Sepsis is a medical emergency that occurs when the body has a strong response to an infection of any type but is most typically seen as a result of bacterial infections. The life-threatening event is a result of when the body releases components of the immune system into the blood, in an effort to combat the infection, triggering massive inflammation. The immune system runs out of controls and triggers a cytokine storm, a condition in which inflammation-causing proteins flood the blood. Organs may break down, and death follows.
Each year, at least 1.7 million adults in America develop sepsis and nearly 270,000 die as a result. Discovering sepsis early can be life-saving, so the development of a biomarker is a critical piece to saving lives. Now, a team from the University of Connecticut has found that the sugar-binding protein galectin-1 could not only fuel terrible inflammation and worsen sepsis, but it could also act as a biomarker for patients at risk of life-threatening sepsis.
This work is published in Nature Immunology in the paper, “Intracellular immune sensing promotes inflammation via gasdermin D–driven release of a lectin alarmin.”
A main trigger for the cytokine storms during sepsis is the overreaction of the body when it detects an infection inside the cells. Other diseases can also cause cytokine storms; medical historians believe cytokine storms were behind the lethality of the 1918–1919 flu epidemic, as well as the Black Death. Cytokine storms are also observed in patients with severe COVID-19 and believed to be involved in patient death in COVID-19.
When a cell detects bacteria or pieces of bacteria inside itself, it immediately activates enzymes that in turn activate a protein that pokes holes on the cell membrane from within, eventually causing the cell to burst open and spill cytokines into the bloodstream which activate the immune system. Usually, the system calms down after some time. But in sepsis, it spins out of control, causing more and more cells to burst and die, releasing even more cytokines into the bloodstream.
More specifically, the inflammatory caspase sensing of cytosolic lipopolysaccharide (LPS) triggers programmed cell death and the release of damage-associated molecular patterns (DAMPs). Collectively, DAMPs are key determinants that shape the aftermath of inflammatory cell death. However, the identity and function of the individual DAMPs that are released are poorly defined.
Vijay Rathinam, DVM, PhD, associate professor and immunology director at the University of Connecticut, sought to understand which DAMPs were released when a cell detected the bacterial lipopolysaccharide. The proteomics study revealed that Galectin-1, a β-galactoside-binding lectin that binds sugars and sugar-coated proteins, was released from the cells. Interestingly, they found that galectin-1 is small enough to be slipping out of the holes poked in the cells’ membrane, even before the cells burst open.
Galectin-1 seemed to be suppressing a brake on inflammation, causing the cytokine storm to ramp up. The research found that mice lacking galectin-1 had less inflammation, less organ damage, and survived longer than normal mice did during sepsis resulting from a bacterial infection and lipopolysaccharide.
The team collaborated with the Jena University Hospital to find out if galectin-1 is released during sepsis in human patients. Indeed, they found that sepsis patients had higher levels of galectin-1 than other non-sepsis patients in critical care and healthy people.
The team is considering whether galectin-1 might be a good drug target to help dampen cytokine storms during sepsis, as well as a useful marker doctors could use to identify critically ill patients at risk.
