Eosinophil-driven immunopathology exacerbates SARS-CoV-2 pneumonia in an OVA-induced airway allergy mouse model

Asthma is an allergic airway disease characterized by distinct immune environments that can alter host responses to respiratory viral infections; however, its impact on coronavirus disease 2019 (COVID-19) severity remains unclear. To investigate how allergic airway inflammation affects severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced pneumonia, we used an ovalbumin (OVA)-induced airway allergy mouse model and infected mice with QHmusX, a mouse-passaged SARS-CoV-2 strain that causes severe acute pneumonia. Compared with phosphate-buffered saline-treated controls, OVA-sensitized mice exhibited persistent weight loss, a shift toward prominent alveolar involvement by viral infection, increased inflammatory cell infiltration, and higher histopathological scores, despite comparable viral burden. Enhanced apoptosis and increased numbers of CC10-positive epithelial cells indicated pronounced epithelial injury and repair responses in allergic mice. The post-infection decline in tissue eosinophils, together with histological evidence of eosinophil degranulation and lung cytokine profiling, was associated with amplified inflammatory and granulocyte-associated mediator responses in the airways. To define the functional contribution of eosinophils, we depleted eosinophils using an anti-interleukin-5 monoclonal antibody. Eosinophil depletion improved weight recovery, attenuated lung inflammation, and reduced CC10-associated repair responses without altering viral load. These findings demonstrate that airway allergy exacerbates SARS-CoV-2-induced pneumonia through eosinophil-mediated immunopathology and identify eosinophils as key contributors to disease severity. Targeting eosinophilic inflammation may therefore represent a potential therapeutic strategy for allergic individuals with COVID-19.IMPORTANCEAirway allergy profoundly alters host immunity; however, its impact on coronavirus disease 2019 severity remains unresolved. Using an ovalbumin-induced airway allergy mouse model, we show that pre-existing allergic airway inflammation exacerbates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced pneumonia despite comparable viral burden. Allergic mice exhibited rapid eosinophil degranulation accompanied by extracellular eosinophil cationic protein deposition, amplified inflammatory mediator responses, and increased epithelial injury. Depletion of eosinophils with anti-interleukin-5 improved weight recovery and lung pathology without measurably affecting viral burden, supporting a pathogenic role for eosinophils in disease exacerbation. These findings indicate that the allergic airway environment can redirect the pulmonary response to SARS-CoV-2 infection and promote immunopathology independently of increased viral replication. The study provides a mechanistic framework for understanding how active allergic inflammation may contribute to severe viral pneumonia and supports further evaluation of eosinophil-targeted therapies in selected clinical contexts.