title: Influenza A viral replication is blocked by inhibition of the inositol-requiring enzyme 1 (IRE1) stress pathway.
abstract: Known therapies for influenza A virus infection are complicated by the frequent emergence of resistance. A therapeutic strategy that may escape viral resistance is targeting host cellular mechanisms involved in viral replication and pathogenesis. The endoplasmic reticulum (ER) stress response, also known as the unfolded protein response (UPR), is a primitive, evolutionary conserved molecular signaling cascade that has been implicated in multiple biological phenomena including innate immunity and the pathogenesis of certain viral infections. We investigated the effect of influenza A viral infection on ER stress pathways in lung epithelial cells. Influenza A virus induced ER stress in a pathway-specific manner. We showed that the virus activates the IRE1 pathway with little or no concomitant activation of the PERK and the ATF6 pathways. When we examined the effects of modulating the ER stress response on the virus, we found that the molecular chaperone tauroursodeoxycholic acid (TUDCA) significantly inhibits influenza A viral replication. In addition, a specific inhibitor of the IRE1 pathway also blocked viral replication. Our findings constitute the first evidence that ER stress plays a role in the pathogenesis of influenza A viral infection. Decreasing viral replication by modulating the host ER stress response is a novel strategy that has important therapeutic implications.
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA. ihab-hassan@uiowa.edu
authors.forename: Ihab H
authors.initials: IH
authors.lastname: Hassan
authors.forename: Michael S
authors.initials: MS
authors.lastname: Zhang
authors.forename: Linda S
authors.initials: LS
authors.lastname: Powers
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Shao
authors.forename: Jonas
authors.initials: J
authors.lastname: Baltrusaitis
authors.forename: D Thomas
authors.initials: DT
authors.lastname: Rutkowski
authors.forename: Kevin
authors.initials: K
authors.lastname: Legge
authors.forename: Martha M
authors.initials: MM
authors.lastname: Monick
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004722:Endoribonucleases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D007251:Influenza, Human / Q000188:drug therapy* / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018832:Molecular Chaperones / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects* / Q000502:physiology; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D000998:Antiviral Agents; D004722:Endoribonucleases; D008565:Membrane Proteins; D018832:Molecular Chaperones; D017346:Protein Serine-Threonine Kinases; D013655:Taurochenodeoxycholic Acid; D019892:eIF-2 Kinase; C497111:ATF6 protein, human; C031655:ursodoxicoltaurine; C403982:ERN2 protein, human