title: Bik Mediates Caspase-Dependent Cleavage of Viral Proteins to Promote Influenza A Virus Infection.
abstract: Influenza virus induces apoptosis in infected cells to promote viral replication by manipulating the host cell death signaling pathway. Although some Bcl-2 family proteins play a role in the replication of influenza A virus (IAV), the role of cell death pathways in the viral replication cycle is unclear. We investigated whether deficiency of the proapoptotic Bcl-2 family protein, Bik, plays a role in IAV replication. IAV replication was attenuated in mouse airway epithelial cells (MAECs) from bik(-/-) compared with bik(+/+) mice, as indicated by reduced viral titers. Bik(-/-) MAECs showed more stable transepithelial resistance after infection than did bik(+/+) MAECs, were less sensitive to infection-induced cell death, and released fewer copies of viral RNA. Similar results were obtained when Bik expression was suppressed in human airway epithelial cells (HAECs). Bik(+/+) mice lost weight drastically and died within 8 days of infection, whereas 75% of bik(-/-) mice survived infection for 14 days and were 10-fold less likely to die from infection compared with bik(+/+) mice. IAV infection activated caspase 3 in bik(+/+) but not in bik(-/-) MAECs. Cleavage of viral nucleoprotein and M2 proteins were inhibited in bik(-/-) MAECs and when caspase activation was inhibited in HAECs. Furthermore, Bik deficiency impaired cytoplasmic export of viral ribonucleoprotein. These studies suggest a link between Bik-mediated caspase activation and cleavage of viral proteins. Thus, inhibition of proapoptotic host factors such as Bik and downstream mediators of cell death may represent a novel approach to influenza treatment.
authors.affiliation: 1 Chronic Obstructive Pulmonary Disease Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Yohannes A
authors.initials: YA
authors.lastname: Mebratu
authors.affiliation: 2 Department of Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama Birmingham, Birmingham, Alabama.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tipper
authors.affiliation: 1 Chronic Obstructive Pulmonary Disease Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Hitendra S
authors.initials: HS
authors.lastname: Chand
authors.affiliation: 1 Chronic Obstructive Pulmonary Disease Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Walton
authors.affiliation: 2 Department of Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama Birmingham, Birmingham, Alabama.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Harrod
authors.affiliation: 1 Chronic Obstructive Pulmonary Disease Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico.
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Tesfaigzi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D056809:Alveolar Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism*; D016923:Cell Death; D002642:Chick Embryo; D003593:Cytoplasm / Q000378:metabolism; D004285:Dogs; D004789:Enzyme Activation; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D007251:Influenza, Human / Q000378:metabolism* / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000378:metabolism* / Q000821:virology; D012261:Ribonucleoproteins / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; C111741:Bik protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D012261:Ribonucleoproteins; D014764:Viral Proteins; D053148:Caspase 3
keywords: Bcl-2 family protein; Bik; caspase; influenza A virus infection; mice