key: cord-264013-8jnae6ig
authors: Tsilingiris, Dimitrios; Tentolouris, Anastasios; Eleftheriadou, Ioanna; Tentolouris, Nikolaos
title: Telomere length, epidemiology, and pathogenesis of severe COVID‐19
date: 2020-08-09
journal: Eur J Clin Invest
DOI: 10.1111/eci.13376
sha: 
doc_id: 264013
cord_uid: 8jnae6ig

In December of 2019, an outbreak of pneumonia of unknown cause was reported in Wuhan, Hubei Province, China. By January 2020 a novel coronavirus ‐ that was named severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) ‐ was isolated from patients in Wuhan and was identified as the causative pathogen of the disease, which was named Coronavirus disease of 2019 (COVID‐19). In the middle of March the World Health Organization (WHO) announced COVID‐19 outbreak a pandemic. According to the daily report of the WHO, as of 18 July 2020, COVID‐19 has spread rapidly to infect more than 14000000 people and has caused roughly 597000 deaths globally.

In December of 2019, an outbreak of pneumonia of unknown cause was reported in Wuhan, Hubei Province, China. By January 2020 a novel coronavirus -that was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) -was isolated from patients in Wuhan and was identified as the causative pathogen of the disease, which was named Coronavirus disease of 2019 . In the middle of March the World Health Organization (WHO) announced COVID-19 outbreak a pandemic. 1 According to the daily report of the WHO, as of 18 July 2020, COVID-19 has spread rapidly to infect more than 14000000 people and has caused roughly 597000 deaths globally. 2 The typical clinical presentation of SARS-CoV-2 infection is that of viral pneumonia, while the most severe of cases are marked by development of respiratory failure and multi-organ dysfunction 1 , occasionally in the frame of a "cytokine-storm" syndrome driven by a dysregulated immune response. 3 So far, several patient-related features that associate with greater disease severity and mortality have been recognized. Age is a principal factor driving disease course and mortality in reports from China, Italy, and the United Kingdom. 4-6 Mortality is relatively low across a broad age range from 0 to 50 years, followed by an exponential increase with progressing age. In a summary report from the Chinese Center Disease Control and Prevention among 72 314 cases records of COVID-19, the overall case-fatality rate (CFR) was 2.3%, but in the age-group 70 -79 and > 80 years the CFR increased to 8.0% and 14.8%, respectively. 7 The reported CFR for these age groups in Italy were 12.8% and 20.8%, respectively 4 . The risk of acquisition of SARS-CoV-2 infection for children is roughly similar to that of adults, although they present a substantially lower likelihood for severe disease. 8 Apart from advancing age, severe infection is more commonly observed among males 5,6 , in patients with obesity, 5,6,9 diabetes mellitus, 6,10 hypertension 5 , coronary artery disease 11 , chronic kidney disease disease, 6 among smokers, 5,10 , Accepted Article and among individuals with chronic obstructive pulmonary disease (COPD) 12, 13 . Trends towards a more severe course have been observed for certain racial/ethnic backgrounds, with Black 5,6 , Asian or mixed-race individuals 6 more prone to severe disease and death compared to those of Caucasian origin 13 .

Interestingly, these factors that foretell a severe course of SARS-CoV-2 and mortality considerably overlap with conditions known to associate with decreased telomere length. This allows for a hypothesis of a potential pathogenetic link between telomere shortening and severe SARS-CoV-2 infection to be made.

Telomeres are regions of repetitive sequences at the end of eucaryote chromosomes that ensure genome integrity and prevent fusion between adjacent chromosomes. 14 With each cell cycle telomeres become gradually shorter, so that decreases in telomere length following consecutive cellular divisions correspond to a constantly diminishing replicative capacity 15 . In rapidly replicating cells such as germline and hematopoietic stem cells, their length is maintained relatively stable by action of the enzyme telomerase and its catalytical subunit telomerase reverse transcriptase (hTERT). 14 A shorter telomere length and/or telomere dysfunction has been ascertained with advancing age, 16 in males versus females, in obese versus to lean adults, in smokers versus non-smokers, and in people with type 2 diabetes mellitus, hypertension, chronic kidney disease 17 , COPD 12 as well as coronary artery disease versus those without these diseases 18 

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The conceptual idea of susceptibility to acute viral infection with respect to telomere length is not new. Cohen et al reported that in a relatively selected population of healthy adults aged between 18 and 55 years, following experimental exposure to Rhinovirus 39 (a single-stranded RNA virus), a shorter telomer length in PBMCs, total lymphocytes, as well as CD4+ and CD8+ Tlymphocyte subsets was associated with an increased probability of upper respiratory infection 23 .

