Sex- and age-specific regulation of ACE2: Insights into severe COVID-19 susceptibility.
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ABSTRACT:
SUBMITTER: Viveiros A
PROVIDER: S-EPMC8582230 | biostudies-literature | 2022 Mar
REPOSITORIES: biostudies-literature
Publications
Sex- and age-specific regulation of ACE2: Insights into severe COVID-19 susceptibility.
Viveiros Anissa A Gheblawi Mahmoud M Aujla Preetinder K PK Sosnowski Deanna K DK Seubert John M JM Kassiri Zamaneh Z Oudit Gavin Y GY
Journal of molecular and cellular cardiology 20211111
Aged males disproportionately succumb to increased COVID-19 severity, hospitalization, and mortality compared to females. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2) facilitate SARS-CoV-2 viral entry and may have sexually dimorphic regulation. As viral load dictates disease severity, we investigated the expression, protein levels, and activity of ACE2 and TMPRSS2. Our data reveal that aged males have elevated ACE2 in both mice and humans across organs. W ...[more]
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Project description:BackgroundCoronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has now been confirmed worldwide. Yet, COVID-19 is strangely and tragically selective. Morbidity and mortality due to COVID19 rise dramatically with age and co-existing health conditions, including cancer and cardiovascular diseases. Human genetic factors may contribute to the extremely high transmissibility of SARS-CoV-2 and to the relentlessly progressive disease observed in a small but significant proportion of infected individuals, but these factors are largely unknown.Main bodyIn this study, we investigated genetic susceptibility to COVID-19 by examining DNA polymorphisms in ACE2 and TMPRSS2 (two key host factors of SARS-CoV-2) from ~ 81,000 human genomes. We found unique genetic susceptibility across different populations in ACE2 and TMPRSS2. Specifically, ACE2 polymorphisms were found to be associated with cardiovascular and pulmonary conditions by altering the angiotensinogen-ACE2 interactions, such as p.Arg514Gly in the African/African-American population. Unique but prevalent polymorphisms (including p.Val160Met (rs12329760), an expression quantitative trait locus (eQTL)) in TMPRSS2, offer potential explanations for differential genetic susceptibility to COVID-19 as well as for risk factors, including those with cancer and the high-risk group of male patients. We further discussed that polymorphisms in ACE2 or TMPRSS2 could guide effective treatments (i.e., hydroxychloroquine and camostat) for COVID-19.ConclusionThis study suggested that ACE2 or TMPRSS2 DNA polymorphisms were likely associated with genetic susceptibility of COVID-19, which calls for a human genetics initiative for fighting the COVID-19 pandemic.
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Project description:Background Angiotensin-converting enzyme 2 (ACE2) is a metallopeptidase that primarily functions as a negative regulator of renin angiotensin system (RAS) by converting angiotensin II (Ang II) to angiotensin 1-7. Contrary to this, another RAS component, angiotensin-converting enzyme (ACE) catalyzes synthesis of Ang II from angiotensin I (Ang I) that functions as active compound in blood pressure regulation. This indicates importance of ACE/ACE2 level in regulating blood pressure by targeting Ang II. An outbreak of severe acute respiratory syndrome (SARS) highlighted the additional role of ACE2 as a receptor for SARS coronavirus (SARS-CoV) infection. Main body of the abstract ACE2 is a functional receptor for SARS-CoV and SARS-CoV-2. Activation of spike (S)-protein by either type II transmembrane serine proteases (TTSPs) or cathepsin-mediated cleavage initiates receptor binding and viral entry. In addition to TTSPs, ACE2 can also be trimmed by ADAM 17 (a disintegrin and metalloproteinase 17) that competes for the same receptor. Cleavage by TTSPs activates ACE2 receptor for binding, whereas ADAM17 releases extracellular fragment called soluble ACE2 (sACE2). Structural studies of both ACE2 and S-protein have found critical sites involved in binding mechanism. In addition to studies on structural motifs, few single-nucleotide polymorphism (SNPs) studies have been done to find an association between genetic variants and SARS susceptibility. Though no association was found in those reports, but seeing the non-reproducibility of SNP studies among different ethnic groups, screening of ACE2 SNPs in individual population can be undertaken. Short conclusion Thus, screening for novel SNPs focussing on recently identified critical regions of ACE2 can be targeted to monitor susceptibility towards coronavirus disease 2019 (COVID-19).
