title: Critical role of phospholipase A2 group IID in age-related susceptibility to severe acute respiratory syndrome-CoV infection.
abstract: Oxidative stress and chronic low-grade inflammation in the lungs are associated with aging and may contribute to age-related immune dysfunction. To maintain lung homeostasis, chronic inflammation is countered by enhanced expression of proresolving/antiinflammatory factors. Here, we show that age-dependent increases of one such factor in the lungs, a phospholipase A2 (PLA2) group IID (PLA2G2D) with antiinflammatory properties, contributed to worse outcomes in mice infected with severe acute respiratory syndrome-coronavirus (SARS-CoV). Strikingly, infection of mice lacking PLA2G2D expression (Pla2g2d(-/-) mice) converted a uniformly lethal infection to a nonlethal one (>80% survival), subsequent to development of enhanced respiratory DC migration to the draining lymph nodes, augmented antivirus T cell responses, and diminished lung damage. We also observed similar effects in influenza A virus-infected middle-aged Pla2g2d(-/-) mice. Furthermore, oxidative stress, probably via lipid peroxidation, was found to induce PLA2G2D expression in mice and in human monocyte-derived macrophages. Thus, our results suggest that directed inhibition of a single inducible phospholipase, PLA2G2D, in the lungs of older patients with severe respiratory infections is potentially an attractive therapeutic intervention to restore immune function.
authors.affiliation: Interdisciplinary Program in Immunology and Department of Otolaryngology, Department of Pathology, and Department of Microbiology, University of Iowa, Iowa City, IA 52242.
authors.forename: Rahul
authors.initials: R
authors.lastname: Vijay
authors.affiliation: Interdisciplinary Program in Immunology and Department of Otolaryngology, Department of Pathology, and Department of Microbiology, University of Iowa, Iowa City, IA 52242.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Hua
authors.affiliation: Interdisciplinary Program in Immunology and Department of Otolaryngology, Department of Pathology, and Department of Microbiology, University of Iowa, Iowa City, IA 52242.
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Miki
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Chemistry and Department of Biochemistry, University of Washington, Seattle, WA 98195 Department of Chemistry and Department of Biochemistry, University of Washington, Seattle, WA 98195.
authors.forename: Michael
authors.initials: M
authors.lastname: Gelb
authors.affiliation: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Interdisciplinary Program in Immunology and Department of Otolaryngology, Department of Pathology, and Department of Microbiology, University of Iowa, Iowa City, IA 52242 Interdisciplinary Program in Immunology and Department of Otolaryngology, Department of Pathology, and Department of Microbiology, University of Iowa, Iowa City, IA 52242 Stanley-Perlman@uiowa.edu.
authors.forename: Stanley
authors.initials: S
authors.lastname: Perlman
mesh_terms: D000367:Age Factors; D000818:Animals; D039521:CD11c Antigen / Q000032:analysis; D003713:Dendritic Cells / Q000502:physiology; D004198:Disease Susceptibility; D054501:Group II Phospholipases A2 / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D008055:Lipids / Q000032:analysis; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D045169:Severe Acute Respiratory Syndrome / Q000209:etiology*
chemical_list: D039521:CD11c Antigen; D008055:Lipids; D054501:Group II Phospholipases A2