A Mouse Model of Ovalbumin-Induced Airway Allergy Exhibits Altered Localization of SARS-CoV-2-Susceptible Cells in the Lungs, Which Reflects Omicron BA.5 Infection Dynamics, Viral Mutations, and Immunopathology.

Abstract

Asthma, an allergic disease of the airways, is a risk factor for severity of common respiratory viral infections; however, the relationship between asthma and severity in COVID-19 remains unclear. Here, we examined the effects of SARS-CoV-2 (Omicron BA.5 strain) infection in a mouse model of airway allergy. First, stimulation of allergic mice with OVA resulted in the appearance of ACE2-negative mucus-secreting goblet cells in the bronchiolar region, and an increase in the number of ACE2-expressing cells in the alveoli. As a result, ACE2-expressing cells, which are susceptible to SARS-CoV-2, were limited to the distal portion of the bronchioles while they increased in the alveolar area. After viral infection, the peak infectious viral load in the OVA group was 100-fold lower than that in the phosphate buffered saline (PBS) group; however, clearance of viral RNA from the upper/lower airways was delayed. There were notable differences in acquisition of nsp5 and nsp6 mutations by the Omicron BA.5 strain recovered from BALF samples obtained from the OVA and PBS groups. Immune responses associated with viral clearance were essentially the same, but expression of granulocyte-associated chemokines was higher, M2 macrophage responses were predominant, and the higher spike-specific IgG1/IgG2a ratio in the OVA group post-infection. Infection localized in the alveolar region earlier in the OVA group, resulting in more severe alveolar damage than in the PBS group. These data suggest a Th2-shifted immune background and altered localization of SARS-CoV-2 susceptible cells in mice with OVA-induced airway allergy, which reflect Omicron BA.5 infection dynamics, viral mutations, and immunopathology.