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

Clausen, Thomas; Sandoval, Daniel R.; Spliid, Charlotte B.; Pihl, Jessica; Painter, Chelsea D.; Thacker, Bryan E.; Glass, Charles; Narayanan, A.; Majowicz, Sydney A.; Yang, Zifeng; Torres, Jonathan L.; Golden, Gregory J.; 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.; Leibel, Sandra L.; Chanda, Summit K.; Schmidt, Aaron; Godula, Kamil; Jose, Joyce; Corbett, K.D.; Ward, Andrew B.; Carlin, Aaron F.

doi:10.2139/ssrn.3657535

Cited by 21 publications

(5 citation statements)

References 48 publications

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“…EXTL2 encodes a glycosyltransferase involved in the chain elongation step of heparan sulfate (HS) biosynthesis [54,55]. Several heparan sulfate biosynthetic genes were also markedly enriched in other CRISPR knockout SARS-CoV-2 screens conducted in Huh7.5.1 cells [22,23] consistent with a recent report that SARS-CoV-2 infection is co-dependent on heparan sulfate and ACE2 [56]. Since HS is ubiquitously expressed on the surfaces and in the extracellular matrix of all cell types, EXTL2 may play a central pro-viral role through heparan sulfate production that may determine SARS-CoV-2 tropism.…”

Section: Sars-cov-2 Infectionsupporting

confidence: 73%

CRISPR screens for host factors critical for infection by SARS-CoV-2 variants of concern identify GATA6 as a central modulator of ACE2

Finkel

Israeli

Beth-Din

et al. 2021

Preprint

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The global spread of SARS-CoV-2 lead to the most challenging pandemic in this century, posing major economic and health challenges worldwide. Revealing host genes essential for infection by multiple variants of SASR-CoV-2 can provide insights into the virus pathogenesis, and facilitates the development of novel broad-spectrum host-directed therapeutics. Here, employing genome-scale CRISPR screens, we provide a comprehensive data-set of cellular factors that are exploited by WT-SARS-CoV-2 as well as two additional recently emerged variants of concerns (VOCs), Alpha and Beta. These screens identified known and novel host factors critical for SARS-CoV-2 infection, including various components belonging to the Clathrin-dependent transport pathway, ubiquitination and Heparan sulfate biogenesis. In addition, the host metabolic pathways pertaining to mitochondrial activity as well as phosphatidylglycerol biosynthesis processes appeared to have major anti-viral functions. Comparative analysis between the different VOCs revealed the receptor KREMEN2 as unique gene required only to the Alpha variant, providing a possible explanation for the increased infectivity of this variant. Furthermore, the analysis identified GATA6, a zinc finger transcription factor, as an essential pro-viral gene for all variants inspected. We reveal that GATA6 directly regulates ACE2 transcription and is accordingly, critical for SARS-CoV-2 cell entry. Analysis of clinical samples collected from SARS-CoV-2 infected individuals showed an elevated level of GATA6, indicating the important role GATA6 may be playing in COVID-19 pathogenesis. Finally, pharmacological inhibition of GATA6 results in down-modulation of ACE2 and consequently to inhibition of the viral infectivity. Overall, we show GATA6 represents a target for the development of anti-SARS-CoV-2 therapeutic strategies and reaffirm the value of the CRISPR loss-of-function screens in providing a list of potential new targets for therapeutic interventions.

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Section: Sars-cov-2 Infectionsupporting

confidence: 73%

CRISPR screens for host factors critical for infection by SARS-CoV-2 variants of concern identify GATA6 as a central modulator of ACE2

Finkel

Israeli

Beth-Din

et al. 2021

Preprint

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“…These findings suggested that ACE2 expression levels may vary substantially between individuals or during an infection 81 or that SARS-CoV-2 can use alternate receptors to enter certain cell types (ie, the cell surface protein basigin (BSG, also known as CD147) 82 and CD26. 83 Several proteins have been recently identified to interact with SARS-CoV-2, including lectin receptors and multiple innate immune receptors, 84 heparan sulfate, 85 neuropilins, asialoglycoprotein receptor 1, and Kremen protein 1. 86 However, most of them lack virologyrelated evidence to support their roles as SARS-CoV-2 entry factors.…”

