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Hypercapnia and Suppression of Anti-viral Host Defense

高碳酸血症和抗病毒宿主防御的抑制

基本信息

批准号：
9336504
负责人：
PETER H SPORN
金额：
$ 39.13万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-17 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9336504
关键词：
Acute respiratory failure Antiviral Agents Autophagocytosis BCL2 gene Bacterial Infections Binding Blood Carbon Dioxide Cells Cessation of life ChIP-seq Chronic Obstructive Airway Disease Chronic lung disease Clinical Communities Cystic Fibrosis Defect Drosophila genus Exposure to Future Gene Expression Genes Genetic Genetic Transcription Health Homeobox Host Defense Human Hypercapnia Immune Immune system Immunosuppression In Vitro Individual Infection Influenza Influenza A virus Interferon Type I Interferon-alpha Interferon-beta Interferons Investigation Lung Lung diseases Mammals Mediating Mediator of activation protein Molecular Mus Myelogenous NF-kappa B Orthologous Gene Outcome Pathology Pathway interactions Patients Phagocytosis Play Pneumonia Predisposition RNA interference screen Reporting Research Risk Risk Factors Role Small Interfering RNA System Testing Tissues Viral Virus Diseases Virus Replication Work ZFHX3 gene Zinc Fingers adverse outcome antimicrobial peptide base clinically relevant genome-wide immune function in vivo influenzavirus inhibition of autophagy killings knock-down lung injury macrophage mortality mouse model mutant novel prevent research study transcription factor

项目摘要

DESCRIPTION (provided by applicant): Hypercapnia the elevation of PCO2 in blood and tissue, commonly occurs in advanced COPD and in acute respiratory failure. Patients with COPD frequently develop bacterial and viral lung infections, including influenza, and hypercapnia is a risk factor for mortality in such individuals. We have shown that hypercapnia suppresses transcription of multiple NF-κB-regulated innate immune genes required for host defense and inhibits phagocytosis and autophagy-mediated bacterial killing by macrophages (MØs). Moreover, we found that hypercapnia increases mortality due to bacterial infections in both mice and Drosophila. These findings strongly suggest that hypercapnia is not simply a marker of advanced lung disease, but that it plays a causal role in poor clinical outcomes by suppressing immune function and increasing susceptibility to infection. The similarity of hypercapnia's effects in Drosophila and mammalian systems suggested that elevated CO2 inhibits innate immune gene expression by conserved pathway(s). Thus, we conducted a genome-wide RNAi screen in Drosophila and identified the zinc finger homeobox transcription factor, zfh2, as a candidate mediator of CO2's immunosuppressive effects. Notably, mutant Drosophila deficient in zfh2 were protected against the CO2-induced increase in mortality from bacterial infection. Next, we found that ZFHX3, a mammalian zfh2 ortholog, is expressed in MØs; that ZFHX3 binds in a CO2-sensitive manner to multiple hypercapnia-regulated MØ genes; and that siRNA knockdown of ZFHX3 blocked hypercapnic immune gene suppression. In preliminary experiments for the current application, we observed that hypercapnia inhibited LPS- and influenza A virus (IAV)-induced expression of type I interferon (IFN) pathway antiviral genes in human and mouse MØs. Notably, ZFHX3 bound IFN regulatory factors (IRFs) and NF-κB genes, and this binding was CO2-sensitive, suggesting that ZFHX3 mediates hypercapnia's effect on antiviral gene expression by blocking IRF- and NF-κB- activated transcription of IFN-α and IFN-β. We also found that hypercapnia suppressed IAV-induced autophagy, another antiviral pathway, and that this followed hypercapnia-induced increases in expression of the negative autophagy regulators, Bcl-2 and Bcl-xL, and activation of Akt. Finally, of critical importance, exposure to elevated CO2 enhanced IAV replication in MØs and other cells and increased the mortality of IAV infection in mice. The proposed studies will test the hypotheses that hypercapnia inhibits expression of IFN pathway antiviral genes via CO2-dependent changes in transcription mediated by ZFHX3; that hypercapnia inhibits IAV-induced autophagy via increased expression of Bcl-2 and Bcl-xL and activation of Akt; and that myeloid ZFHX3 deficiency or blocking hypercapnic inhibition of autophagy will decrease IAV-associated lung injury and mortality in mice. This investigation will define novel mechanisms by which elevated levels of CO2 suppress antiviral host defense, a previously-unrecognized adverse consequence of hypercapnia, and will lay the basis for future studies aimed at preventing hypercapnia-induced immunosuppression in patients with advanced lung disease.