The inflammatory microenvironment of the lung at the time of infection governs innate control of SARS-CoV-2 replication

Abstract

SARS-CoV-2 infection leads to vastly divergent clinical outcomes ranging from asymptomatic infection to fatal disease. Co-morbidities, sex, age, host genetics and vaccine status are known to affect disease severity. Yet, how the inflammatory milieu of the lung at the time of SARS-CoV-2 exposure impacts the control of viral replication remains poorly understood. We demonstrate here that immune events in the mouse lung closely preceding SARS-CoV-2 infection significantly impact viral control and we identify key innate immune pathways required to limit viral replication. A diverse set of pulmonary inflammatory stimuli, including resolved antecedent respiratory infections with S. aureus or influenza, ongoing pulmonary M. tuberculosis infection, ovalbumin/alum-induced asthma or airway administration of defined TLR ligands and recombinant cytokines, all establish an antiviral state in the lung that restricts SARS-CoV-2 replication upon infection. In addition to antiviral type I interferons, the broadly inducible inflammatory cytokines TNFα and IL-1 precondition the lung for enhanced viral control. Collectively, our work shows that SARS-CoV-2 may benefit from an immunologically quiescent lung microenvironment and suggests that heterogeneity in pulmonary inflammation that precedes or accompanies SARS-CoV-2 exposure may be a significant factor contributing to the population-wide variability in COVID-19 disease outcomes.

High burden of viruses and bacterial pathobionts drives heightened nasal innate immunity in children

“…For seasonal respiratory viruses, bacterial pathobionts are known to contribute to acute symptoms and can also cause impactful secondary bacterial infections ( Bosch et al, 2017 ; Brealey et al, 2018 ; de Steenhuijsen Piters et al, 2022 ; Kloepfer et al, 2014 ; Rodrigues et al, 2013 ; Teo et al, 2015 ). For SARS-CoV-2, there is also evidence from experimental models that pre-existing proinflammatory responses in the lung can contribute to protection from SARS-CoV-2, but the effects of specific bacterial pathobionts are not well-established ( Baker et al, 2024 , Preprint ). It is also possible that the inflammatory response to bacterial coinfection could both increase acute upper respiratory symptoms and protect from systemic infection by enhancing innate and/or adaptive immune responses.…”