Name
Hypoxia increases intestinal epithelial cell susceptibility to rotavirus infection through repression of type III interferon
Presenter
Sorin Jacobs, University of Florida
Co-Author(s)
Sorin Jacobs 1, Stephanie Muenchau 2, Zina M. Uckeley 1, Gianna V. Passarelli 1, Asher David 1, Megan L. Stanifer 1*, Steeve Boulant 1,2*
1. Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL, USA
2. Department of Infectious Disease, Virology, University Hospital Heidelberg, Heidelberg, Germany
Abstract Category
Pathogenesis and Immunity
Abstract
Intestinal epithelial cells form the primary barrier against enteric viruses like rotavirus. Our study reveals that hypoxia, a natural condition in the intestinal tract, significantly increases intestinal epithelial cells susceptibility to rotavirus infection, resulting in enhanced viral replication and production. This heightened susceptibility is lost in interferon (IFN)-deficient cell lines, indicating that hypoxia alters immune responses to facilitate infection. We have found that hypoxia decreases type III IFN induction following rotavirus infection, subsequently reducing interferon-stimulated gene (ISG) expression. This hypoxia-dampened immune response extends beyond rotavirus, as hypoxia diminishes both type I and III IFN responses to various viral stimuli, suggesting a fundamental role for hypoxia in viral susceptibility within intestinal epithelial cells.
Further dissecting the mechanisms of hypoxia-mediated inhibition of IFN production, we found a reduction in phosphorylation of the master signaling molecule TBK1 and identified the protein phosphatase PP2A as a mediator in this reduction. Hypoxia results in an upregulation of the PP2A regulatory subunit PPP2R5B in intestinal epithelial cells, and a loss of this subunit rescued IFN response in hypoxia, suggesting PPP2R5B as a critical factor in regulation of host-pathogen interactions in intestinal epithelial cells. Our findings suggest hypoxia creates an immunosuppressive environment through IFN downregulation, representing a novel proviral mechanism within the gut. These results highlight the importance of incorporating physiological hypoxia in studies of intestinal innate immunity.
Further dissecting the mechanisms of hypoxia-mediated inhibition of IFN production, we found a reduction in phosphorylation of the master signaling molecule TBK1 and identified the protein phosphatase PP2A as a mediator in this reduction. Hypoxia results in an upregulation of the PP2A regulatory subunit PPP2R5B in intestinal epithelial cells, and a loss of this subunit rescued IFN response in hypoxia, suggesting PPP2R5B as a critical factor in regulation of host-pathogen interactions in intestinal epithelial cells. Our findings suggest hypoxia creates an immunosuppressive environment through IFN downregulation, representing a novel proviral mechanism within the gut. These results highlight the importance of incorporating physiological hypoxia in studies of intestinal innate immunity.