Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate

Prieto-Fernández, Endika; Egia-Mendikute, Leire; Vila-Vecilla, Laura; Bosch, Alexandre; Barreira-Manrique, Adrián; Lee, So Young; Río, Ana García-del; Antoñana-Vildosola, Asier; Jiménez-Lasheras, Borja; Moreno‐Cugnon, Leire; Jiménez‐Barbero, Jesús; Berra, Edurne; Ereño‐Orbea, June; Palazón, Asís

doi:10.1080/22221751.2021.1932607

Cited by 28 publications

(23 citation statements)

References 45 publications

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“…Our latest SARS-CoV-2 study showed that SDCs, especially SDC4 enriched in the lung, facilitate SARS-CoV-2’s entry into the cells by attaching the S1 subunit of the spike protein [ 25 ]. Other research groups also implied the role of SDC1 in SARS-CoV-2 infection [ 24 , 36 , 37 , 38 ]. Thus, SDC1 and SDC4 transfectants, created in human myeloid K562 cells, were incubated with WT and Delta spike proteins.…”

Section: Resultsmentioning

confidence: 99%

Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission

Hudák¹,

Veres²,

Letoha

et al. 2022

IJMS

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Emerging SARS-CoV-2 variants pose threats to vaccination campaigns against COVID-19. Being more transmissible than the original virus, the SARS-CoV-2 B.1.617 lineage, named the Delta variant, swept through the world in 2021. The mutations in the Delta’s spike protein shift the protein towards a net positive electrostatic potential. To understand the key molecular drivers of the Delta infection, we investigate the cellular uptake of the Delta spike protein and Delta spike-bearing SARS-CoV-2 pseudoviruses. Specific in vitro modification of ACE2 and syndecan expression enabled us to demonstrate that syndecan-4, the syndecan isoform abundant in the lung, enhances the transmission of the Delta variant by attaching its mutated spike glycoprotein and facilitating its cellular entry. Compared to the wild-type spike, the Delta one shows a higher affinity towards heparan sulfate proteoglycans than towards ACE2. In addition to attachment to the polyanionic heparan sulfate chains, the Delta spike’s molecular interactions with syndecan-4 also involve syndecan-4’s cell-binding domain that mediates cell-to-cell adhesion. Regardless of the complexity of these interactions, exogenously added heparin blocks Delta’s cellular entry as efficiently as syndecan-4 knockdown. Therefore, a profound understanding of the molecular mechanisms underlying Delta infections enables the development of molecularly targeted yet simple strategies to reduce the Delta variant’s spread.

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Section: Resultsmentioning

confidence: 99%

Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission

Hudák¹,

Veres²,

Letoha

et al. 2022

IJMS

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“…Due to the role of syndecans in viral infections, Hudaḱ et al explored the possible interactions between SARS-CoV-2 S protein and the isoforms of syndecans, identifying that syndecan-3 and -4 facilitated the uptake of SARS-CoV-2 (Figure 1), and syndecan-4 specifically interacts with the S1 subunit of the S protein to mediate SARS-CoV-2 internalization (15). Moreover, syndecan-1 mediates cell attachment of S protein in lung epithelial cells (136). The hypoxia could modulate the expression of ACE-2 and syndecan-1 receptors, suggesting that low oxygen levels in COVID-19 patients are a defense mechanism to reduce the expression of entry receptors and attachment factors located in cholesterol-rich lipid rafts (136).…”

Section: Syndecansmentioning

confidence: 99%

“…Moreover, syndecan-1 mediates cell attachment of S protein in lung epithelial cells (136). The hypoxia could modulate the expression of ACE-2 and syndecan-1 receptors, suggesting that low oxygen levels in COVID-19 patients are a defense mechanism to reduce the expression of entry receptors and attachment factors located in cholesterol-rich lipid rafts (136). Notably, the distribution of syndecan-4 is ubiquitous, and its expression is abundant in the lungs, one of the target organs of SARS-CoV-2 (137).…”

