Lung regulatory T cells and inflammatory mediators associate with heterogeneous outcomes in a SARS-CoV-2 infected mouse model

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to heterogeneous clinical outcomes, suggesting that dysregulated host immune responses and inflammation contribute to divergent disease trajectories. We examined early immune correlates of disease severity using 32-week-old C57BL/6J mice and evaluated whether modulation of regulatory T cells (Tregs) would alter disease outcome. Oral administration of the CDK8/19 inhibitor AS2863619 did not markedly improve early weight loss, gross lung inflammatory scores, bronchoalveolar lavage fluid (BALF) viral RNA levels, or histopathological findings. Despite this limited impact on clinical outcomes, AS2863619 increased the frequency of KLRG1+ subsets in lung Foxp3+ CD4+ Tregs at 5 days post-infection. Across infected animals, lung Foxp3+ CD4+ Treg numbers inversely correlated with early weight loss. In parallel, several BALF inflammatory cytokines and chemokines were associated with disease severity, and the frequency of KLRG1+ Tregs inversely correlated with multiple inflammatory mediators. These findings indicate that endogenous lung Treg numbers and KLRG1+ Treg frequencies were linked to a less inflammatory airway milieu during acute SARS-CoV-2 infection.