Abstract
Influenza A virus (IAV) infection causes severe pulmonary disease characterized by intense leukocyte infiltration. Phosphoinositide-3 kinases (PI3Ks) are central signaling enzymes, involved in cell growth, survival, and migration. Class IB PI3K or phosphatidyl inositol 3 kinase-gamma (PI3Kγ), mainly expressed by leukocytes, is involved in cell migration during inflammation. Here, we investigated the contribution of PI3Kγ for the inflammatory and antiviral responses to IAV. PI3Kγ knockout (KO) mice were highly susceptible to lethality following infection with influenza A/WSN/33 H1N1. In the early time points of infection, infiltration of neutrophils was higher than WT mice whereas type-I and type-III IFN expression and p38 activation were reduced in PI3Kγ KO mice resulting in higher viral loads when compared with WT mice. Blockade of p38 in WT macrophages infected with IAV reduced levels of interferon-stimulated gene 15 protein to those induced in PI3Kγ KO macrophages, suggesting that p38 is downstream of antiviral responses mediated by PI3Kγ. PI3Kγ KO-derived fibroblasts or macrophages showed reduced type-I IFN transcription and altered pro-inflammatory cytokines suggesting a cell autonomous imbalance between inflammatory and antiviral responses. Seven days after IAV infection, there were reduced infiltration of natural killer cells and CD8+ T lymphocytes, increased concentration of inflammatory cytokines in bronchoalveolar fluid, reduced numbers of resolving macrophages, and IL-10 levels in PI3Kγ KO. This imbalanced environment in PI3Kγ KO-infected mice culminated in enhanced lung neutrophil infiltration, reactive oxygen species release, and lung damage that together with the increased viral loads, contributed to higher mortality in PI3Kγ KO mice compared with WT mice. In humans, we tested the genetic association of disease severity in influenza A/H1N1pdm09-infected patients with three potentially functional PIK3CG single-nucleotide polymorphisms (SNPs), rs1129293, rs17847825, and rs2230460. We observed that SNPs rs17847825 and rs2230460 (A and T alleles, respectively) were significantly associated with protection from severe disease using the recessive model in patients infected with influenza A(H1N1)pdm09. Altogether, our results suggest that PI3Kγ is crucial in balancing antiviral and inflammatory responses to IAV infection.
Highlights
Influenza A and B viruses are among the most common causes of acute respiratory viral diseases and account for 3–5 million cases of severe infection and 290,000–650,000 deaths worldwide every year [1]
Due to the importance of PI3Kγ for the recruitment and survival of macrophages and neutrophils, which might cause lung damage when excessively activated during influenza A virus (IAV) infection, we aimed to investigate the role of PI3Kγ in the innate immunity and inflammatory responses during IAV infection
PI3Kγ has been associated with exacerbated inflammatory responses in several models of inflammation, we demonstrated here that during IAV infection PI3Kγ plays a regulatory role
Summary
Influenza A and B viruses are among the most common causes of acute respiratory viral diseases and account for 3–5 million cases of severe infection and 290,000–650,000 deaths worldwide every year [1]. Natural killer (NK) cells, macrophages, and neutrophils are the first cell types actively recruited by the action of cytokines and chemokines to the lungs and airways in response to the virus infection [7]. Whereas the activation and recruitment of leukocytes is important to control infection, excessive activation of neutrophils and macrophages, might be harmful to the host [9, 10]. Different genetic polymorphisms on host factors genes of recognition, signaling or activating molecules have been investigated to explain the diversity of immune responses to influenza infection and how this might affect disease outcome [11,12,13,14,15]
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