It could be argued that the presented overlap between the epidemiological features of COVID-19 and telomere length may be confounded by advanced age itself, since short telomers can be considered as an index of aging and physical frailty 24, 25 as well as by the presence of comorbidities that limit cardiovascular reserves. Nonetheless, the telomere shortening-related functional changes of cellular components of the immune system could, at least partly, be explanatory to these observations. A diminishing telomere length in human lymphocytes is related to the process of their replicative senescence (or biological "aging") 26 . The hypothesis that cellular senescence may be a key factor that drives susceptibility to severe SARS-CoV-2 infection has been recently postulated in a review article by Malavolta et al 27 . The authors additionally reviewed putative therapeutic strategies utilizing agents that target senescent cells or aspects of their secretory physiology. As regards lymphocyte senescence in particular, this is marked by loss of telomerase activity and telomere shortening which may lead to differential effects based on lymphocyte type and functional setting 26 . Although the process of immune cell senescence and its relationship to telomere shortening has been fairly well characterized in the setting of chronic viral infections such as HIV and chronic hepatitis B and C 28 , its relevance in the setting of acute viral exposure is less well defined. Disruption of telomere integrity by antitelomerase agent KLM-001 inhibits proliferation and cellular dysfunction and induces apoptosis in human CD4+ lymphocytes in vitro. 29 Conversely, CD8+ lymphocyte senescence associated with critical telomere shortening induces a state of "hyper-function" with evasion of apoptosis, increased secretion of pro-inflammatory cytokines such as Tumor Necrosis Factor-alpha and interleukin-6 and loss of surface CD28, a co-stimulatory receptor necessary for the mobilization of targeted T-cell immune responses. 30 In the previously mentioned study by Cohen et al, the risk of development of clinical illness after viral exposure was negatively associated with telomere length in CD8+CD28-lymphocytes 23 . It is possible that this distinctive mode of cytokine secretory hyperfunction of functionally aged lymphocytes may establish an increased cytokine in vivo environment, which may accelerate telomere shortening and loss of CD28 in co-existing nonsenescent lymphocytes 26 . Hence, in the setting of an acute infection this vicious circle may present a hindrance to effective immune responses in on one hand and predispose to Accepted Article exaggerated and uncontrolled inflammatory responses, much the same as the case of SARS-CoV-2 "cytokine storm". 3 Furthermore, in vitro studies have highlighted the feasibility of partial reversal of the senescent functional phenotype through manipulation of components of the telomere/telomerase system. Preservation of telomere length through constitutive expression of telomerase (hTERT) gene in CD8+ lymphocytes from HIV-infected human donors can restore their antiviral activity. 31 Likewise, exposure of CD8+ lymphocytes to telomerase activator TAT2 enhances their antiviral immune function. 32 Besides, the complex interplay between telomere-related pathways and other aging-associated physiological changes such as decreased activity of proteins of the sirtuin family 33, 34 , intracellular nicotinamide adenine dinucleotide (NAD+) depletion 33 and mitochondrial dysfunction 25,34 may play an complementary role as regards the aforementioned observations ( Figure 1 ).

Based on the above evidence, we hypothesize that individuals who exhibit lymphocyte telomere shortening may be more prone to severe and potentially lethal SARS-CoV-2 infection. We further speculate that this observation is driven by a complex immune dysregulation tracing back to immune cell senescence associated with telomere shortening, leading to increased susceptibility to infection and clinical disease (particularly pneumonia) by SARS-CoV-2, as well as unfavorable disease progression potentially marked by cytokine storm syndrome. This hypothesis would explain certain unique epidemiological aspects of the current pandemic, namely the continuous relationship of ascending age with disease severity and the susceptibility of certain patient groups to severe infection. Already, several therapeutic agents currently undergoing clinical testing for SARS-CoV-2 infection target components of the senescence-associated pro-inflammatory cellular phenotype 27 . Taking into consideration that manipulation of the telomere/telomerase system can ameliorate the deleterious effects of senescence on lymphocyte function in vitro 31,32 , the presented theory could also harbor implications for identifying high risk individuals and potentially guiding future therapeutic research against SARS-CoV-2 and other viral pathogens.

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The authors declare no conflicts of interest.

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