SARS‐CoV‐2 infection induces thymic atrophy mediated by IFN‐γ in hACE2 transgenic mice

Abstract

Pathogenic infections cause thymic atrophy, perturb thymic T‐cell development, and alter immunological response. Previous studies reported dysregulated T‐cell function and lymphopenia in coronavirus disease‐19 (COVID‐19). However, immunopathological changes in the thymus associated with severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection have not been elucidated. Here, we report that SARS‐CoV‐2 infects thymocytes, and induces CD4+CD8+ (double positive; DP) T‐cell apoptosis leading to thymic atrophy and loss of peripheral TCR repertoire in K18‐hACE2 transgenic mice. Infected thymus led to increased CD44+CD25− T‐cells, indicating an early arrest in the T‐cell maturation pathway. Thymic atrophy was notably higher in male hACE2‐Tg mice than in females and involved an upregulated de‐novo synthesis pathway of thymic glucocorticoid. Further, IFN‐γ was crucial for thymic atrophy, as anti‐IFN‐γ ‐antibody neutralization blunted thymic involution. Therapeutic use of Remdesivir also rescued thymic atrophy. While the Omicron variant and its sub‐lineage BA.5 variant caused marginal thymic atrophy, the delta variant of SARS‐CoV‐2 exhibited severe thymic atrophy characterized by severely depleted DP T‐cells. Recently characterized broadly SARS‐CoV‐2 neutralizing monoclonal antibody P4A2 was able to rescue thymic atrophy and restore the thymic maturation pathway of T‐cells. Together, we report SARS‐CoV‐2‐associated thymic atrophy resulting from impaired T‐cell maturation pathway which may contribute to dyregulated T cell response during COVID‐19.