Contribution of the Purinergic Receptor P2X7 to Development of Lung Immunopathology during Influenza Virus Infection.

Victor H Leyva-Grado,Ma G Gonzalez,Jean K Lim,Virginia Gillespie,Michael Schotsaert,Megan E Ermler,Adolfo García-Sastre,Christine A Biron

doi:10.1128/mbio.00229-17

Victor H Leyva-Grado, Ma G Gonzalez + Show 6 more

Open Access

https://doi.org/10.1128/mbio.00229-17

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Journal: mBio	Publication Date: Mar 28, 2017
Citations: 83	License type: CC BY 4.0

Affiliation: Icahn School of Medicine at Mount Sinai

Abstract

ABSTRACTAn 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.

Highlights

An exacerbated immune response is one of the main causes of influenza-induced lung damage during infection
The causes of immunopathology such as excessive production of cytokines and infiltration of inflammatory cells have been reported for influenza virus infection [2, 3], the mechanisms shared by the antiviral host defense required for viral clearance and those required for development of immunopathology are not clearly understood [5, 6]
To determine whether activation of the P2X7r has an effect on influenza virus growth, we tested the addition of brilliant blue G (BBG), AZ11645373 {3-[1-[[(3=-nitro[1,1=-biphenyl]-4-yl)oxy]methyl]-3-(4-pyridinyl)propyl]-2,4thiazolidinedione} (AZ), or BzATP [2=(3=)-O-(4-benzoylbenzoyl)ATP triethylammonium] to A549 cell cultures before infection

Summary

Introduction

An exacerbated immune response is one of the main causes of influenza-induced lung damage during infection. 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. The causes of immunopathology such as excessive production of cytokines and infiltration of inflammatory cells have been reported for influenza virus infection [2, 3], the mechanisms shared by the antiviral host defense required for viral clearance and those required for development of immunopathology are not clearly understood [5, 6]. It triggers the release of proinflammatory cytokines, including interleukin-1␣ (IL-1␣), IL-1␤, IL-6, IL-10, and IL-18 [14, 15] and prompts activation of NLPR3 inflammasome [12, 16, 17], production of reactive oxygen species [18,19,20], and induction of apoptosis [21, 22]

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