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Pathogenic potential of interferon αβ in acute influenza infection.

ABSTRACT: Influenza symptoms vary from mild disease to death; however, determinants of severity are unclear. Type I interferons (IFNαβ) are recognized as key antiviral cytokines. Here we show that, surprisingly, influenza-infected 129 mice have increased lung damage, morbidity and mortality, yet higher levels of IFNαβ, than C57BL/6 mice. Consistently, IFNα treatment of influenza-infected C57BL/6 mice increases morbidity. IFNαβ receptor deficiency in 129 mice decreases morbidity, lung damage, proinflammatory cytokines and lung-infiltrating inflammatory cells, and reduces expression of the death-inducing receptor DR5 on lung epithelia and its ligand TRAIL on inflammatory monocytes. Depletion of PDCA-1+ cells or interruption of TRAIL-DR5 interaction protects infected 129 mice. Selective lack of IFNαβ signalling in stromal cells abolishes epithelial DR5 upregulation and apoptosis, reducing host susceptibility. Hence, excessive IFNαβ signalling in response to acute influenza infection can result in uncontrolled inflammation and TRAIL-DR5-mediated epithelial cell death, which may explain morbidity and has important implications for treatment of severe disease.

SUBMITTER: Davidson S

PROVIDER: S-EPMC4033792 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:We have shown that membrane-associated guanylate kinase with inverted domain structure-1 (MAGI1), a scaffold protein with six PSD95/DiscLarge/ZO-1 (PDZ) domains, is involved in the regulation of endothelial cell (EC) activation and atherogenesis in mice. In addition to causing acute respiratory disease, influenza A virus (IAV) infection plays an important role in atherogenesis and triggers acute coronary syndromes and fatal myocardial infarction. Therefore, the aim of this study is to investigate the function and regulation of MAGI1 in IAV-induced EC activation. Whereas, EC infection by IAV increases MAGI1 expression, MAGI1 depletion suppresses IAV infection, suggesting that the induction of MAGI1 may promote IAV infection. Treatment of ECs with oxidized low-density lipoprotein (OxLDL) increases MAGI1 expression and IAV infection, suggesting that MAGI1 is part of the mechanistic link between serum lipid levels and patient prognosis following IAV infection. Our microarray studies suggest that MAGI1-depleted ECs increase protein expression and signaling networks involve in interferon (IFN) production. Specifically, infection of MAGI1-null ECs with IAV upregulates expression of signal transducer and activator of transcription 1 (STAT1), interferon b1 (IFNb1), myxovirus resistance protein 1 (MX1) and 2'-5'-oligoadenylate synthetase 2 (OAS2), and activate STAT5. By contrast, MAGI1 overexpression inhibits Ifnb1 mRNA and MX1 expression, again supporting the pro-viral response mediated by MAGI1. MAGI1 depletion induces the expression of MX1 and virus suppression. The data suggests that IAV suppression by MAGI1 depletion may, in part, be due to MX1 induction. Lastly, interferon regulatory factor 3 (IRF3) translocates to the nucleus in the absence of IRF3 phosphorylation, and IRF3 SUMOylation is abolished in MAGI1-depleted ECs. The data suggests that MAGI1 inhibits IRF3 activation by maintaining IRF3 SUMOylation. In summary, IAV infection occurs in ECs in a MAGI1 expression-dependent manner by inhibiting anti-viral responses including STATs and IRF3 activation and subsequent MX1 induction, and MAGI1 plays a role in EC activation, and in upregulating a pro-viral response. Therefore, the inhibition of MAGI1 is a potential therapeutic target for IAV-induced cardiovascular disease.

Project description:BackgroundToxoplasma gondii is a worldwide spread pathogen which can infect all tissues of its host. The transcriptomic responses of infected brain and spleen have been reported. However, our knowledge of the global transcriptomic change in infected liver is limited. Additionally, T. gondii infection represents a highly dynamic process involving complex biological responses of the host at many levels. Herein, we describe such processes at a global level by discovering gene expression changes in mouse livers after acute infection with T. gondii ToxoDB#9 strain.ResultsGlobal transcriptomic analysis identified 2,758 differentially expressed transcripts in infected liver, of which 1,356 were significantly downregulated and 1,402 upregulated. GO and KEGG database analyses showed that host immune responses were upregulated, while the metabolic-related processes/pathways were downregulated, especially xenobiotic metabolism, fatty acid metabolism, energy metabolism, and bile biosynthesis and secretion. The metabolism of more than 800 chemical compounds including anti-Toxoplasma prescribed medicines were predicted to be modulated during acute T. gondii infection due to the downregulation of enzymes involved in xenobiotic metabolism.ConclusionsTo the best of our knowledge, this is the first global transcriptomic analysis of mouse liver infected by T. gondii. The present data indicate that during the early stage of liver infection, T. gondii can induce changes in liver xenobiotic metabolism, upregulating inflammatory response and downregulating hepatocellular PPAR signaling pathway, altering host bile biosynthesis and secretion pathway; these changes could enhance host intestinal dysbacteriosis and thus contribute to the pathological changes of both liver and intestine of infected mice. These findings describe the biological changes in infected liver, providing a potential mechanistic pathway that links hepatic and intestinal pathologies to T. gondii infection.

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Pathogenic potential of interferon αβ in acute influenza infection.

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