epithelial and vascular endothelial cells form a natural barrier to prevent protein and other substances from infiltrating into the alveoli and developing edema (Short et al, 2016). The tight junction is formed largely by the members of the Occludin or Claudin families, both of which contain four circular transmembrane proteins (Herrero et al, 2018; Van Itallie and Anderson, 2018; Wittekindt, 2017). The cytoplasmic regions of the tight junction and adherens junction contain structural proteins that bind to the adaptor protein ZO-1, which interacts with actin to form filaments to increase the stability of the junctional structure (Herrero et al, 2018; Van Itallie and Anderson, 2018; Wittekindt, 2017)

Results

Discussion

Conclusion