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Ashwell receptor reduces mortality during sepsis
May 19, 2008In 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.
The researchers made a breakthrough when they discovered that platelet counts and vWF that are reduced during pneumococcal infection remained high and unchanged in the absence of the Ashwell receptor. Pivotal results 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," said Marth. "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."
More than 35 years ago, researcher Gilbert Ashwell and colleagues discovered that the liver controls the removal of proteins in the bloodstream. 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.
"This research provides a whole new way of thinking about coagulation problems in sepsis produced by pneumococcus and related pathogens" said Victor Nizet, M.D., UCSD professor of pediatrics and pharmacy whose laboratory assisted in the study. "Drugs designed to support the normal capabilities of the Ashwell receptor in the liver would represent a new approach to limiting mortality in these life-threatening conditions."
University of California - San Diego
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.
The researchers made a breakthrough when they discovered that platelet counts and vWF that are reduced during pneumococcal infection remained high and unchanged in the absence of the Ashwell receptor. Pivotal results 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," said Marth. "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."
More than 35 years ago, researcher Gilbert Ashwell and colleagues discovered that the liver controls the removal of proteins in the bloodstream. 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.
"This research provides a whole new way of thinking about coagulation problems in sepsis produced by pneumococcus and related pathogens" said Victor Nizet, M.D., UCSD professor of pediatrics and pharmacy whose laboratory assisted in the study. "Drugs designed to support the normal capabilities of the Ashwell receptor in the liver would represent a new approach to limiting mortality in these life-threatening conditions."
University of California - San Diego
Sepsis Current Events and Sepsis News RSSProgress made on group B streptococcus vaccine
Scientists supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, have completed a Phase II clinical study that indicates a vaccine to prevent Group B Streptococcus (GBS) infection is possible.
Canadian scientists link fat hormone to death from potentially deadly blood infection
A new Canadian study has found that lower-than-normal levels of a naturally-occurring fat hormone may increase the risk of death from sepsis-an overwhelming infection of the blood which claims thousands of lives each year.
OMRF scientists discover promising new path for treating traumas
A discovery by scientists at the Oklahoma Medical Research Foundation could help save lives threatened by traumatic injuries like those sustained in car crashes or on the battlefield. The work also holds potential for treating severe infectious diseases and diabetes.
Scientists create NICE solution to pneumonia vaccine testing problems
Medical clinics the world over could benefit from new software* created at the National Institute of Standards and Technology (NIST), where a team of scientists has found a way to improve the efficiency of a pneumonia vaccine testing method developed at the University of Alabama at Birmingham (UAB).
Compound shows potential for slowing progression of ALS
A chemical cousin of a drug currently used to treat sepsis dramatically slows the progression of amyotrophic lateral sclerosis, better known as ALS or Lou Gehrig's disease, in mice.
Review: Pneumococcal conjugate vaccines effective at preventing child deaths
A study published in The Cochrane Review this month concludes that pneumococcal conjugate vaccines (PCV), already known to prevent invasive pneumococcal disease (IPD) and x-ray defined pneumonia, was also effective against child deaths.
Key feature of immune system survived in humans, other primates for 60 million years
A new study has concluded that one key part of the immune system, the ability of vitamin D to regulate anti-bactericidal proteins, is so important that is has been conserved through almost 60 million years of evolution and is shared only by primates, including humans - but no other known animal species.
Discovery may lead to powerful new therapy for asthma
University of Texas Medical Branch at Galveston researchers have found that a single enzyme is apparently critical to most allergen-provoked asthma attacks - and that activity of the enzyme, known as aldose reductase, can be significantly reduced by compounds that have already undergone clinical trials as treatments for complications of diabetes.
Abnormal Brain Circuits May Prevent Movement Disorder
Most people who carry a genetic mutation for a movement disorder called dystonia will never develop symptoms, a phenomenon that has puzzled scientists since the first genetic mutation was identified in the 1990's.
Scientists uncork a potential secret of red wine's health benefits
Scientists from Scotland and Singapore have unraveled a mystery that has perplexed scientists since red wine was first discovered to have health benefits: how does resveratrol control inflammation?
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