A Mechanism for Severity of Disease in Older Patients with COVID-19: The Nexus between Telomere Length and Lymphopenia

Abstract

Background: Lymphopenia due to a plummeting T-cell count is a major feature of severe COVID-19. T-cell proliferation is telomere length (TL)-dependent and TL shortens with age. Older persons are disproportionally affected by severe COVID-19, and we hypothesized that those with short TL have less capacity to mount an adequate T-cell proliferative response to SARS-CoV-2. This hypothesis predicts that among older patients with COVID-19, shorter telomeres of peripheral blood mononuclear cells (PBMCs) will be associated with a lower lymphocyte count.
Methods: Our sample comprised 17 COVID-19 and 21 non-COVID-19 patients, aged 87(8) (mean(SD)) and 87 (9) years, respectively. We measured TL by the Telomere Shortest Length Assay, a novel method that measures and tallies the short telomeres directly relevant to telomere-mediated biological processes. The primary analysis quantified TL as the proportion of telomeres shorter than 2 kilobases. For comparison, we also quantified TL by Southern blotting, which measures the mean length of telomeres.
Results: Lymphocyte count (109/L) was 0.91 (0.42) in COVID-19 patients and 1.50(0.50) in non-COVID-19 patients (P < 0.001). In COVID-19 patients, but not in non-COVID-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kilobases (P = 0.005) and positively correlated with the mean of telomeres measured by TeSLA (P = 0.03). Lymphocyte counts showed no statistically significant correlations with Southern blotting results in COVID-19 or non-COVID-19 patients.
Conclusions: These results support the hypothesis that a compromised TL-dependent T-cell proliferative response contributes to lymphopenia and the resulting disproportionate severity of COVID-19 among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons.

Competing Interest Statement

The authors have declared no competing interest.

Clinical Trial

NCT04325646

Funding Statement

This study has been supported by the French National Research Agency (ANR), Translationnelle: ID RCB: 2014-A00298-39: 2014-2017 and partially supported by the French PIA project Lorraine Universite d Excellence, reference ANR-15-IDEX-04-LUE and the Investments for the Future program under grant agreement ANR-15-RHU-0004.
AA research is supported by National Institutes of Health grants R01HL134840, U01AG066529, and Norwegian Institute of Public Health grants 262700 and 262043.

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I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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ETHICS APPROVAL STATEMENT
This study was approved by the COMITE DE PROTECTION DES PERSONNES, ILE DE France III. CPP File Number: Am8448-6-3765, and by the Rutgers University, New Jersey Medical School IRB, Pro2020000669.

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Data Availability

All data are available upon request to the corresponding author

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