title: Influenza A virus enhances its propagation through the modulation of Annexin-A1 dependent endosomal trafficking and apoptosis.
abstract: The influenza virus infects millions of people each year and can result in severe complications. Understanding virus recognition and host responses to influenza infection will enable future development of more effective anti-viral therapies. Previous research has revealed diverse yet important roles for the annexin family of proteins in modulating the course of influenza A virus (IAV) infection. However, the role of Annexin-A1 (ANXA1) in IAV infection has not been addressed. Here, we show that ANXA1 deficient mice exhibit a survival advantage, and lower viral titers after infection. This was accompanied with enhanced inflammatory cell infiltration during IAV infection. ANXA1 expression is increased during influenza infection clinically, in vivo and in vitro. The presence of ANXA1 enhances viral replication, influences virus binding, and enhances endosomal trafficking of the virus to the nucleus. ANXA1 colocalizes with early and late endosomes near the nucleus, and enhances nuclear accumulation of viral nucleoprotein. In addition, ANXA1 enhances IAV-mediated apoptosis. Overall, our study demonstrates that ANXA1 plays an important role in influenza virus replication and propagation through various mechanisms and that we predict that the regulation of ANXA1 expression during IAV infection may be a viral strategy to enhance its infectivity.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore.|NUS Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
authors.forename: S
authors.initials: S
authors.lastname: Arora
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore.|NUS Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
authors.forename: W
authors.initials: W
authors.lastname: Lim
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore.|NUS Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
authors.forename: P
authors.initials: P
authors.lastname: Bist
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore.|NUS Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
authors.forename: R
authors.initials: R
authors.lastname: Perumalsamy
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore.|NUS Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
authors.forename: H M
authors.initials: HM
authors.lastname: Lukman
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore.
authors.forename: F
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore.|NUS Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
authors.forename: L B
authors.initials: LB
authors.lastname: Welker
authors.affiliation: Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore, Singapore.
authors.forename: B
authors.initials: B
authors.lastname: Yan
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore.
authors.forename: G
authors.initials: G
authors.lastname: Sethi
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore.
authors.forename: P A
authors.initials: PA
authors.lastname: Tambyah
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology & Research, Singapore, Singapore.
authors.forename: A-M
authors.initials: AM
authors.lastname: Fairhurst
authors.affiliation: NUS Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, Singapore.|Department of Microbiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore.
authors.forename: S
authors.initials: S
authors.lastname: Alonso
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore.|NUS Immunology Program, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
authors.forename: L H K
authors.initials: LH
authors.lastname: Lim
mesh_terms: D000072283:A549 Cells; D000818:Animals; D017305:Annexin A1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D009980:Influenza A virus / Q000472:pathogenicity / Q000502:physiology*; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D019590:Nucleocapsid Proteins; D009976:Orthomyxoviridae Infections / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016601:RNA-Binding Proteins / Q000378:metabolism; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014758:Viral Core Proteins / Q000378:metabolism; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: D017305:Annexin A1; D016328:NF-kappa B; C048842:NP protein, Influenza A virus; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins; C573274:annexin A1, mouse; D053148:Caspase 3