Ashwell Receptor in Liver Reduces Sepsis Mortality

Researchers at the University of California, San Diego School of Medicine have found that a liver molecule called the Ashwell receptor is vital in reducing coagulation abnormalities found in the organ during sepsis and thus reducing mortality from the same.

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, Sepsis is a life-threatening complication of bacterial infection in the blood is a major cause of death worldwide.

The research has solved the longest-standing mystery in glycobiology - a field that studies complex sugar chains called glycans, by stating that the Ashwell receptor plays a major role in helping the body fight off the abnormal and lethal blood clotting caused by bacterial infection.

Till date, the researchers believed that this receptor might help in discarding abnormal proteins from circulation, however the affected proteins and the main objective of this receptor is still a mystery.

Also, it was found that the death in patients with sepsis is mainly caused by a condition called disseminated intravascular coagulation, which accelerates blood clotting.

Now, researchers have found that a protective response, initiated by the Ashwell receptor in the liver, puts an end to this lethal side effect by reducing the levels of circulating blood coagulation factors, including platelets.

It is known that the bacterial pathogen Streptococcus pneumoniae (pneumococcus) is the main cause behind 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 to initiate spread of the pathogen through the body.

The researchers made use of a mouse model of sepsis, and 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). At this time, the Ashwell receptor identifies the change in the glycoprotein structure and eliminates those pro-coagulation factors from circulation before they result in increased blood coagulation.

They then made a breakthrough after discovering that platelet counts and vWF that are reduced during pneumococcal infection were actually high and unchanged when the Ashwell receptor was absent. The main findings came when mice lacking the Ashwell receptor developed severe tissue and organ damage due to increased coagulation and died at significantly higher frequency and more rapidly than expected.

"This finding contradicts the prevailing notion that the low platelet count of sepsis is due to the consumption of coagulation factors caused by the pathogen and is therefore harmful. Rather, this low platelet count is due an adaptive response by the Ashwell receptor that is beneficial by reducing tissue damage and organ failure and thereby improving the chance of survival," Nature quoted Marth, as saying.

It was found that the Ashwell receptor, also known as the hepatic asialoglycoprotein receptor, was the first glycan-binding receptor, or lectin, ever discovered in animals.

"The Ashwell receptor is 'turned on' after birth, and this was a clue that it is needed for environmental and pathogenic challenges," said Marth.

The study is published online in advance of publication in the upcoming issue of Nature Medicine.

Source-ANI
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