ACE2: Evidence of role as entry receptor for SARS-CoV-2 and implications in comorbidities

eLife, Год журнала: 2020, Номер 9

Опубликована: Ноя. 9, 2020

Pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes 19 disease (COVID-19) which presents a large spectrum of manifestations with fatal outcomes in vulnerable people over 70-years-old and hypertension, diabetes, obesity, cardiovascular disease, COPD, smoking status. Knowledge the entry receptor is key to understand SARS-CoV-2 tropism, transmission pathogenesis. Early evidence pointed angiotensin-converting enzyme (ACE2) as receptor. Here, we provide critical summary current knowledge highlighting limitations remaining gaps that need be addressed fully characterize ACE2 function infection associated We also discuss expression potential role context comorbidities poor COVID-19 outcomes. Finally, co-receptors/attachment factors such neuropilins, heparan sulfate sialic acids putative alternative receptors, CD147 GRP78.

Язык: Английский

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The N501Y mutation in SARS-CoV-2 spike leads to morbidity in obese and aged mice and is neutralized by convalescent and post-vaccination human sera

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2021, Номер unknown

Опубликована: Янв. 20, 2021

Abstract The current COVID-19 (coronavirus disease 19) pandemic, caused by SARS-CoV-2, disproportionally affects the elderly and people with comorbidities like obesity associated type 2 diabetes mellitus. Small animal models are crucial for successful development validation of antiviral vaccines, therapies to study role that have on outcome viral infections. initially available SARS-CoV-2 isolates require adaptation in order use mouse angiotensin converting enzyme (mACE-2) entry receptor productively infect cells murine respiratory tract. We “mouse-adapted” serial passaging a clinical virus isolate lungs mice. then used low doses this advanced age, obesity. Similar infection humans, mouse-adapted resulted enhanced morbidity aged diabetic obese Mutations occurred S, M, N ORF8 genes. Interestingly, one mutation binding domain S protein results change an asparagine tyrosine residue at position 501 (N501Y). This is also present newly emerging variant viruses reported U.K. (20B/501Y.V1, B1.1.7 lineage) epidemiologically high human transmission. show convalescent post vaccination sera can neutralize N501Y similar efficiency as reference USA-WA1/2020 virus, suggesting vaccines will protect against 20B/501Y.V1 strain.

Язык: Английский

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SARS-CoV-2 infection drives an inflammatory response in human adipose tissue through infection of adipocytes and macrophages

Science Translational Medicine, Год журнала: 2022, Номер 14(674)

Опубликована: Сен. 22, 2022

Obesity, characterized by chronic low-grade inflammation of the adipose tissue, is associated with adverse coronavirus disease 2019 (COVID-19) outcomes, yet underlying mechanism unknown. To explore whether severe acute respiratory syndrome 2 (SARS-CoV-2) infection tissue contributes to pathogenesis, we evaluated COVID-19 autopsy cases and deeply profiled response SARS-CoV-2 in vitro. In cases, identified RNA adipocytes an inflammatory infiltrate. We two distinct cellular targets infection: a subset tissue-resident macrophages. Mature were permissive infection; although macrophages abortively infected, initiated responses within both infected bystander preadipocytes. These data suggest that could contribute severity through replication virus induction local systemic driven

Язык: Английский

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miR-98 Regulates TMPRSS2 Expression in Human Endothelial Cells: Key Implications for COVID-19

Biomedicines, Год журнала: 2020, Номер 8(11), С. 462 - 462

Опубликована: Окт. 30, 2020

The two main co-factors needed by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to enter human cells are angiotensin-converting enzyme (ACE2) and transmembrane protease serine (TMPRSS2). Here, we focused on study of microRNAs that specifically target TMPRSS2. Through a bioinformatic approach, identified miR-98-5p as suitable candidate. Since others have shown endothelial play pivotal role in pathogenesis disease 2019 (COVID-19), mechanistically validated regulator TMPRSS2 transcription different cell types, derived from lung umbilical vein. Taken together, our findings indicate represents valid COVID-19 treatment, which may be achieved specific non-coding-RNA approaches.

