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
Affiliations
Tao Ruan
College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC
Jing Sun
College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC; Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC
Wei Liu
College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC; Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC
Richard A. Prinz
Department of Surgery, NorthShore University Health System, Evanston, IL 60201, USA
Daxin Peng
Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, PRC; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC
Xiufan Liu
Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, PRC; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC
Xiulong Xu
College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC; Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC; Institutes of Agricultural Science and Technology Development, Yangzhou University, Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC; Corresponding author
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.
