single nuclei combined ATAC/RNA sequencing (10X Multiome) of airway-resident cells isolated from bronchoalveolar lavage fluid (BALF) of naive mice or mice recovered from SARS-CoV-2 (mouse-adapted strain MA10)

Pathogen encounter results in long-lasting epigenetic imprinting that shapes diseases caused by heterologous pathogens. The breadth of this innate immune memory is of particular interest in the context of respiratory pathogens with increased pandemic potential and wide-ranging impact on global health. Here, we investigated epigenetic imprinting across cell lineages in a disease relevant murine model of SARS-CoV-2 recovery. Past SARS-CoV-2 infection resulted in increased chromatin accessibility of type I interferon (IFN-I) related transcription factors and transcriptionally poised antiviral genes in airway-resident macrophages. Mechanistically, viral pattern recognition and canonical IFN-I signaling were required for establishment of this innate immune memory and resulting augmented secondary antiviral responses. SARS-CoV-2-associated innate immune memory in airway-resident macrophages was necessary and sufficient to ameliorate secondary disease caused by the heterologous respiratory pathogen influenza A virus. Insights into how innate immune memory shapes outcome of heterologous secondary diseases could facilitate the development of broadly effective therapeutic strategies.