How sugars on our cells help COVID-19 virus sneak into the body and damage blood vessels
Nikhil Prasad Fact checked by:Thailand Medical News Team Apr 21, 2025 6 hours, 10 minutes ago
Medical News: Scientists Discover How SARS-CoV-2 Bypasses Defenses and Triggers Vascular Damage in the Body
A new groundbreaking study has revealed how the SARS-CoV-2 virus, even in its newer variants, continues to find clever ways to infect cells in the body—especially cells lining our blood vessels—without using the main receptor it is known for, ACE2. Instead, the virus uses a more discreet route involving sugar-like molecules found on cell surfaces called heparan sulfate proteoglycans or HSPGs. These molecules essentially help the virus unlock another entrance into the body, potentially worsening COVID-19 outcomes by triggering blood vessel damage and promoting abnormal growth of new vessels.
Proposed mechanisms for SARS-CoV-2-induced angiogenesis on ACE2-negative HL-mECs. HSPGs mediate spike/αvβ3 interaction enhancing phosphorylation of FAK, Src and ERK, which mediates Ang-2 and vWF accumulation in WPBs of SARS-CoV-2-infected HL-mECs. Then, Ang-2 secretion and vWF degradation induces infected-HL-mECs toward an angiogenic phenotype.
This
Medical News report is based on a study led by researchers from several prestigious European institutions, including the University of Brescia in Italy, the University Campus Bio-Medico of Rome, and the “George Emil Palade” University of Medicine in Romania.
The Hidden Viral Entry Point Most People Never Heard Of
For most people, it’s now common knowledge that the coronavirus gets into human cells by latching onto a protein called ACE2. But this study shows that SARS-CoV-2 can also sneak into certain cells that don’t even have ACE2 on them—specifically, the endothelial cells that line our blood vessels. These cells are crucial for controlling everything from blood pressure to the immune response.
So how does the virus do this? It turns out the virus has a tiny sequence in its spike protein known as the RGD motif, a three-amino-acid code that allows it to connect with a different protein on human cells: the integrin avβ3. But the twist is that the RGD motif is usually hidden and needs to be revealed for this interaction to happen.
That’s where HSPGs come in. These sugar molecules reshape the virus’s spike protein, exposing the RGD motif and making it possible for the virus to bind to the integrin and get inside the cells—completely bypassing ACE2.
Why This Discovery Matters for COVID-19 and Its Long-Term Effects
The implications of this finding are huge. It explains why the virus can cause widespread blood vessel inflammation, clotting problems, and organ damage—even in people with low viral loads or mild respiratory symptoms. Once the virus enters these endothelial cells through the HSPG and integrin route, it doesn't even need to replicate massively to cause chaos. Its presence alone triggers a chain reaction, releasing pro-inflammatory and pro-angiogenic (vessel-growing) molecules.
The study found that w
hen this route is activated, the infected endothelial cells begin secreting a cocktail of harmful proteins including IL-8, FGF-2, and Angiopoietin-2. These molecules inflame blood vessels and trigger the growth of unstable new ones—a hallmark of severe COVID-19 complications.
Some Variants Lost This Ability but Others Are Gaining It Back
Interestingly, not all variants are equally capable of using this stealth pathway. Variants like Omicron BA.5 carry a mutation (D405N) in the RGD motif, which makes them less effective at binding to avβ3 integrin. This means they’re less likely to infect endothelial cells via this backdoor. However, researchers recently discovered a disturbing trend: some newer strains are developing reverse mutations like S405D, effectively regaining the ability to enter cells through this hidden mechanism.
This suggests that the virus is evolving in complex ways, potentially responding to changing immune landscapes or treatment pressures. It raises concerns about future variants once again becoming better at targeting blood vessels, which could increase the severity of disease in vulnerable individuals.
Can We Block This Backdoor to Stop the Virus
The scientists behind the study also tested whether it’s possible to shut this alternate door before the virus can enter. They used substances like Heparinase III and sodium chlorate, which break down or prevent the formation of HSPGs. The result? When these molecules were blocked, the virus could no longer infect the endothelial cells or trigger harmful responses.
Even more excitingly, they found that ordinary heparin—the same drug used to prevent blood clots in hospitals—might double as a preventive measure by interfering with this hidden viral entry. However, more clinical research is needed to confirm this.
Key Findings from the Study in Simple Terms
SARS-CoV-2 can infect blood vessel cells without using ACE2 by revealing a hidden part of its spike protein called the RGD motif.
This exposure is only possible thanks to HSPGs, sugar-like molecules found on most human cells.
The virus uses the RGD motif to latch onto a different protein (integrin avβ3), triggering inflammation and abnormal blood vessel growth.
Variants like Omicron BA.5 have lost this ability due to a mutation, but some newer strains are reversing this change and regaining the ability.
Blocking HSPGs prevents infection and inflammation, making them a potential therapeutic target.
Heparin and similar compounds could help stop the virus from entering through this lesser-known route.
What This Means for the Future of COVID-19 Treatment and Surveillance
The findings offer a new and urgent perspective on how SARS-CoV-2 can continue to cause harm in the body, even in the absence of traditional ACE2 pathways. By showing that endothelial cells can be infected through this alternate route, the study uncovers a major missing link in our understanding of COVID-19’s vascular complications, including blood clotting, stroke, and long COVID symptoms.
From a treatment point of view, the study opens the door to novel strategies focused on blocking HSPGs or modulating integrin interactions. Such approaches could supplement vaccines and antiviral drugs, especially for high-risk patients who are more vulnerable to vascular damage.
From a public health standpoint, the discovery that the virus is evolving to potentially regain this endothelial-infecting ability is concerning. It suggests that we need more robust genomic surveillance, especially of mutations in the RGD motif. These could be early warning signs of new variants with increased potential to cause systemic damage—even in people with strong immunity or mild symptoms.
In conclusion, this study paints a clearer picture of how the coronavirus manipulates human biology to bypass defenses and spark severe illness. The manipulation of HSPGs to expose hidden viral tools like the RGD motif is a powerful reminder that the virus remains adaptable and dangerous. It also highlights the need for therapies that go beyond neutralizing antibodies and address the broader, more insidious ways the virus invades and damages the human body.
The study findings were published in the peer reviewed journal: Frontiers in Cellular and Infection Microbiology
https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2025.1552116/full
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https://www.thailandmedical.news/news/breaking-sars-cov-2-encodes-circular-rnas-that-can-impair-endothelial-cells-and-cause-cardiovascular-issues
https://www.thailandmedical.news/news/sulodexide-effectively-mitigates-thromboinflammation-and-endothelial-damage-reducing-risks-associated-with-long-covid
https://www.thailandmedical.news/news/piezo1-identified-as-playing-a-key-role-in-covid-19-associated-endothelial-dysfunction
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