Antiviral innate immune memory in alveolar macrophages after SARS-CoV-2 infection ameliorates secondary disease caused by influenza A virus

Alexander Lercher, Jin Gyu Cheong, Michael J. Bale, Chenyang Jiang, Hans Heinrich Hoffmann, Alison W. Ashbrook, Tyler Lewy, Yue S. Yin, Corrine Quirk, Emma J. DeGrace, Luis Chiriboga, Brad R. Rosenberg, Steven Z. Josefowicz, Charles M. Rice

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Pathogen encounter can result in epigenetic remodeling that shapes disease caused by heterologous pathogens. Here, we examined innate immune memory in the context of commonly circulating respiratory viruses. Single-cell analyses of airway-resident immune cells in a disease-relevant murine model of SARS-CoV-2 recovery revealed epigenetic reprogramming in alveolar macrophages following infection. Post-COVID-19 human monocytes exhibited similar epigenetic signatures. In airway-resident macrophages, past SARS-CoV-2 infection increased activity of type I interferon (IFN-I)-related transcription factors and epigenetic poising of antiviral genes. Viral pattern recognition and canonical IFN-I signaling were required for the establishment of this innate immune memory and augmented secondary antiviral responses. Antiviral innate immune memory mounted by airway-resident macrophages post-SARS-CoV-2 was necessary and sufficient to ameliorate secondary disease caused by influenza A virus and curtailed hyperinflammatory dysregulation and mortality. Our findings provide insights into antiviral innate immune memory in the airway that may facilitate the development of broadly effective therapeutic strategies.

Original languageEnglish
Pages (from-to)2530-2546.e13
JournalImmunity
Volume57
Issue number11
DOIs
StatePublished - 12 Nov 2024

Keywords

  • SARS-CoV-2
  • alveolar macrophages
  • epigenetic memory
  • immunology
  • influenza
  • innate immune memory
  • lung disease
  • respiratory virus
  • trained immunity
  • viral infection

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