Язык: Английский

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SARS-CoV-2 infection in nonhuman primates alters the composition and functional activity of the gut microbiota

Gut Microbes, Год журнала: 2021, Номер 13(1)

Опубликована: Янв. 1, 2021

The current pandemic of coronavirus disease (COVID) 2019 constitutes a global public health issue. Regarding the emerging importance gut-lung axis in viral respiratory infections, analysis gut microbiota's composition and functional activity during severe acute syndrome 2 (SARS-CoV-2) infection might be instrumental understanding controling COVID 19. We used nonhuman primate model (the macaque), that recapitulates mild COVID-19 symptoms, to analyze effects SARS-CoV-2 on dynamic changes microbiota. 16S rRNA gene profiling β diversity indicated significant microbiota with peak at 10-13 days post-infection (dpi). Analysis bacterial abundance correlation networks confirmed disruption community dpi. Some alterations persisted after resolution until day 26. relative taxon associated infectious parameters. Interestingly, Acinetobacter (Proteobacteria) some genera Ruminococcaceae family (Firmicutes) was positively correlated presence upper tract. Targeted quantitative metabolomics drop short-chain fatty acids (SCFAs) several bile tryptophan metabolites infected animals. taxa known SCFA producers (mostly from family) negatively systemic inflammatory markers while opposite seen members genus Streptococcus. Collectively, is activity.

Язык: Английский

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MMP-2 and MMP-9 levels in plasma are altered and associated with mortality in COVID-19 patients

Biomedicine & Pharmacotherapy, Год журнала: 2021, Номер 142, С. 112067 - 112067

Опубликована: Авг. 20, 2021

Respiratory symptoms are one of COVID-19 manifestations, and the metalloproteinases (MMPs) have essential roles in lung physiology. We sought to characterize plasmatic levels matrix metalloproteinase-2 9 (MMP-2 MMP-9) patients with severe investigate an association between plasma MMP-2 MMP-9 clinical outcomes mortality. from treated ICU (COVID-19 group) Control were measured zymography. The study groups matched for age, sex, hypertension, diabetes, BMI, obesity profile. lower higher a group (p < 0.0001) compared Controls. not affected by comorbidity such as hypertension or obesity. 0.05), but unaffected status. Notably, hypertensive had non-hypertensive group, albeit still than Controls 0.05). No corticosteroid treatment acute kidney injury was found patients. survival analysis showed that mortality associated increased levels. Age, better predictors during hospitalization SAPS3 SOFA scores at hospital admission. In conclusion, significant found. predicted risk in-hospital death suggesting possible pathophysiologic prognostic roles.

Язык: Английский

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Therapeutic Potential of Metformin in COVID-19: Reasoning for Its Protective Role