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Project description:ACE2 on epithelial cells is the SARS-CoV-2 entry receptor. Single-cell RNA-sequencing data derived from two COVID-19 cohorts revealed that MAP4K3/GLK-positive epithelial cells were increased in patients. SARS-CoV-2-induced GLK overexpression in epithelial cells correlated with COVID-19 severity and vesicle secretion. GLK overexpression induced the epithelial cell-derived exosomes containing ACE2; the GLK-induced exosomes transported ACE2 proteins to recipient cells, facilitating pseudovirus infection. Consistently, ACE2 proteins were increased in the serum exosomes from another COVID-19 cohort. Remarkably, SARS-CoV-2 spike protein stimulated GLK, and GLK stabilized ACE2 in epithelial cells. Mechanistically, GLK phosphorylated ACE2 at two serine residues (Ser776, Ser783), leading to dissociation of ACE2 from its E3 ligase UBR4. Reduction of UBR4-induced Lys48-linked ubiquitination at three lysine residues (Lys26, Lys112, Lys114) of ACE2 prevented its degradation. Furthermore, SARS-CoV-2 pseudovirus or live virus infection in humanized ACE2 mice induced GLK and ACE2 protein levels, as well as ACE2-containing exosomes. Collectively, ACE2 stabilization by SARS-CoV-2-induced MAP4K3/GLK may contribute to the pathogenesis of COVID-19.
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Project description:The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide administration. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.
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Project description:The Angiotensin-Converting Enzyme-2 (ACE2) gene, located on Xp22.2, attracts a great deal of attention because the protein it encodes is believed to be the functional cellular receptor for the new coronavirus (SARS-CoV-2). However, recent studies are controversial, especially concerning the intrinsic link between ACE2 diversity and COVID-19 susceptibility. Here, we conduct a population genetic study on ACE2 in 6354 individuals representing 210 present-day populations and 5329 individuals of ancient or archaic groups. We dissected the genetic architecture of ACE2 and identified two major haplogroups (hg) in East Asians, i.e. ACE2-hg1 (43%) and ACE2-hg2 (53%), while other populations harbor more diverse ACE2-hgs. Accordingly, there was a significant loss of ACE2 common variations in East Asians in contrast to the X-chromosome-wide and genome-wide patterns. Notably, association analysis between ACE2-hgs and COVID-19 severity in 1229 Han Chinese individuals with various levels of COVID-19 severity showed a higher risk of ACE2-hg1 (odds ratio = 1.56, P < 0.01) and a lower risk of ACE2-hg2 (odds ratio = 0.65, P < 0.01). Interestingly, ACE2-hg1 is in strong linkage disequilibrium with rs1849863-C, which is an assumed risk factor of elevated plasma ACE2 level and is related to a higher risk of COVID-19 severity, hospitalization and infection. Strikingly, remarkable signatures of positive selection were detected, especially on ACE2-hg2, and were traced back to 100 000 years ago (but rose to a strong level during the Bronze Age, 5000∼3000 years ago, in East Asians). The selection pressures could have stemmed from multiple sources, but pre-COVID-19 viral epidemics and pandemics might have been potential driving forces, which consequently contributed to the genetic susceptibility to COVID-19 within and between populations.
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Project description:IntroductionMembrane-bound angiotensin-converting enzyme-2 (ACE2) in epithelial cells is the main receptor for SARS-CoV-2. The extracellular portion of ACE2 may be shedded to plasma in which process ADAM17 (a disintegrin and metalloproteinase 17) is important. Results on the relationship between circulating levels of the soluble form of ACE2 (sACE2) and disease severity are inconclusive. This study investigates if sACE2 concentration correlates with COVID-19 severity, and whether this is affected by sex.Materials and methodsSoluble form of ACE2 was analyzed in three groups: 104 patients (23 women and 81 men) with severe COVID-19 admitted to an intensive care unit (ICU), patients with moderate COVID-19 who required hospital care (n = 19, 4 women and 15 men), and age and sex matched healthy controls (n = 20, 4 women and 16 men). Blood samples were collected at hospital admission between 18 March 2020, and 3 May 2021, and at follow-up between 27 October 2020, and 19 October 2021. Circulating sACE2 (μg/L) was measured in EDTA plasma with a sensitive enzyme-linked immunosorbent assay. Additionally, CRP, ferritin, and lymphocyte count were analyzed during hospital stay.ResultsIn total, 23 patients (22%) died in the ICU. When comparing healthy controls [mean age 58.1 (SD 11.4) years] and patients with moderate COVID-19 [mean age 61.0 (SD 13.2) years] with patients in the ICU [mean age 63.6 (SD 11.6) years], we found that sACE2 concentration decreased (70% reduction) with disease severity in men (p = 0.002) but increased 3.7-fold with severity in women (p = 0.043), suggesting a sex-related difference in how COVID-19 severity is related to sACE2 concentration. Moreover, we identified a relationship between inflammatory biomarkers and sACE2 concentration during the intensive care treatment, such that higher CRP and higher ferritin concentration correlated with lower sACE2 concentration in men.ConclusionThe decrease in sACE2 concentration, selectively in men, in severe COVID-19 is of pathophysiological interest since men are affected more severely by the disease compared to women. Additionally, the inflammatory biomarkers, CRP and ferritin, correlated inversely with sACE2 concentration, suggesting a role in severe disease. Our findings imply that sACE2 is a possible biomarker of disease severity in a sex-specific manner.
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