Hypercapnia suppresses macrophage antiviral activity and increases mortality of influenza a infection via akt1

S. Marina Casalino-Matsuda*, Fei Chen, Francisco J. Gonzalez-Gonzalez, Aisha Nair, Sandra Dib, Alex Yemelyanov, Khalilah L. Gates, G. R.Scott Budinger, Greg J. Beitel, Peter H.S. Sporn

*Corresponding author for this work

Research output: Contribution to journalArticle

Abstract

Hypercapnia (HC), elevation of the partial pressure of CO2 in blood and tissues, is a risk factor for mortality in patients with severe acute and chronic lung diseases. 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's 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.

Original languageEnglish (US)
Pages (from-to)489-501
Number of pages13
JournalJournal of Immunology
Volume205
Issue number2
DOIs
StatePublished - Jul 15 2020

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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