The study findings were published on a preprint server: Research Square and is currently being peer reviewed.
https://www.researchsquare.com/article/rs-1581769/v1
SARS-CoV-2 which was first reported in Wuhan, China in Dec, 2019 has so far infected around 6.3% of the total world population with around 1.23% mortality rate as on 18th April, 2022 (https://covid19.who.int/). Furthermore, emerging variants of concern (VoC) from the ancestral SARS-CoV-2 strain has led to sporadic emergence of COVID-19 related morbidity and mortality world-wide.
While majority of clinical cases report pulmonary pathologies associated with pneumonia and acute respiratory distress syndrome (ARDS), growing number of evidences suggest cardiovascular, gastrointestinal, renal, neurological, endocrinological manifestations of SARS-CoV-2 infection 1–4.
Thymic atrophy is described as shrinking of the thymus and is related to aging or disease condition and leads to immuno-senescence (loss of T cell repertoire) and inflammaging (self-reactive T cell) (6–11). Moreover, lymphopenia due to pathogenic infection could occur due to direct cellular killing induced by the pathogen or due to changes in the T cell developmental pathway in the thymus.
Several mechanisms have been suggested for pathogen induced thymic atrophy which is governed by virus entry and infection. For example thymic atrophy by influenza A virus infection is mediated by IFN-γ cytokine or NK cells cytotoxicity and results in impaired negative selection 7,12. For highly pathogenic avian influenza A virus (HPAIV), thymic atrophy occurs by impaired negative selection for T cells and involvement of glucocorticoids 13,14.
For chronic infection caused by hepatitis C virus, HIV infection, etc destruction of thymus usually occurs through CD8 T cells and results in impaired negative selection 15,16. Previous clinical post-mortem studies have suggested changes in the thymic structure which may be lead to changes in the thymic output post COVID-19 6,11,17.
However, direct evidence of thymic atrophy and the mechanism involved in it have not been reported mostly due to lack of any animal model study. Golden Syrian hamster and humanized ACE2-transgenic mice are two routinely used models for SARS-CoV-2 infection which mimics upper and lower respiratory tract pathology. Interestingly, several reports have pointed that COVID-19 leads to extra-pulmonary pathologies ranging from gastrointestinal, cardiovascular, neurological, etc in both hamsters and hACE2 mice 18,19.
While hACE2 mice infected with SARS-CoV-2 develops acute COVID-19 and ultimately succumbs to infection, hamster represents a mild to moderate model for COVID-19 and have been shown to start recovering post day 6–7 of infection 19–22.
In the current study, we utilized golden Syrian hamster and hACE2 mice model for SARS-CoV-2 infection to investigate the cause of lymphopenia as seen in COVID-19 patients.
The loss of T cells was found to be due to apoptosis and was mediated by IFN-γ as neutralization of IFN-γ abrogated thymic atrophy. Rescue of thymic atrophy was also observed with anti-viral drug remdesivir (RDV) which reduces viral load. Interestingly, infected hamsters do not develop severe thymic atrophy.
Severe thymic atrophy was also absent from Omicron infection in hACE-Tg mice, however Delta variant infection seems to worsen thymic atrophy. Finally, we showed that P4A2 antibody, which has been recently reported as broadly SARS-CoV-2 neutralizing antibody effect against Delta variant, treated mice were rescued from thymic atrophy and showed no impaired T cell development.
