Histopathologic Pulmonary Involvement of COVID-19: A Comparative Study of SARS-CoV-2 Variants in Mouse Models

ABSTRACT

Background: A thorough understanding of the inflammatory reaction to SARS-CoV-2 variants, specifically the Delta and Alpha variants, can provide crucial insight into future treatment of individuals infected with these strains. Mice are an effective model for predicting the pathologic processes of these viruses in humans. Design: K18-hACE2 transgenic mice were raised either under normal conditions (control) or infected with either the Alpha (strain B.1.1.7) or Delta (B.1.617.2) variant of SARS-CoV-2, via intranasal challenge with 1000 PFU virus. Mice were then euthanized at days 2 and 6 post-challenge. Lung sections were used for pathological evaluation of H&E stained slides scanned using the Dynamyx software. Blood vessel cross sections were examined and the average number of marginating inflammatory cells per millimeter of vessel were quantified. Additionally, the percentage of total tissue area that was inflamed was calculated. Results: Our data indicates that the Delta variant elicits a strong lymphocytic immune response in the lungs. At two days postchallenge, Inflammation and margination of inflammatory cells could be appreciated in Delta infected mice, but not in Alpha infected mice. The inflammatory infiltrate was composed predominantly of lymphocytes and occasional histiocytes at 2 days. By day 6, marked perivascular inflammation and margination was appreciated, more prominently in Delta (36 lymphocytes per mm. of endothelium) than Alpha infected mice (22 lymphocytes per mm. endothelium) (p=0.022). At this time point, Alpha infected mice showed 4% involvement of pulmonary area by inflammation, compared to 20% for Delta infected mice (p=0.014). Conclusions: This study quantifies the lymphocytic immune response in the lungs to the Alpha and Delta variants of SARS-CoV-2 in mouse models. Both variants showed a lymphocyte predominant inflammatory response. However, the response was much more robust and severe in Delta infected mice compared to Alpha. The results support why the Delta variant is more virulent and fatal compared to Alpha. Ongoing longer term studies and effects in other organs are ongoing and will help to provide further insight into pathogenesis of long COVID-19.