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Disclosures: Stowell reports no relevant financial disclosures.
March 04, 2021
4 min read
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Study suggests link between COVID-19, blood group A and ‘ancient’ protein family

Disclosures: Stowell reports no relevant financial disclosures.
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The influence of blood group on COVID-19 susceptibility and severity has been studied extensively since the start of the pandemic, with inconsistent results.

Most recently, a study conducted by researchers at Brigham and Women’s Hospital and published in Blood Advances indicated that SARS-CoV-2, the virus responsible for COVID-19, may be drawn to the blood group antigen A found on the lining of the lungs. In addition, the researchers discovered that the receptor binding domain of SARS-CoV-2 had general structures that were comparable to those of galectins, an ancient family of carbohydrate-binding proteins found in all metazoans.

Sean R. Stowell, MD, PhD, associate professor of pathology at Brigham and Women’s Hospital

“Blood group antigens were the first polymorphic structures ever described in the human population, and so we’ve known about them for a really long time,” Sean R. Stowell, MD, PhD, associate professor of pathology at Brigham and Women’s Hospital, said in an interview with Healio. “We’re still trying to figure this out, but it’s amazing to me that blood group antigens might be influencing this huge pandemic, and that they may be doing so through this really ancient carbohydrate-binding protein that viruses share with us. Whether or not blood group proves to be associated with COVID-19, there’s something going on there that’s intriguing.”

Stowell spoke with Healio about the findings, ongoing research into COVID-19 and blood group, and the need for further investigation.

Healio: Research into blood group and COVID-19 has yielded contradictory findings. Do you think we know conclusively whether there is an association?

Stowell: To be fair, I don’t think we do. The challenge with blood group association studies is that commonly, we look at patients who have COVID-19 and then look at healthy blood donors, because there is a repository of data that has already been developed. The question then arises of whether blood donors really represent the general population. So, we have had studies that showed associations and those that did not, and there are caveats to both in how the studies are designed. The only way to really look at it is to prospectively follow people over time who have already been described in terms of blood group status and see if they develop COVID-19 and how severe it is. That’s never been done, and I don’t think it will be. So, the jury is still out.

Healio: What prompted you to study blood group and COVID-19?

Stowell: Studies done early on, which were on preprint servers and not yet published, showed that people with blood group A were more likely to get infected with SARS-CoV-2 and, if they did get infected, to have a severe disease course. Our lab studied blood group antigens, so we were intrigued by the findings. As we developed a serological test for completely different reasons — to help diagnose people who had COVID-19 — we started to look at the biochemistry surrounding the spike protein that the virus uses to infect cells. We realized — and other labs have shown this, as well — that the little “finger,” if you will, on that protein called the receptor-binding domain responsible for binding to and helping gain entry into cells looked a lot like proteins we study called galectins.

Galectins are an ancient protein family. They’re in all metazoans. You can find them in sponges. They’ve been around for a long time. From our previous work, we knew that galectins bind to blood group antigens. They are carbohydrate-binding proteins, but they didn’t necessarily prefer blood group A vs. blood group B.

To determine whether SARS-CoV-2 could recognize blood group antigens, we examined the specific domain that looks a lot like galectins and determined whether it possesses the ability to bind blood group A or blood group B using a glycan microarray platform populated with many different types of blood group antigens.

Sure enough, we found that it bound to blood group antigens. However, the postdoctoral fellow, Peter Wu, working on this initially looked at the types of blood group antigens on red cells and saw there was no difference between blood groups. He said, “It doesn’t look like there is a preference.” However, as he looked at the blood group antigens on the respiratory lining of our lungs, because they are a different flavor of blood group antigens than found on red blood cells, he found that the blood group A that’s specifically expressed on the respiratory lining of our lungs was bound at a higher level than blood groups B and O. I thought, “this is kind of crazy.”

Healio: What did you do next?

Stowell: Then Peter looked more specifically at red blood cells and saw that, just as in the array, there was no preference for red blood cells whether they were isolated from blood group A, B or O individuals. However, when we looked at glycans that mimic what is present in the lung, there was a preference for blood group A. We then looked back at the SARS virus, which studies had also shown appeared to preferentially infect blood group A individuals. Examination of the same domain on SARS resulted the exact same thing — a preference for the blood group A antigen, but only the one that’s in the lung.

We wanted to do additional studies, but I was moving from Emory to Harvard and realized we wouldn’t have time. We didn’t have a BSL3 facility to test what the virus prefers. So, we decided to submit the findings.

Healio: Will this study prompt any recommendations?

Stowell: Other studies need to be done. We need to look at the intact virus and actual respiratory epithelial cells. We started doing a bit of this, but that was put on hold due to relocating my lab.

We don’t know where this research ultimately will lead, but presumably, if the virus is binding to blood group antigens or blood group A — even if it just influences the likelihood that the virus attaches to the lungs or gets into the cells — you can envision a scenario where, regardless of blood type, you could have an aerosolized pharmaceutical that could be used to prevent the virus or influence its ability to attach to the lungs. Is it practical to give everyone a nebulizer vs. wearing a mask? Probably not, but if you have someone with an early infection, you might be able to design a carbohydrate mimic of blood group A that is even more potent in its ability to bind.

First, we need to figure out whether this is influencing the ability of the virus to attach to the cells and get in. If it does, developing ways to prevent that may be useful. Molecules like carbohydrate blood group antigens are very small. This could lend itself to a nebulized or aerosolized approach. Once again, it’s too soon to know. Further studies are certainly needed.

For more information:

Sean R. Stowell, MD, PhD, can be reached at Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115; email: srstowell@bwh.harvard.edu.