Trends in Microbiology, Год журнала: 2021, Номер 29(10), С. 894 - 907

Опубликована: Март 14, 2021

Hyperglycemia (irrespective of whether it is acute in nondiabetics or due to pre-existing diabetes/new-onset diabetes) influences the severity coronavirus disease 2019 (COVID-19) disease, rate hospitalizations and intensive care unit (ICU) admission, mortality among affected patients.Proper management blood glucose levels reduced severity, incidence respiratory distress syndrome (ARDS), requirement for ICU admissions ventilator support, promoted recovery COVID-19 patients.Diabetes-associated endothelial dysfunction related prothrombotic state increase risk thromboembolic events diabetic patients.The safe, well-tolerated, economical antidiabetic drug metformin could prove be beneficial therapy multiple ways efficiently improve treatment outcomes reduce patients.Metformin decreases increases insulin sensitivity possibly, inhibit viral infection, multiplication, maturation, translation proteins, regulate protein–host protein interactions, modulate inflammation immune response patients. Severe 2 (SARS-CoV-2) infections present with increased poor clinical patients compared their nondiabetic counterparts. Diabetes/hyperglycemia-triggered hyperactive inflammatory responses are correlated twofold threefold higher more than twice While comorbidities such as obesity, cardiovascular hypertension worsen prognosis patients, also associated new-onset diabetes, severe metabolic complications, thrombotic backdrop aberrant function. several medications used manage levels, we discuss multifaceted ability control possibly attenuate dysfunction, entry modify during SARS-CoV-2 infections. These actions make a viable candidate considered repurposing gaining ground against SARS-CoV-2-induced tsunami On January 7, 2020, novel beta-coronavirus, (see Glossary), was identified causative agent 'atypical pneumonia' that surfaced Wuhan, China, on December 30, [1.Apicella M. et al.COVID-19 people diabetes: understanding reasons worse outcomes.Lancet Diabetes Endocrinol. 2020; 8: 782-792Abstract Full Text PDF PubMed Scopus (553) Google Scholar]. Since World Health Organization (WHO) declared SARS-CoV-2-caused outbreak pandemic March 11, date (March 5, 2021), over 116 million cases have been reported, 2.5 lost lives globallyi Finding an effective way rapid spread cure remains at forefront battle this even vaccines – Tozinameran/BNT162b2/Comirnaty (Pfizer/BioNTech), mRNA-1273 (Moderna), AZD1222/Covishield (University Oxford/AstraZeneca), Ad26.COV2.S/JNJ-78436735 (Janssen Vaccines Prevention) being approved authorized emergency use countries [2.Polack F.P. al.Safety efficacy BNT162b2 mRNA Covid-19 vaccine.N. Engl. J. Med. 383: 2603-2615Crossref (8482) Scholar, 3.Baden L.R. al.Efficacy safety 384: 403-416Crossref (5785) 4.Voysey ChAdOx1 nCoV-19 vaccine (AZD1222) SARS-CoV-2: interim analysis four randomised controlled trials Brazil, South Africa, UK.Lancet. 2021; 397: 99-111Abstract (3010) 5.Sadoff al.Interim results phase 1–2a Trial Ad26.COV2.S (Published online 13, 2021. https://doi.org/10.1056/NEJMoa2034201)Crossref (764) However, emergence highly transmissible mutants raised concerns these variants evade body's response, threaten efficacy, may cause resurgence [6.Kupferschmidt K. New mutations raise specter 'immune escape'.Science. 371: 329Crossref (58) The contagious virus can affect all individuals irrespective age, gender, ethnicity, but varying degrees [7.Chakravarty D. al.Sex differences infection rates potential link prostate cancer.Commun. Biol. 3: 374Crossref (90) Most remain asymptomatic relatively mild flu-like symptoms, increasing transmission significant [8.Oran D.P. Topol E.J. proportion asymptomatic.Ann. Intern. 22, https://doi.org/10.7326/M20-6976)Crossref (28) Nevertheless, vulnerability, aggressiveness/severity hospitalization rates, significantly men, elderly, those one comorbidities/pre-existing conditions hypertension, cerebrovascular diseases, cancers, renal damage Scholar,9.Zhou F. al.Clinical course factors adult inpatients China: retrospective cohort study.Lancet. 