Abstract
The incidence of severe manifestations of COVID-19 increases with age with older patients showing the highest mortality, suggesting that molecular pathways underlying aging contribute to the severity of COVID-19. One mechanism of aging is the progressive shortening of telomeres, which are protective structures at chromosome ends. Critically short telomeres impair the regenerative capacity of tissues and trigger loss of tissue homeostasis and disease. The SARS-CoV-2 virus infects many different cell types, forcing cell turn-over and regeneration to maintain tissue homeostasis. We hypothesize that presence of short telomeres in older patients limits the tissue response to SARS-CoV-2 infection. We measure telomere length in peripheral blood lymphocytes COVID-19 patients with ages between 29 and 85 years-old. We find that shorter telomeres are associated to increased severity of the disease. Individuals within the lower percentiles of telomere length and higher percentiles of short telomeres have higher risk of developing severe COVID-19 pathologies.
Highlights
The current COVID-19 pandemic is produced by the SARS-CoV-2 virus, a novel zoonotic Coronavirus of the betacoronavirus genus that most likely crossed species from bats to humans leading to a pneumonia outbreak initially reported in Wuhan, China and affecting the majority of countries
Induction of telomere dysfunction in alveolar type II (ATII) cells by deletion of an essential telomere protective protein in these cells, TRF1, is sufficient to induce progressive and lethal pulmonary fibrosis phenotypes in mice, which are concomitant with induction of telomeric DNA damage, cell death and senescence [43]. These findings demonstrate that dysfunctional telomeres in lungs ATII cells lead to loss of viability of these cells and induction of fibrosis. In support of this notion, we have demonstrated that therapies aimed to elongate telomeres, such as a telomerase gene therapy using adeno-associated vectors (AAV9-TERT) can stop the progression of pulmonary fibrosis associated to short telomeres in mouse models of the disease by increasing telomere length in ATII cells, as well as their proliferative potential [44], demonstrating the importance of sufficiently long telomeres to allow tissue regeneration
In order to assess the potential impact of telomere length on pathologies associated to COVID-19 disease, we obtained both DNA and mononuclear cells from peripheral blood samples from patients hospitalized at the IFEMA field hospital in Madrid, which was constructed to treat COVID-19 patients
Summary
The current COVID-19 pandemic (https://www.who.int/) is produced by the SARS-CoV-2 virus, a novel zoonotic Coronavirus of the betacoronavirus genus that most likely crossed species from bats to humans leading to a pneumonia outbreak initially reported in Wuhan, China and affecting the majority of countries. The human ACE protein is expressed in alveolar type II (ATII) cells in the lung [8], as well as in the kidney, the heart and the gut [9,10,11,12,13,14] This expression pattern of the ACE protein explains that a preferential site for SARS-CoV-2 infection is the lung [4, 15, 16], the virus can infect kidney, intestine, and heart cells causing severe pathologies in all these tissues [1,2,3, 11, 17, 18]. It caught our attention that a common outcome of SARS-CoV-2 infection seems to be induction of fibrosis-like phenotypes in the lung and kidney, suggesting that the viral infection maybe exhausting the regenerative potential of tissues [11, 16,17,18]
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