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.; Esko, Jeffrey D.

doi:10.1101/2020.07.14.201616

Cited by 169 publications

(270 citation statements)

References 61 publications

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“…Of these, severe acute respiratory syndrome coronavirus (SARS-CoV-2) (Lang et al, 2011), dengue (Chen et al, 1997), human papillomavirus (Giroglou et al, 2001), hepatitis B (Schulze et al, 2007), herpes simplex virus (Spear et al, 1992), human immunodeficiency virus (Connell and Lortat-Jacob, 2013), and others, target heparan sulfate (HS), a highly negatively charged linear polysaccharide present on the surface of all mammalian cells (Esko and Selleck, 2002). Infection by SARS-CoV-2, the causative agent of COVID-19, can be blocked with the HS derivative heparin (Kim et al, 2020;Mycroft-West et al, 2020;Clausen and Sandoval et al, 2020). SARS-CoV-2 attachment and infection requires binding to both HS and angiotensin converting enzyme 2 (ACE2) via distinct regions of the receptor binding domain (RBD) (Clausen and Sandoval et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Infection by SARS-CoV-2, the causative agent of COVID-19, can be blocked with the HS derivative heparin (Kim et al, 2020;Mycroft-West et al, 2020;Clausen and Sandoval et al, 2020). SARS-CoV-2 attachment and infection requires binding to both HS and angiotensin converting enzyme 2 (ACE2) via distinct regions of the receptor binding domain (RBD) (Clausen and Sandoval et al, 2020). Reducing the interaction between the SARS-CoV-2 spike protein and host-cell HS is therefore an attractive approach to reduce viral docking and subsequent infection.…”

Section: Introductionmentioning

confidence: 99%

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Bacterial modification of the host glycosaminoglycan heparan sulfate modulates SARS-CoV-2 infectivity

Martino

Kellman

Sandoval

et al. 2020

Preprint

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The human microbiota has a close relationship with human disease and it remodels components of the glycocalyx including heparan sulfate (HS). Studies of the severe acute respiratory syndrome coronavirus (SARS-CoV-2) spike protein receptor binding domain suggest that infection requires binding to HS and angiotensin converting enzyme 2 (ACE2) in a codependent manner. Here, we show that commensal host bacterial communities can modify HS and thereby modulate SARS-CoV-2 spike protein binding and that these communities change with host age and sex. Common human-associated commensal bacteria whose genomes encode HS-modifying enzymes were identified. The prevalence of these bacteria and the expression of key microbial glycosidases in bronchoalveolar lavage fluid (BALF) was lower in adult COVID-19 patients than in healthy controls. The presence of HS-modifying bacteria decreased with age in two large survey datasets, FINRISK 2002 and American Gut, revealing one possible mechanism for the observed increase in COVID-19 susceptibility with age. In vitro, bacterial glycosidases from unpurified culture media supernatants fully blocked SARS-CoV-2 spike binding to human H1299 protein lung adenocarcinoma cells. HS-modifying bacteria in human microbial communities may regulate viral adhesion, and loss of these commensals could predispose individuals to infection. Understanding the impact of shifts in microbial community composition and bacterial lyases on SARS-CoV-2 infection may lead to new therapeutics and diagnosis of susceptibility.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bacterial modification of the host glycosaminoglycan heparan sulfate modulates SARS-CoV-2 infectivity

Martino

Kellman

Sandoval

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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“…Another therapeutic application of heparin is its use as an inhibitor of viral adhesion. 13 This is also supported by the observation that heparin disrupts the interaction of the SARS-CoV-2 surface protein Spike with its host cell receptors of various organs via its S1 receptor 14 as follows:…”

Section: Heparin's Nonanticoagulant Antiviral Actionsmentioning

confidence: 81%

The Multiple Faces of Heparin: Opportunities in COVID-19 Infection and Beyond

2020

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“…However, the failure of highly speci c ACE2 pharmaceuticals to stop SARS-CoV-2 infection and related disease, COVID-19, clearly highlights the complexity of SARS-CoV-2 internalization 85 . Emerging evidence show the collaboration of ACE2 and HSPGs during SARS-CoV-2 uptake 37 .…”

Section: Discussionmentioning

confidence: 99%

“…S1). According to most recent models for SARS-CoV-2 infection, viral attachment and infection involve the formation of a complex between heparan sulfate (HS) and ACE2 37 .…”

Section: Development Of E Cient Therapeutics Against Covid-19 Is Hampmentioning

confidence: 99%

Contribution of syndecans to the cellular entry of SARS-CoV-2

Hudák

Szilák

Letoha

2020

Preprint

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel emerging pathogen causing an unprecedented pandemic in 21st century medicine. Due to the significant health and economic burden of the current SARS-CoV-2 outbreak, there is a huge unmet medical need for novel interventions effectively blocking SARS-CoV-2 infection. Unknown details of SARS-CoV-2 cellular biology significantly hamper the development of potent and highly specific SARS-CoV-2 therapeutics. Angiotensin-converting enzyme-2 (ACE2) has been reported to be the primary receptor for SARS-CoV-2 cellular entry. However, emerging scientific evidence suggests the involvement of additional membrane proteins, such as heparan sulfate proteoglycans, in SARS-CoV-2 internalization. Here we report that syndecans, the evolutionarily conserved family of transmembrane proteoglycans facilitate the cellular entry of SARS-CoV-2. Among syndecans, syndecan-4 was the most efficient in mediating SARS-CoV-2 uptake, yet overexpression of other isoforms, including the neuronal syndecan-3, also increased SARS-CoV-2 internalization. The S1 subunit of the SARS-CoV-2 spike protein plays a dominant role in the virus’s interactions with syndecans. Besides the polyanionic heparan sulfate chains - the established binding sites for several viruses - other parts of the syndecan ectodomain, such as the cell-binding domain, also contribute to the interaction with SARS-CoV-2. During virus internalization, syndecans colocalize with ACE2, suggesting a jointly shared internalization pathway. Both ACE2 and syndecan inhibitors exhibited significant efficacy in reducing cellular entry of SARS-CoV-2, thus supporting the complex nature of internalization. Among these inhibitors, a peptide compromising the spike protein’s heparin-binding PRRAR motif significantly reduced SARS-CoV-2 cellular uptake, highlighting the need to go beyond the ACE2 paradigm for developing efficient therapeutics against SARS-CoV-2. Data obtained on syndecan specific in vitro assays present syndecans as novel cellular targets of SARS-CoV-2 and offers molecularly precise, yet simple strategies in overcoming the complex nature of SARS-CoV-2 infection.

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

Cited by 169 publications

References 61 publications

Bacterial modification of the host glycosaminoglycan heparan sulfate modulates SARS-CoV-2 infectivity

Bacterial modification of the host glycosaminoglycan heparan sulfate modulates SARS-CoV-2 infectivity

The Multiple Faces of Heparin: Opportunities in COVID-19 Infection and Beyond

Contribution of syndecans to the cellular entry of SARS-CoV-2

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