Scientists Discover That Omicron Sub-Lineages Use Heparan Sulfate to Infect Cells with Low ACE-2
Nikhil Prasad Fact checked by:Thailand Medical News Team Jul 02, 2025 6 days, 9 hours, 35 minutes ago
Thailand Medical News:
New Mechanism Behind Omicron's Infectivity Uncovered
A groundbreaking study from a team of Japanese scientists has shed light on a new mechanism by which the Omicron variant of SARS-CoV-2, including its many sub-lineages, infects human cells. Unlike earlier versions of the virus that relied heavily on the ACE2 receptor to enter cells, Omicron variants have evolved to exploit another molecule present on the surface of human cells — heparan sulfate — to boost their infectivity.
Scientists Discover That Omicron Sub-Lineages Use Heparan Sulfate to Infect Cells with Low ACE-2
This
Thailand Medical News report reveals that Omicron variants have developed a higher affinity for heparan sulfate, a negatively charged sugar molecule commonly found on the surface of many cells in the body. This allows the virus to efficiently infect cells that express very low levels of ACE2, a situation where earlier variants like the original Wuhan strain or Delta would struggle to establish infection.
What the Study Found
Researchers from several leading institutions in Japan, including Osaka University, the Research Institute for Microbial Diseases, National Institute of Infectious Diseases (Tokyo), and Kyoto University, conducted a wide-ranging investigation into how the Omicron spike protein interacts with human cells. They used advanced CRISPR screening techniques to identify which molecules on the cell surface bind most effectively with the Omicron variant.
They discovered that Omicron’s spike protein has significantly increased its ability to bind to heparan sulfate by accumulating several positively charged mutations. These changes enhance electrostatic attraction to the negatively charged sugar, effectively creating a new viral entry route.
Further experiments demonstrated that this binding to heparan sulfate enables Omicron to infect cells with low ACE2 expression — including cells in the nasal cavity — explaining why Omicron variants are more successful at infecting the upper respiratory tract and spreading rapidly between people.
Variant Evolution and Structural Changes
The study analyzed various Omicron sub-lineages including BA.1, BA.2, BA.4/5, XBB.1, and BA.2.86. While all retained high heparan sulfate binding abilities, the location of the spike protein’s binding sites appeared to shift in newer variants. For example, early variants like BA.1 and BA.2 had binding regions on one part of the spike, while BA.2.86 had them on a different part. This shift suggests the virus is continually adapting to optimize its interaction with heparan sulfate.
Interestingly, not all spike proteins expose these binding sites in the same way. Variants like BA.4/5 and XBB.1 tend to keep their spike proteins in a “closed” conformation, hiding some of their binding sites until the moment of infection. When scientists reversed key mutations in these subvariants to m
atch earlier ones, heparan sulfate binding increased dramatically.
Heparan Sulfate as a Key Infection Tool
The research further confirmed that when heparan sulfate was removed from cells using enzymes or blocked using heparin (a medically used drug similar to heparan sulfate), Omicron’s ability to infect low-ACE2 cells was significantly reduced. This proves that heparan sulfate isn’t just an optional tool — it is now central to Omicron’s infectivity.
Additionally, the team discovered that a human enzyme called TMPRSS2, previously known to aid in infection for older SARS-CoV-2 variants, actually reduces the amount of heparan sulfate on the surface of cells. This may explain why Omicron variants are less effective in infecting lung tissue, where TMPRSS2 is highly active, and more successful in nasal tissues, where TMPRSS2 is less prominent.
Conclusion
This study provides strong evidence that the SARS-CoV-2 Omicron variant has evolved to depend heavily on heparan sulfate to enter and infect human cells, particularly those with low levels of ACE2. This adaptation likely contributes to Omicron’s enhanced transmissibility and shift in tissue targeting from the lungs to the upper respiratory tract. These findings not only enhance our understanding of viral evolution but also open the door to new therapeutic strategies — such as using heparan sulfate blockers to prevent infection.
The study findings were published in the peer-reviewed journal mBio.
https://journals.asm.org/doi/10.1128/mbio.01303-25
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