SARS-CoV-2 Causes Thymic Dysregulation

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A new study by Indian researchers from the Translational Health Science and Technology Institute-India, Reginal Centre Biotechnology -India and the All India Institute of Medical Sciences has found that the SARS-CoV-2 coronavirus causes thymic dysregulation and thymic atrophy that results in lymphopenia and peripheral T cell receptor repertoire changes.

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.

Clinical cases of COVID-19 are also characterized by lymphopenia which is defined by T cell lymphodepletion 5. Previous studies have shown that lymphopenia induced by pathogenic infection could be related to thymic atrophy 6–8.

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.

We observed severe thymic atrophy in hACE2 mice infected with SARS-CoV-2. Immune profile of the thymocytes suggested skewed frequencies of DN and DP population and impaired T cell developmental pathway represented by changes in CD44 vs CD25 frequencies.

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.

Together, we provide the first direct evidence of thymic atrophy induced by SARS-CoV-2 infection and show that the mechanism of thymic atrophy is through IFN-γ. Further, we show this impaired T cell development as a contributing factor for dysregulated peripheral T cell profile. Our results provide mechanism for the induction of lymphopenia and may explain waning T cell immunity post COVID-19 due to loss of TCR repertoire.

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