Ashwell receptor reduces mortality during sepsis

In research that solves the longest-standing mystery in glycobiology – a field that studies complex sugar chains called glycans – researchers at the University of California, San Diego School of Medicine have discovered that a molecule in the liver of all animals, called the Ashwell receptor, is critical in helping the body fight off the abnormal and lethal blood clotting caused by bacterial infection. Until now, it was suspected that this receptor might serve to remove abnormal proteins from circulation, but it wasn’t understood which proteins were affected or what biological purpose this receptor served.

The study, published online in advance of publication in the June issue of Nature Medicine, shows that the Ashwell receptor plays an essential role in reducing coagulation abnormalities during infection and sepsis, significantly improving the probability of survival.

Sepsis, a life-threatening complication of bacterial infection in the blood, remains a major cause of death worldwide, according to the study’s principal investigator, Jamey Marth, Ph.D., UCSD Professor of Cellular and Molecular Medicine and Investigator with the Howard Hughes Medical Institute. One of the major factors contributing to death in patients with sepsis is a condition called disseminated intravascular coagulation, which accelerates blood clotting.

UCSD researchers discovered that a protective response, triggered by the Ashwell receptor in the liver, limits this lethal side effect by reducing the levels of circulating blood coagulation factors, including platelets.

The bacterial pathogen Streptococcus pneumoniae (pneumococcus) is a leading cause of sepsis, especially in the young, the elderly and the immuno-compromised. The pneumococcus makes an enzyme called sialidase, which removes sugar molecules called sialic acid from host cells, and helps facilitate spread of the pathogen through the body. Using a mouse model of sepsis, the researchers found that the pneumococcal sialidase also removes sialic acid from circulating host factors involved in blood coagulation, including platelets and a glycoprotein called von Willebrand Factor (vWF). When this occurs, the Ashwell receptor recognizes the change in the glycoprotein structure and removes those pro-coagulation factors from circulation before they can cause increased blood coagulation.