Section: Syndecansmentioning

confidence: 99%

Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry

et al. 2021

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Since its appearance, the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), the causal agent of Coronavirus Disease 2019 (COVID-19), represents a global problem for human health that involves the host lipid homeostasis. Regarding, lipid rafts are functional membrane microdomains with highly and tightly packed lipid molecules. These regions enriched in sphingolipids and cholesterol recruit and concentrate several receptors and molecules involved in pathogen recognition and cellular signaling. Cholesterol-rich lipid rafts have multiple functions for viral replication; however, their role in SARS-CoV-2 infection remains unclear. In this review, we discussed the novel evidence on the cholesterol-rich lipid rafts as a platform for SARS-CoV-2 entry, where receptors such as the angiotensin-converting enzyme-2 (ACE-2), heparan sulfate proteoglycans (HSPGs), human Toll-like receptors (TLRs), transmembrane serine proteases (TMPRSS), CD-147 and HDL-scavenger receptor B type 1 (SR-B1) are recruited for their interaction with the viral spike protein. FDA-approved drugs such as statins, metformin, hydroxychloroquine, and cyclodextrins (methyl-β-cyclodextrin) can disrupt cholesterol-rich lipid rafts to regulate key molecules in the immune signaling pathways triggered by SARS-CoV-2 infection. Taken together, better knowledge on cholesterol-rich lipid rafts in the SARS-CoV-2-host interactions will provide valuable insights into pathogenesis and the identification of novel therapeutic targets.

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“…Cell culture data derived from alveolar and bronchial epithelial cells have revealed that although some of the HIF-α targets, such as VEGF, are upregulated by SARS-CoV-2, VHL that targets HIF-α to degradation is also upregulated [28]. In turn, HIF-1α activation inhibits SARS-CoV-2 infection in the these cells [22], at least in part due to lower ACE2 expression and subsequent reduction of cell attachment of the viral spike protein [29]. In serum, lower levels of EPO have been detected in COVID-19 critical and deceased patient groups than in healthy ones [30].…”

Section: Introductionmentioning

confidence: 99%

Alteration of L-Dopa decarboxylase expression in SARS-CoV-2 infection and its association with the interferon-inducible ACE2 isoform

et al. 2021

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L-Dopa decarboxylase (DDC) is the most significantly co-expressed gene with ACE2, which encodes for the SARS-CoV-2 receptor angiotensin-converting enzyme 2 and the interferon-inducible truncated isoform dACE2. Our group previously showed the importance of DDC in viral infections. We hereby aimed to investigate DDC expression in COVID-19 patients and cultured SARS-CoV-2-infected cells, also in association with ACE2 and dACE2. We concurrently evaluated the expression of the viral infection- and interferon-stimulated gene ISG56 and the immune-modulatory, hypoxia-regulated gene EPO. Viral load and mRNA levels of DDC, ACE2, dACE2, ISG56 and EPO were quantified by RT-qPCR in nasopharyngeal swab samples from COVID-19 patients, showing no or mild symptoms, and from non-infected individuals. Samples from influenza-infected patients were analyzed in comparison. SARS-CoV-2-mediated effects in host gene expression were validated in cultured virus-permissive epithelial cells. We found substantially higher gene expression of DDC in COVID-19 patients (7.6-fold; p = 1.2e-13) but not in influenza-infected ones, compared to non-infected subjects. dACE2 was more elevated (2.9-fold; p = 1.02e-16) than ACE2 (1.7-fold; p = 0.0005) in SARS-CoV-2-infected individuals. ISG56 (2.5-fold; p = 3.01e-6) and EPO (2.6-fold; p = 2.1e-13) were also increased. Detected differences were not attributed to enrichment of specific cell populations in nasopharyngeal tissue. While SARS-CoV-2 virus load was positively associated with ACE2 expression (r≥0.8, p<0.001), it negatively correlated with DDC, dACE2 (r≤−0.7, p<0.001) and EPO (r≤−0.5, p<0.05). Moreover, a statistically significant correlation between DDC and dACE2 expression was observed in nasopharyngeal swab and whole blood samples of both COVID-19 and non-infected individuals (r≥0.7). In VeroE6 cells, SARS-CoV-2 negatively affected DDC, ACE2, dACE2 and EPO mRNA levels, and induced cell death, while ISG56 was enhanced at early hours post-infection. Thus, the regulation of DDC, dACE2 and EPO expression in the SARS-CoV-2-infected nasopharyngeal tissue is possibly related with an orchestrated antiviral response of the infected host as the virus suppresses these genes to favor its propagation.

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Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2, neuropilin-1, syndecan-1 and cellular heparan sulfate

Cited by 28 publications

References 45 publications

Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission

Syndecan-4 Is a Key Facilitator of the SARS-CoV-2 Delta Variant’s Superior Transmission

Cholesterol-Rich Lipid Rafts as Platforms for SARS-CoV-2 Entry

Alteration of L-Dopa decarboxylase expression in SARS-CoV-2 infection and its association with the interferon-inducible ACE2 isoform

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