title: Contribution of the Purinergic Receptor P2X7 to Development of Lung Immunopathology during Influenza Virus Infection.
abstract: An exacerbated immune response is one of the main causes of influenza-induced lung damage during infection. The molecular mechanisms regulating the fate of the initial immune response to infection, either as a protective response or as detrimental immunopathology, are not well understood. The purinergic receptor P2X7 is an ionotropic nucleotide-gated ion channel receptor expressed on immune cells that has been implicated in induction and maintenance of excessive inflammation. Here, we analyze the role of this receptor in a mouse model of influenza virus infection using a receptor knockout (KO) mouse strain. Our results demonstrate that the absence of the P2X7 receptor results in a better outcome to influenza virus infection characterized by reduced weight loss and increased survival upon experimental influenza challenge compared to wild-type mice. This effect was not virus strain specific. Overall lung pathology and apoptosis were reduced in virus-infected KO mice. Production of proinflammatory cytokines and chemokines such as interleukin-10 (IL-10), gamma interferon (IFN-γ), and CC chemokine ligand 2 (CCL2) was also reduced in the lungs of the infected KO mice. Infiltration of neutrophils and depletion of CD11b+macrophages, characteristic of severe influenza virus infection in mice, were lower in the KO animals. Together, these results demonstrate that activation of the P2X7 receptor is involved in the exacerbated immune response observed during influenza virus infection.IMPORTANCEA hallmark of influenza virus infection is the development of lung pathology induced by an exacerbated immune response. The mechanisms shared by the antiviral host defense required for viral clearance and those required for development of immunopathology are not clearly understood. Purinergic receptors, and in particular the purinergic receptor P2X7 (P2X7r), are involved in activation of the immune response. We used mice lacking the P2X7r (P2X7r KO mice) to better understand the mechanisms that lead to development of lung pathology during influenza virus infection. In our studies, we observed that P2X7r KO mice developed less lung immunopathology and had better survival than the wild-type mice. These results implicate P2X7r in the induction of an exacerbated local immune response to influenza virus and help us to better understand the mechanisms leading to the lung immunopathology observed during severe viral infections.
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA victor.leyva-grado@mssm.edu.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Victor H
authors.identifier: 0000-0002-9211-6160
authors.initials: VH
authors.lastname: Leyva-Grado
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Ermler
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Schotsaert
authors.affiliation: Center for Comparative Medicine and Surgery, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Ma G
authors.initials: MG
authors.lastname: Gonzalez
authors.affiliation: Center for Comparative Medicine and Surgery, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Gillespie
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Jean K
authors.initials: JK
authors.lastname: Lim
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
mesh_terms: D000818:Animals; D001835:Body Weight; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D054884:Host-Pathogen Interactions; D008168:Lung / Q000473:pathology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D009975:Orthomyxoviridae / Q000472:pathogenicity*; D009976:Orthomyxoviridae Infections / Q000473:pathology* / Q000821:virology; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D016207:Cytokines; D058486:Receptors, Purinergic P2X7
keywords: cytokines; extracellular ATP; immunopathology; influenza; purinergic receptor