SarsCov-2, the virus causing COVID-19, became deadly for 1-2% of people infected , causing 7-8 million deaths worldwide. Although in most cases the fatal outcome was associated with old age and/or pre-existing debilitating conditions, it can occur in younger healthy individuals. Indeed, there are certain genes responsible for  fighting infections that may markedly impair our chances of survival. 

 

During the first phase of the COVID-19 pandemic, we observed an unexpected feature while studying patients with very severe pulmonary involvement caused by SARS-CoV-2. Many patients showed an unexpected enlargement of their thymus, and this feature was associated with decreased mortality and superior recovery, compared with patients without modification of this organ. The thymus is an organ of the immune system, located in the upper part of the chest behind the sternum, which produces a category of white blood cells essential for fighting pathogens and helping to produce antibodies, known as T-lymphocytes. The thymus is very active during the first part of life, up to early adulthood, and then becomes progressively less and less active. It can nevertheless be reactivated in older individuals, precisely during infections. Thymic activity, which consists of the release of new T-lymphocytes into the blood, can be quantified by laboratory tests. The maturation of T-lymphocytes within the thymus produces by-products known as T-cell receptor excision circles or TRECs, which can be measured by DNA amplification (PCR) from a blood sample. These tests confirmed that, in case of severe COVID-19 pneumonia, a higher production of new T-lymphocytes could contribute to a more favorable prognosis, regardless of the presence of thymus enlargement. 

 

A previous unrelated study, conducted on a general healthy population, had shown that, independently of age and sex, the variation of a single DNA feature (referred to as Single Nucleotide Polymorphism or SNP) in the gene coding for the T-cell receptor (TCR) was associated with different levels of T-lymphocyte production by the thymus. The DNA code is based on 4 nucleotides identified by the A, T, G, and C letters, and every gene is present in two copies (one from the mother and the other from the father). In a specific position of the TCR gene, the presence of two “G” leads to a high level of T-lymphocyte production by the thymus. In case of the presence of two “A”, the production is much lower on average, and the presence of one “G” and one “A” results in an intermediate situation. We made the hypothesis of a potential connection between this finding and the higher production of T-lymphocyte in SARS-CoV-2-infected patients better recovering from severe pneumonia. We therefore investigated whether the SNP, which drives the thymus activity, might also affect the clinical outcome and the immune response in patients with severe COVID-19. 

 

We conducted the study during the second burst of COVID-19 pandemics in Europe on a similar group of patients. We evaluated the SNP in each patient by gene sequencing of a PCR product from white blood cells, which resulted to correlate with both thymic production and the anti-SARS-CoV-2 immune response. Overall, we could validate our hypothesis that GG patients develop a stronger and long-lasting immune response against SARS-CoV-2 than GA and AA patients, independently of age, sex, and confounding factors. Clinically, the pneumonia of individuals harboring the GG genotype was less severe than that of the other patients. GG patients produced more T-lymphocytes (established by higher TREC values), compared to AA and GA individuals. They consequently developed a stronger and more efficient immune response against the virus and produced virus-neutralizing antibodies more often. A subgroup of patients was followed for a longer period and object of repeated tests, which provided interesting additional information. The signal “to produce more lymphocytes” that reaches the thymus during the acute phase of SARS-Cov-2 infection, causes the same increase in T-lymphocyte production in all individuals. However, since the basal level of production is higher in GG individuals, their final amount will reach a sufficient protective threshold after this amplification, a level which cannot be met in AA and GA individuals. 

 

In conclusion, this study demonstrates that an SNP can affect the clinical and immunological responses against a severe viral infection, by determining both the baseline production of T-lymphocytes by the thymus and its infection-induced enhancement. We propose to include the analysis of this SNP among the predictive tests in critically ill COVID-19 patients and in other clinical situations where thymic production is important to fight a disease.