395: 1054-1062Abstract (17694) In face pre-existing/comorbid conditions, rapidly progress into septic shock, multiple-organ (MODS), organ failure [10.Zhu L. al.Association type diabetes.Cell Metab. 31: 1068-1077.e1063Abstract (1021) infect multiorgan systems dependent expression/distribution pattern host angiotensin-converting enzyme receptor (ACE2; which binds spike protein) transmembrane serine protease (TMPRSS2; cleaves primes protein), various organs tissues, facilitating activation cell [11.Hoffmann al.SARS-CoV-2 depends ACE2 TMPRSS2 blocked by clinically proven inhibitor.Cell. 181: 271-280.e278Abstract (12478) Scholar,12.Ashraf U.M. al.SARS-CoV-2, expression, systemic invasion.Physiol. Genomics. 53: 51-60Crossref (79) Comorbidities, diabetes upregulate ACE2, leading load within tissues [13.Kruglikov I.L. al.Obesity COVID-19: Underlying mechanisms role viral–bacterial interactions.eLife. 9e61330Crossref Furthermore, shedding from surface obese subjects facilitates redistribution body its accumulation lungs Conversely, plays crucial regulating renin–angiotensin–aldosterone system (RAAS) hence supports protects pulmonary function [14.Malhotra A. al.ACE2, Metformin, COVID-19.iScience. 23: 101425Abstract (36) 15.Scheen A.J. Metformin From cellular mortality.Diabetes 46: 423-426Crossref (109) 16.Sharma S. al.Metformin A possible beyond diabetes.Diabetes Res. Clin. Pract. 164: 108183Abstract (136) maintains balance downregulating angiotensin II (AngII) activating ACE2/Ang(1-7)/MAS axis RAAS, thereby conferring protective vasodilatory, vascular protective, antifibrotic, antiproliferative, anti-inflammatory effects [17.Banu N. al.Protective downregulation macrophage syndrome: therapeutic implications.Life Sci. 256: 117905Crossref (115) Therefore, depletion binding lead adverse cardiopulmonary injury [12.Ashraf Interestingly, ACE2-expressing cells (ECs) vasculature targets [18.Goshua G. al.Endotheliopathy COVID-19-associated coagulopathy: evidence single-centre, cross-sectional study.Lancet Haematol. 7: e575-e582Abstract (699) 19.Kumar mediated leads thrombosis patients.Med. 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Hyg. 103: 69-72Crossref (190) This opinion article highlights benefits investigates possibility Diabetic compromised prone bacterial infections/diseases, time, longer-lasting [24.Toniolo al.The infections: suggestions microbiology.Rev. Microbiol. 2019; 30: 1-17Crossref (75) Proper maintenance (avoiding consistent hyperglycemia) closely fight An aggravated response-related observed bacterial/viral hyperglycemic/diabetic reversed maintaining levels. Plotting glycated hemoglobin (HbA1c) infection/COVID-19-related shows characteristic J-curve, indicates (respiratory particular) Although did not COVID-19, there Elderly severely ill exhibited exaggerated were likely mechanical markedly without [25.Yan Y. characteristics covid-19 diabetes.BMJ Open Care. 8e001343Crossref (345) Worldwide studies corroborated pneumonia cases, (Table 1).Table 1Prevalence Pre-existing Outcomes (Adapted Scholar])Study typeStudy originStudy populationPrevalence (%)OutcomeRefsRetrospectiveChina25824↑ Mortality[26.Zhang mellitus study.Diabetes 165: 108227Abstract Scholar]Meta-analysisIndia16 003 (from 33 studies)9.8↑ Disease severity↑ Mortality[27.Kumar al.Is COVID-19? meta-analysis.Diabetes Syndr. 14: 535-545Crossref (402) Scholar]RetrospectiveChina1590NA↑ invasive ventilation, death[28.Guan W.-j. al.Comorbidity impact 1590 nationwide analysis.Eur. Respir. 55: 2000547Crossref (8) Scholar]Meta-analysisChina1527 6 studies)9.7↑ admissions[29.Li B. al.Prevalence diseases China.Clin. Cardiol. 109: 531-538Crossref (1280) Scholar]Meta-analysisItaly1687 studies)NA↑ severity[30.Fadini G.P. infected SARS-CoV-2.J. Investig. 43: 867-869Crossref (314) Scholar]Meta-analysisItaly355 studies)35.5↑ Mortality[30.Fadini Scholar]RetrospectiveUSA527922.6↑ Hospitalization[31.Petrilli C.M. al.Factors hospital admission critical illness 5279 York City: prospective study.BMJ. 369m1966Crossref (1652) Scholar]Meta-analysisItaly1382 4 admissions[32.Roncon al.Diabetic short-term outcome.J. 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Язык: Английский

