SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2

Clausen, Thomas; Sandoval, Daniel R.; Spliid, Charlotte B.; Pihl, Jessica; Perrett, Hailee R.; Painter, Chelsea D.; Narayanan, A.; Majowicz, Sydney A.; Kwong, Elizabeth M.; McVicar, Rachael N.; Thacker, Bryan E.; Glass, Charles; Yang, Zifeng; Torres, Jonathan L.; Golden, Gregory J.; Bartels, Phillip L.; Porell, Ryan N; Garretson, Aaron F.; Laubach, Logan K.; Feldman, Jared; Yin, Xin; Pu, Yuan; Hauser, Blake M.; Caradonna, Timothy M.; Kellman, Benjamin P.; Martino, Cameron; Gordts, Philip L.S.M.; Chanda, Sumit K.; Schmidt, Aaron; Godula, Kamil; Leibel, Sandra L.; Jose, Joyce; Corbett, K.D.; Ward, Andrew B.; Carlin, Aaron F.; Esko, Jeffrey D.

doi:10.1016/j.cell.2020.09.033

Cited by 988 publications

(1,287 citation statements)

References 67 publications

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“…In addition, we also found that heparin could also significantly inhibited SARS-CoV-2 pseudovirus infection ( Fig. S2A-C ), indicating heparins potential for treatment of SARS-CoV-2 infection, and the heparan sulphate could be the potential co-receptor for SARS-CoV-2 infection 14 . These findings suggest that hLPCs and also hAFECs are permissive for SARS-CoV-2 pseudovirus and GX_P2V infection.…”

Section: Resultsmentioning

confidence: 69%

SARS-CoV-2 and Malayan pangolin coronavirus infect human endoderm, ectoderm and induced lung progenitor cells

Hong

Lai

Chen

et al. 2020

Preprint

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Since the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in several somatic cells, little is known about the infection of SASRS-CoV-2 and its related pangolin coronavirus (GX_P2V). Here we present for the first time that SARS-CoV-2 pseudovirus and GX_P2V could infect lung progenitor and even anterior foregut endoderm cells causing these cells death, which differentiated from human embryonic stem cells (hESCs). The infection and replication of SARS-CoV-2 and GX_P2V were inhibited when treated with whey protein of breastmilk and Remdesivir, confirming that these two viruses could infect lung progenitor and even anterior foregut endoderm. Moreover, we found that SARS-CoV-2 pseudovirus could infect endoderm and ectoderm. We found that whey protein blocked SARS-CoV-2 infecting these cells. In line with the SARS-CoV-2 results, GX_P2V could also infected endoderm and ectoderm, and also was inhibited by Remdesivir treatment. Although expressing coronavirus related receptor such as ACE2 and TMPRSS2, mesoderm cells are not permissive for SARS-CoV-2 and GX_P2V infection, which needed further to study the mechanisms. Interestingly, we also found that hESCs, which also express ACE2 and TMPRSS2 markers, are permissive for GX_P2V but not SARS-CoV-2 pseudovirus infection and replication, indicating the widespread cell types for GX_P2V infection. Heparin treatment blocked efficiently viral infection. These results provided insight that these stem cells maybe provided a stable repository of coronavirus function or genome. The potential consequence of SARS-CoV-2 and animal coronavirus such as GX_P2V infection in hESCs, germ layer and induced progenitors should be closely monitored.

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Section: Resultsmentioning

confidence: 69%

SARS-CoV-2 and Malayan pangolin coronavirus infect human endoderm, ectoderm and induced lung progenitor cells

Hong

Lai

Chen

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…8,9,[38][39][40][41][42][43][44][45][46][47] Further, heparin has been shown to block SARS-CoV-2 viral spike protein binding in experimental studies. [48][49][50] We postulate that the combination of heparin's known antithrombotic and anti-inflammatory effects, 6,7 in addition to viral infectivity attenuation may, at least in part, explain the observed benefit associated with prophylactic anticoagulation.…”

Section: Comparison With Other Evidencementioning

confidence: 99%

Early initiation of prophylactic anticoagulation for prevention of COVID-19 mortality: a nationwide cohort study of hospitalized patients in the United States

