tetano
Editor, Senior Moderator
Eur J Immunol
. 2024 Apr 24:e2350624.
doi: 10.1002/eji.202350624. Online ahead of print. SARS-CoV-2 infection induces thymic atrophy mediated by IFN-γ in hACE2 transgenic mice
Zaigham Abbas Rizvi[SUP] 1 2 [/SUP], Srikanth Sadhu[SUP] 1 2 [/SUP], Jyotsna Dandotiya[SUP] 1 2 [/SUP], Puja Sharma[SUP] 3 [/SUP], Akshay Binayke[SUP] 1 2 [/SUP], Virendra Singh[SUP] 1 2 [/SUP], Vinayaka Das[SUP] 1 2 [/SUP], Ritika Khatri[SUP] 4 [/SUP], Rajesh Kumar[SUP] 4 [/SUP], Sweety Samal[SUP] 4 [/SUP], Manjula Kalia[SUP] 3 [/SUP], Amit Awasthi[SUP] 1 2 [/SUP]
Affiliations
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[SUP]+[/SUP]CD8[SUP]+[/SUP] (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[SUP]+[/SUP]CD25[SUP]-[/SUP] 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.
Keywords: COVID‐19; Omicron; SARS‐CoV‐2; Thymic atrophy; T‐cell maturation; T‐cells.
. 2024 Apr 24:e2350624.
doi: 10.1002/eji.202350624. Online ahead of print. SARS-CoV-2 infection induces thymic atrophy mediated by IFN-γ in hACE2 transgenic mice
Zaigham Abbas Rizvi[SUP] 1 2 [/SUP], Srikanth Sadhu[SUP] 1 2 [/SUP], Jyotsna Dandotiya[SUP] 1 2 [/SUP], Puja Sharma[SUP] 3 [/SUP], Akshay Binayke[SUP] 1 2 [/SUP], Virendra Singh[SUP] 1 2 [/SUP], Vinayaka Das[SUP] 1 2 [/SUP], Ritika Khatri[SUP] 4 [/SUP], Rajesh Kumar[SUP] 4 [/SUP], Sweety Samal[SUP] 4 [/SUP], Manjula Kalia[SUP] 3 [/SUP], Amit Awasthi[SUP] 1 2 [/SUP]
Affiliations
- PMID: 38655818
- DOI: 10.1002/eji.202350624
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[SUP]+[/SUP]CD8[SUP]+[/SUP] (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[SUP]+[/SUP]CD25[SUP]-[/SUP] 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.
Keywords: COVID‐19; Omicron; SARS‐CoV‐2; Thymic atrophy; T‐cell maturation; T‐cells.