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We previously showed that HC inhibits multiple macrophage and neutrophil antimicrobial functions and increases the mortality of bacterial pneumonia in mice. In this study, we show that normoxic HC increases viral replication, lung injury, and mortality in mice infected with influenza A virus (IAV). Elevated CO2 increased IAV replication and inhibited antiviral gene and protein expression in macrophages in vivo and in vitro. HC potentiated IAV-induced activation of Akt, whereas specific pharmacologic inhibition or short hairpin RNA knockdown of Akt1 in alveolar macrophages blocked HC\u2019s effects on IAV growth and the macrophage antiviral response. Our findings suggest that targeting Akt1 or the downstream pathways through which elevated CO2 signals could enhance macrophage antiviral host defense and improve clinical outcomes in hypercapnic patients with advanced lung disease.<\/jats:p>","DOI":"10.4049\/jimmunol.2000085","type":"journal-article","created":{"date-parts":[[2020,6,15]],"date-time":"2020-06-15T15:44:36Z","timestamp":1592235876000},"page":"489-501","source":"Crossref","is-referenced-by-count":33,"title":["Hypercapnia Suppresses Macrophage Antiviral Activity and Increases Mortality of Influenza A Infection via Akt1"],"prefix":"10.1093","volume":"205","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7566-4560","authenticated-orcid":false,"given":"S Marina","family":"Casalino-Matsuda","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco J","family":"Gonzalez-Gonzalez","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9575-3077","authenticated-orcid":false,"given":"Aisha","family":"Nair","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9648-270X","authenticated-orcid":false,"given":"Sandra","family":"Dib","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Yemelyanov","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalilah L","family":"Gates","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3114-5208","authenticated-orcid":false,"given":"G R Scott","family":"Budinger","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"},{"name":"Jesse Brown Veterans Affairs Medical Center , Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4413-6324","authenticated-orcid":false,"given":"Greg J","family":"Beitel","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, Weinberg College of Arts and Sciences, Northwestern University , Evanston, IL 60208"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1006-9437","authenticated-orcid":false,"given":"Peter H S","family":"Sporn","sequence":"additional","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611"},{"name":"Jesse Brown Veterans Affairs Medical Center , Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,7,15]]},"reference":[{"key":"2025030417504259400_r1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15585\/mmwr.ss6810a1","article-title":"Potentially excess deaths from the five leading causes of death in metropolitan and nonmetropolitan counties - United States, 2010-2017","volume":"68","author":"Garcia","year":"2019","journal-title":"MMWR Surveill. 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