09:24pm Tuesday 26 May 2020

Scientists report a new and effective method to increase survival in sepsis

American hospitals spend over $20 billion each year combating sepsis—and still on average 30% of patients diagnosed with sepsis do not survive. Unfortunately, the treatment of sepsis, which currently includes antibiotics, vasopressors and hormones, hasn’t been improved upon in decades.  Early detection and more effective therapies are the best hope for survival.

The study, led by Jamey Marth, Ph.D., professor at Sanford-Burnham’s NCI-Designated Cancer Center and the Tumor Microenvironment Program and director of the University of California Santa Barbara Center for Nanomedicine., leverages the role of the Ashwell-Morell receptor (AMR) to reduce the abundance of blood platelets and pro-thrombotic components that can otherwise cause harmful and fatal blood clots in response to infection.

The key is neuraminidase, an enzyme that is present in many pathogenic microorganisms, such as Streptococcus pneumoniae, the bacteria used in this study, which remains one of the top five causes of death worldwide. Pathogens use neuraminidase to get into cells, but once the pathogen enters the bloodstream, the enzyme then remodels the surface of platelets and other glycoproteins in circulation. This remodeling signals the AMR to remove those platelets and coagulation factors before they have a chance to contribute to the lethal coagulopathy of sepsis.

“It’s a highly conserved protective mechanism never before identified,” said Marth.  “The host has evolved this protective mechanism over millions of years as a way to compensate for the lethal impact of the pathogen on our coagulation system.”

The scientists wondered what would happen if they could pre-activate and augment AMR function in the early phases of sepsis. To answer that question, they infected mice with a lethal dose of Streptococcus pneumoniae and then gave them a single dose of neuraminidase. “We were able to increase survival twofold,” said Marth. “It’s remarkable, and because we see the same mechanism active in human sepsis there is excitement by the potential of this approach to save millions of lives.”

In teasing out the details of the AMR’s protective mechanism, Marth and his colleagues learned that the receptor has the capability to selectively identify and remove certain blood components that could harm the host if they contributed to blood clotting in sepsis.

Although some scientists have suggested that little may be gained from research on sepsis in non-human species, the study by the Marth team discloses a mechanism of host protection that is conserved through mammalian evolution and which can be easily manipulated. The fact that this mechanism is imperceptible to studies of genomic variation and gene expression may explain why others have not discovered it earlier.  “Much of biomedical research is focused on the gene. In our research, it was the study of metabolism that provided the key,” explained Marth.

Dr. Marth holds both the John Carbon Chair of Biochemistry and Molecular Biology and the Duncan and Suzanne Mellichamp Chair of Systems Biology at UCSB.

Sanford-Burnham Medical Research Institute.

Sanford-Burnham Medical Research Institute.

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