title: OX40 ligand newly expressed on bronchiolar progenitors mediates influenza infection and further exacerbates pneumonia.
abstract: Influenza virus epidemics potentially cause pneumonia, which is responsible for much of the mortality due to the excessive immune responses. The role of costimulatory OX40-OX40 ligand (OX40L) interactions has been explored in the non-infectious pathology of influenza pneumonia. Here, we describe a critical contribution of OX40L to infectious pathology, with OX40L deficiency, but not OX40 deficiency, resulting in decreased susceptibility to influenza viral infection. Upon infection, bronchiolar progenitors increase in number for repairing the influenza-damaged epithelia. The OX40L expression is induced on the progenitors for the antiviral immunity during the infectious process. However, these defense-like host responses lead to more extensive infection owing to the induced OX40L with α-2,6 sialic acid modification, which augments the interaction with the viral hemagglutinin. In fact, the specific antibody against the sialylated site of OX40L exhibited therapeutic potency in mitigating the OX40L-mediated susceptibility to influenza. Our data illustrate that the influenza-induced expression of OX40L on bronchiolar progenitors has pathogenic value to develop a novel therapeutic approach against influenza.
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Taizou
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan kikuchi@med.niigata-u.ac.jp.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tode
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Arif
authors.initials: A
authors.lastname: Santoso
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Mitsuhashi
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Riyo
authors.initials: R
authors.lastname: Komatsu
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawabe
authors.affiliation: Kanonji Institute, The Research Foundation for Microbial Diseases of Osaka University, Kanonji, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tanimoto
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Department of Immunology, Graduate School of Medicine University of the Ryukyus, Okinawa, Japan.
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Virus Research Center, Sendai Medical Center National Hospital Organization, Sendai, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Nishimura
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nukiwa
authors.affiliation: Research Division for Development of Anti-Infective Agents, Institute of Development, Aging and Cancer Tohoku University, Sendai, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ichinose
mesh_terms: D000818:Animals; D004198:Disease Susceptibility; D054884:Host-Pathogen Interactions; D009980:Influenza A virus / Q000502:physiology*; D008810:Mice, Inbred C57BL; D053278:OX40 Ligand / Q000737:chemistry / Q000378:metabolism*; D009976:Orthomyxoviridae Infections / Q000473:pathology* / Q000821:virology; D011024:Pneumonia, Viral / Q000473:pathology* / Q000821:virology; D011499:Protein Processing, Post-Translational; D012794:Sialic Acids / Q000032:analysis; D013234:Stem Cells / Q000378:metabolism* / Q000821:virology; D053585:Virus Attachment
chemical_list: D053278:OX40 Ligand; D012794:Sialic Acids
keywords: OX40 ligand; bronchioles; glycosylation regeneration; viral pneumonia