Rentsch

Beckman

Tomlinson

et al. 2020

Preprint

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ImportanceDeaths among patients with coronavirus disease 2019 (COVID-19) are partially attributed to venous thromboembolism and arterial thromboses. Anticoagulants prevent thrombosis formation, possess anti-inflammatory and anti-viral properties, and may be particularly effective for treating patients with COVID-19.ObjectiveTo evaluate whether initiation of prophylactic anticoagulation within 24 hours of admission is associated with decreased risk of death among patients hospitalized with COVID-19.DesignObservational cohort study.SettingNationwide cohort of patients receiving care in the Department of Veterans Affairs, the largest integrated healthcare system in the United States.ParticipantsAll patients hospitalized with laboratory-confirmed SARS-CoV-2 infection March 1 to July 31, 2020, without a history of therapeutic anticoagulation.ExposuresProphylactic doses of subcutaneous heparin, low-molecular-weight heparin, or direct oral anticoagulants.Main Outcomes and Measures30-day mortality. Secondary outcomes: inpatient mortality and initiating therapeutic anticoagulation.ResultsOf 4,297 patients hospitalized with COVID-19, 3,627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99% (n=3,600) received subcutaneous heparin or enoxaparin. We observed 622 deaths within 30 days of admission, 513 among those who received prophylactic anticoagulation. Most deaths (510/622, 82%) occurred during hospitalization. In inverse probability of treatment weighted analyses, cumulative adjusted incidence of mortality at 30 days was 14.3% (95% CI 13.1-15.5) among those receiving prophylactic anticoagulation and 18.7% (95% CI 15.1-22.9) among those who did not. Compared to patients who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30-day mortality (HR 0.73, 95% CI 0.66-0.81). Similar associations were found for inpatient mortality and initiating therapeutic anticoagulation. Quantitative bias analysis demonstrated that results were robust to unmeasured confounding (e-value lower 95% CI 1.77). Results persisted in a number of sensitivity analyses.Conclusions and RelevanceEarly initiation of prophylactic anticoagulation among patients hospitalized with COVID-19 was associated with a decreased risk of mortality. These findings provide strong real-world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial therapy for COVID-19 patients upon hospital admission.

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“…Enzymatic cleavage of protein S at the level of S1/S2 domains supports fusion of viruses to cell membranes via the S2 subunit (Liu et al, 2020). SARS-CoV2 S-protein interacts with both the cellular HS and ACE2 through its RBD and can simultaneously engage heparin and ACE2 (Clausen et al, 2020). Positively charged amino acids in a subdomain of RBD are responsible for the binding of heparin/HS complex via an interaction site that appears independent on the site involved in ACE2 binding (Clausen et al, 2020).…”

Section: Midkine Heparan Sulfate and Extracellular Matrix: A Role Fmentioning

confidence: 99%

“…SARS-CoV2 S-protein interacts with both the cellular HS and ACE2 through its RBD and can simultaneously engage heparin and ACE2 (Clausen et al, 2020). Positively charged amino acids in a subdomain of RBD are responsible for the binding of heparin/HS complex via an interaction site that appears independent on the site involved in ACE2 binding (Clausen et al, 2020). SARS CoV2 protein S appears to bind HS cooperatively with ACE2 receptor on the cell surface (Clausen et al, 2020).…”

Section: Midkine Heparan Sulfate and Extracellular Matrix: A Role Fmentioning

confidence: 99%

Physiology of Midkine and Its Potential Pathophysiological Role in COVID-19

2020

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SARS-CoV2 infection not only causes abnormal severe pneumonia but also induces other relevant pathophysiological effects on several tissues and organs. In this regard, the clinical complications observed in COVID-19 include acute coronary syndrome, pulmonary thromboembolism, myocarditis and, in the severe cases, the occurrence of disseminated intravascular coagulation. Literature on COVID-19 highlighted the central role of the Renin Angiotensin Aldosterone System in the determinism of SARS-CoV2 cellular internalization in the target tissues. Lung degeneration and respiratory distress appear to be dependent on the perturbance of physiological mechanisms, such as the uncontrolled release of pro-inflammatory cytokines, a dysregulation of the fibrinolytic coagulative cascade and the hyperactivation of immune effector cells. In this mini review, we address the physiology of Midkine, a growth factor able to bind heparin, and its pathophysiological potential role in COVID-19 determinism. Midkine increases in many inflammatory and autoimmune conditions and correlates with several dysfunctional immune-inflammatory responses that appear to show similarities with the pathophysiological elicited by SARS-CoV2. Midkine, together with its receptor, could facilitate the virus entry, fostering its accumulation and increasing its affinity with Ace2 receptor. We also focus on Netosis, a particular mechanism of pathogen clearance exerted by neutrophils, which under certain pathological condition becomes dysfunctional and can cause tissue damage. Moreover, we highlight the mechanism of autophagy that the new coronavirus could try to escape in order to replicate itself, as well as on pulmonary fibrosis induced by hypoxia and on the release of cytokines and mediators of inflammation, correlating the interplay between Midkine and SARS-CoV2.

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SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2

Cited by 988 publications

References 67 publications

SARS-CoV-2 and Malayan pangolin coronavirus infect human endoderm, ectoderm and induced lung progenitor cells

SARS-CoV-2 and Malayan pangolin coronavirus infect human endoderm, ectoderm and induced lung progenitor cells

Early initiation of prophylactic anticoagulation for prevention of COVID-19 mortality: a nationwide cohort study of hospitalized patients in the United States

Physiology of Midkine and Its Potential Pathophysiological Role in COVID-19

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