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Asthma phenotypes, associated comorbidities, and long‐term symptoms in COVID‐19

Allergy, Год журнала: 2021, Номер 77(1), С. 173 - 185

Опубликована: Июнь 4, 2021

It is unclear whether asthma and its allergic phenotype are risk factors for hospitalization or severe disease from SARS-CoV-2. All patients over 28 days old testing positive SARS-CoV-2 between March 1 September 30, 2020, were retrospectively identified characterized through electronic analysis at Stanford. A sub-cohort was followed prospectively to evaluate long-term COVID-19 symptoms. 168,190 underwent testing, 6,976 (4.15%) tested positive. In a multivariate analysis, not an independent factor (OR 1.12 [95% CI 0.86, 1.45], p = .40). Among SARS-CoV-2-positive asthmatics, lowered the of had protective effect compared with non-allergic 0.52 [0.28, 0.91], .026); there no association baseline medication use as by GINA risk. Patients lower eosinophil levels during mild asymptomatic disease, status (p .0014). patient longitudinally, asthmatics non-asthmatics similar time resolution symptoms, particularly respiratory Asthma more disease. Allergic half likely be hospitalized asthmatics. Lower counts (allergic biomarkers) associated trajectory. Recovery among 50% reporting ongoing symptoms 3 months post-infection.

Язык: Английский

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Diabetes and coronavirus (SARS-CoV-2): Molecular mechanism of Metformin intervention and the scientific basis of drug repurposing

PLoS Pathogens, Год журнала: 2021, Номер 17(6), С. e1009634 - e1009634

Опубликована: Июнь 22, 2021

Coronavirus Disease 2019 (COVID-19), caused by a new strain of coronavirus called Severe Acute Respiratory Syndrome 2 (SARS-CoV-2), was declared pandemic WHO on March 11, 2020. Soon after its emergence in late December 2019, it noticed that diabetic individuals were at an increased risk COVID-19–associated complications, ICU admissions, and mortality. Maintaining proper blood glucose levels using insulin and/or other oral antidiabetic drugs (such as Metformin) reduced the detrimental effects COVID-19. Interestingly, COVID-19 patients, while administration associated with adverse outcomes, Metformin treatment correlated significant reduction disease severity mortality rates among affected individuals. extensively studied for antioxidant, anti-inflammatory, immunomodulatory, antiviral capabilities would explain ability to confer cardiopulmonary vascular protection Here, we describe various possible molecular mechanisms contribute therapy’s beneficial lay out scientific basis repurposing use patients.

Язык: Английский

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Possible Involvement of Adipose Tissue in Patients With Older Age, Obesity, and Diabetes With SARS-CoV-2 Infection (COVID-19) via GRP78 (BIP/HSPA5): Significance of Hyperinsulinemia Management in COVID-19

Diabetes, Год журнала: 2021, Номер 70(12), С. 2745 - 2755

Опубликована: Окт. 6, 2021

Aging, obesity, and diabetes are major risk factors for the severe progression outcome of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019 [COVID-19]), but underlying mechanism is not yet fully understood. In this study, we found that SARS-CoV-2 spike protein physically interacts with cell surface GRP78, which promotes binding to accumulation in ACE2-expressing cells. GRP78 was highly expressed adipose tissue increased humans mice older age, diabetes. The overexpression attributed hyperinsulinemia adipocytes, part mediated by stress-responsive transcription factor XBP-1s. Management pharmacological approaches, including metformin, sodium-glucose cotransporter inhibitor, or β3-adrenergic receptor agonist, decreased gene expression tissue. Environmental interventions, exercise, calorie restriction, fasting, cold exposure, reduced This study provides scientific evidence role as a partner ACE2, might be related COVID-19 patients management could therapeutic preventative target.

Язык: Английский

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