Allergic airway inflammation protects against SARS-CoV-2 and MERS-CoV disease but promotes fatal SARS-CoV-1 immunopathology

Abstract

Epidemiological, clinical, and experimental data suggest that allergic asthma may have protective effects against severe Coronavirus Disease 2019 (COVID-19) but are often conflicting between different models of infection and epidemiological analyses. Allergic asthma is characterized by type 2 (T2) inflammation, mucus hypersecretion, and airway remodeling. We used a house dust mite (HDM) respiratory exposure model to determine how preexisting allergic inflammation alters the pathogenesis of three highly pathogenic coronaviruses, SARS-CoV-1, SARS-CoV-2, and MERS-CoV. HDM treatment induced canonical features of allergic asthma, including goblet cell hyperplasia, mucin hypersecretion, eosinophil recruitment, M2 macrophage polarization, and induction of IL-13. Across multiple SARS-CoV-2 variants, HDM treated mice exhibited reduced viral titers, less weight loss, diminished lung immunopathology, and improved survival rates. Similar protection was observed in a mouse model of MERS-CoV, with reduced lethality, lower viral burden, and blunted cytokine storm signatures in HDM treated mice. In contrast, allergic airway inflammation exacerbated SARS-CoV-1 pathogenesis, as HDM-treated mice developed fulminant alveolar inflammation, severe weight loss, elevated pro-inflammatory cytokines and chemokines, and increased mortality despite having reduced virus titer. Thus, in mice, allergic airway inflammation exerts opposing virus specific effects on coronavirus pathogenesis. These results reconcile conflicting epidemiological and mechanistic studies across coronavirus epidemics and highlight the need to consider host allergic status as a key variable influencing disease outcome from emerging coronaviruses.