Balancing Act: It’s a Fine Line Between Inflammation and Immunity When Viruses are Involved

Dr. Mohamed Abdel-Mohsen’s Pioneering Research on Siglecs Spotlights Their Role Helping the Immune System Recognize Viral Infections, and as Promising Future Therapy

Dr. Mohamed Abdel-Mohsen and his virology lab at The Wistar Institute review their work with a new class of immune checkpoints called Siglecs to discover the delicate balance between inflammation and immunity. Their findings could drive novel approaches for reducing damaging inflammation due to viral infections during HIV and possibly SARS-CoV-2, as well.

Twenty-five years ago, it was believed that the sequencing of the full human genome would solve all problems and cure all diseases. Today, scientists are discovering that human biology is much more complicated. To better understand cancer and antiviral activity, the field of glycobiology and the human-specific checkpoints known as Siglecs hold the key for richer, more diverse information and the promise of tailored medicines. 

Every immune cell in the human body has many sugar-binding proteins, and some, called negative checkpoint inhibitors, can suppress the immune function of cells. While immunity is important for health, when the immune system reacts too aggressively, it can harm the body — both by triggering excessive inflammation, and by blocking other critical immune functions, both which can make diseases more severe.

In a recently published, in-depth review in the Lancet journal EBioMedicine, Wistar virologist and glycobiologist Mohamed Abdel-Mohsen, Ph.D., looks at how inhibiting and activating immunological switches by manipulating these negative checkpoint inhibitors may both control inflammation and boost immunity during viral infections. 

The quest to learn more about finding the delicate balance between inflammation and immunity in viruses stems from the Abdel-Mohsen lab’s earlier work with both HIV and SARS-CoV-2. Some of the lab’s previous research looked at the relationship between molecules called glycans and siglecs, and how they help diseases evade the immune system. Glycans are a type of sugar molecule that coats cells in the body. In diseased cells, these glycans change to match special receptors, called siglecs, found on the surface of disease-fighting immune cells such as “natural killer” cells. By binding their glycans to these siglec receptors, researchers showed, the infected cells are able to blind the immune cells and avoid detection.

Previous research by Abdel-Mohsen’s lab has shown how interactions between siglecs and glycans play an important role in regulating the immune system when the body is fighting cancer. In their new paper, the researchers looked at the role this process plays in viruses. 

Viruses use several techniques to help them evade immune surveillance, including employing these negative checkpoint inhibitors to change the glycans, or sugars, on the surface of infected cells. Based on their previous discoveries, Abdel-Mohsen’s lab is now working on new treatments that will manipulate these interactions, supercharging the immune system’s ability to target and destroy infected cells.

They recently discovered a new approach that selectively targets and disables these interactions on the surface of HIV-infected cells, effectively making HIV “killable” for the first time. They’re also studying how these glyco-immune checkpoint interactions may help SARS-CoV-2, the virus that causes COVID-19, evade natural killer immune surveillance — and how those interactions could be targeted.

Siglecs are proteins that bind to glycans (sugars) and regulate the signals of immune cells, as well as the body’s inflammatory responses. By learning how to flip the switch to turn ‘on’ the checkpoints that boost immunity, and turn ‘off’ those that reduce inflammation, Wistar scientists hope to better understand and find new approaches for treating cancer, HIV, and potentially even “long COVID.”

The lab is now exploring siglecs to study the tug-of-war that occurs between viruses and the immune systems, with a goal of better understanding how immunological equilibrium is regulated during viral infections. The challenge, Abdel-Mohsen says, is to find ways of precisely managing this immunological equilibrium in a way that enhances the immune response without triggering excessive inflammation or inhibiting other critical immune functions. 

“If we really want to learn the most about human life, we must look at the glycan,” Abdel-Mohsen says. “Understanding glycobiology will help us as a scientific community to better understand the differences between humans and other organisms—as well as the differences that exists between humans. Investments in this next-level, bold science will allow us to achieve advances in precision medicine by developing specific medicines for specific diseases.”