Section: Introductionmentioning

confidence: 99%

Current status of the COVID‐19 and male reproduction: A review of the literature

et al. 2021

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Background: Coronavirus disease 2019 , which causes serious respiratory illnesses such as pneumonia and lung failure, was first reported in mid-December 2019 in China and has spread around the world. In addition to causing serious respiratory illnesses such as pneumonia and lung failure, there have been conflicting reports about the presence of SARS-CoV-2 in the semen of patients who were previously diagnosed with COVID-19 and possible implications for the male reproductive tract. Objective:The goal for the present study was to review the current status of the literature concerning COVID-19 and male reproduction. Material and methods: An electronic literature search was done by using PubMed and Google Scholar databases. Relevant papers, concerning SARS-COV-2 and COVID-19 and male reproduction, published between January 2020 and December 2020 were selected, analyzed and eventually included in the present literature review.Results: SARS-CoV-2 may infect any cell type expressing angiotensin-converting enzyme 2 (ACE2), including reproductive cells. Besides the presence of the SARS-CoV-2 receptor, the expression of host proteases, such as transmembrane serine protease 2 (TMPRSS2), is needed to cleave the viral S protein, allowing permanent fusion of the viral and host cell membranes. Here, we aimed to review the current status of the literature concerning COVID-19 and male reproduction. The lack of co-expression of ACE2 and TMPRSS2 in the testis suggests that sperm cells may not be at increased risk of viral entry and spread. However, the presence of orchitis in COVID-19-confirmed patients and compromised sex-related hormonal balance among these patients intrigues reproductive medicine.Discussion: SARS-CoV-2 may use alternate receptors to enter certain cell types, or the expression of ACE2 and TMPRSS2 may not be detected in healthy individuals. Conclusion: COVID-19 challenges all medical areas, including reproductive medicine.It is not yet clear what effects, if any, the COVID-19 pandemic will have on male reproduction. Further research is needed to understand the long-term impact of SARS-CoV-2 on male reproductive function. K E Y W O R D SCOVID-19, male reproduction, SARS-CoV-2, testicles, viral 2 | 1 | INTRODUC TI ON Since the first case of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was reported in Wuhan, China, it has rapidly spread and affected more than 21 million people worldwide as of 17 August 2020. 1 SARS-CoV-2 uses angiotensin-converting enzyme II (ACE2) to enter host cells, similar to SARS-CoV, which emerged 18 years ago. 2COVID-19 induces respiratory-predominant multiorgan dysfunction, including myocardial, renal, enteric and hepatic dysfunction, which coincides with the tissue expression of ACE2. 3 Meanwhile, several studies have shown that ACE2 is expressed in human testes (eg spermatogonia, Leydig cells and Sertoli cells), 4,5 suggesting that the testes may be another organ affected by COVID-19.Numerous viruses have been detected in human...

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“…The results of the current study show that enoxaparin effectively hinders the binding of NP to the cell surface in a dose-dependent manner and as a result significantly reduces the levels of C3b deposition, exposing another, yet unreported benefit of heparin analogs beneficial usage for COVID-19 management in addition to their known roles in clot prevention and inhibition of spike mediated virus entry (39–41).…”

Section: Discussionmentioning

confidence: 82%

“…Moreover, enoxaparin showed a dose dependent capacity to reduce cell surface binding of anti-NP IgGs (Figure 6D), in line with the observed NP displacement (Figure 6C). Accordingly, enoxaparin exhibited potent 15 rescue of A549 cells from anti-NP IgG driven complement deposition (Figure 6E, see also Supplementary Figure S5), revealing a novel, previously not yet considered mechanistic facet of immunological COVID-19 management with soluble heparin analogs, in addition to their previously reported benefits such as inhibition of SARS-CoV-2 entry (39,40) and prevention of blood clotting (41).…”

Section: Anti-np Iggs Activate the Classical Complement Pathway Targe...mentioning

confidence: 75%

Binding of SARS-CoV-2 nucleocapsid protein to uninfected epithelial cells induces antibody-mediated complement deposition

Fahoum,

Billan,

Varga

et al. 2024

Preprint

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SARS-CoV-2 infection triggers strong antibody response toward Nucleocapsid-Protein (NP), suggesting extracellular presence beyond its intra-virion RNA binding. Interestingly, NP was found to decorate infected and proximal uninfected cell-surfaces. Here, we propose a new mechanism through which extracellular NP on uninfected cells contributes to COVID-19 pathogenicity. We show that NP binds to cell-surface sulfated linear-glycosaminoglycans by spatial rearrangement of its RNA-binding sites facilitated by the flexible, positively charged, linker. Coating of uninfected lung-derived cells with purified NP attracted anti-NP-IgG from lung fluids and sera collected from COVID-19 patients. The magnitude of this immune recognition was significantly elevated in moderate compared to mild COVID-19 cases. Importantly, binding of anti-NP-IgG present in sera generated clusters that triggered C3b deposition by the classical complement pathway. Heparin analog enoxaparin outcompeted NP-binding, rescuing cells from anti-NP IgG-mediated complement deposition. Our findings unveil how extracellular NP may exacerbate COVID-19 tissue damage, and suggest leads for preventative therapy.

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

Cited by 21 publications

References 48 publications

CRISPR screens for host factors critical for infection by SARS-CoV-2 variants of concern identify GATA6 as a central modulator of ACE2

CRISPR screens for host factors critical for infection by SARS-CoV-2 variants of concern identify GATA6 as a central modulator of ACE2

Current status of the COVID‐19 and male reproduction: A review of the literature

Binding of SARS-CoV-2 nucleocapsid protein to uninfected epithelial cells induces antibody-mediated complement deposition

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