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

By Athanase Benetos, Tsung-Po Lai, Simon Toupance, Carlos Labat, Simon Verhulst, Sylvie Gautier, Marie-Noƫlle Ungeheuer, Christine Perret-Guillaume, Daniel Levy, Ezra Susser, Abraham Aviv

Posted 04 Oct 2020
medRxiv DOI: 10.1101/2020.10.01.20205393

BackgroundLymphopenia 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. MethodsOur 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. ResultsLymphocyte 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. ConclusionsThese 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.

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