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.

The P2X7 Receptor in Inflammatory Diseases: Angel or Demon?

“…Improved outcome observed in these settings correlated with decreased production of inflammatory mediators (i.e., IL-1β and IL-6) and reduced neutrophil infiltration (Lee et al, 2012 ). Similar results were observed in P2X7 KO mice infected with a lethal dose of influenza virus (Leyva-Grado et al, 2017 ).…”

Purinergic Signalling: Therapeutic Developments

“…P2X7R activation regulates inflammatory responses during acute viral infection ( Lee et al, 2012 ) and is involved in the exacerbated immune response seen during influenza virus infection ( Leyva-Grado et al, 2017 ). ATP, released by activated macrophages and damaged cells, modulates lung inflammation in pneumonia in cattle.…”

“…P2X7R modulate the antiviral and inflammatory processes that occur during Dengue virus-2 infection ( Corrêa et al, 2016 ) and exacerbate the immune response that occurs during influenza virus infection ( Leyva-Grado et al, 2017 ). P2X4R antagonists reduce herpetic pain ( Matsumura et al, 2016 ).…”

Purinergic Receptors: Elucidating the Role of these Immune Mediators in HIV-1 Fusion

“…Purinergic signaling has been demonstrated to be key to the immune response in several infectious processes [73][74][75], including bacterial [76][77][78][79][80], protozoal [81][82][83][84], and viral infections including respiratory viral infections [85,86], hepatitides [63,[87][88][89], cytomegalovirus [90], and HIV-1 [91][92][93][94][95][96]. Interestingly, purinergic receptors have been implicated in both immunoprotective and immunopathologic roles in these infection [75,88,97,98]. There is a growing body of evidence that implicates purinergic receptors and both selective and non-selective antagonists of these receptors in HIV-1 infection [99][100][101][102][103][104][105].…”