Cell Reports
Volume 31, Issue 13, 30 June 2020, 107801
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Article
H1N1 Influenza Virus Cross-Activates Gli1 to Disrupt the Intercellular Junctions of Alveolar Epithelial Cells

https://doi.org/10.1016/j.celrep.2020.107801Get rights and content
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Highlights

  • H1N1 virus cross-activates Gli1 by the PI3 and MAP kinase pathway

  • Gli1 induces Snail expression and decreases intercellular junction protein levels

  • Gli1 activation leads to the damage of the alveolar epithelial barrier

  • Gli1 activation leads to increased inflammatory cell infiltration in the lung

Summary

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.

Keywords

influenza A virus
Gli1
epithelial junctions
PI3 kinase
MAP kinase
Snail
E-cadherin
ZO-1
Occludin

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