Scientists from Duke University School of Medicine (NC, USA) have identified a new biomarker–methylthioadenosine (MTA)–which could predict an individual’s probability of dying from sepsis. In a study, published in Science Advances, they explain the importance of the biomarker in also predicting an individual’s response to therapies that either enhance or suppress the immune system.
Sepsis is difficult to diagnose and is currently treated with combinations of antibiotics, which target pathogens but do not address the over-exaggerated immune response. Dennis Ko, assistant professor of molecular genetics and microbiology, Duke University School of Medicine, commented: “This area has been a graveyard for the pharmaceutical industry, with more than 100 failed clinical trials of therapies that target the body’s abnormal response to infection.
“It may be that these failed clinical trials are not actually failures of treatment, but rather failures of diagnosis…with better biomarkers, we may be able to group sepsis patients into more refined categories to more effectively test and possibly even resurrect old drugs.”
Five years ago, in a study published in the Proceedings of the National Academy of Science, Ko identified variations between sepsis patients in the components of the methionine salvage pathway, an intracellular recycling system. In this current study, Ko focused on MTA, which feeds into the salvage pathway.
Researchers measured MTA levels in sepsis survivors and non-survivors from two independent groups and it was demonstrated that patients who died had elevated levels of MTA. This measurement was approximately 80% accurate in predicting death, comparable to the Acute Physiology and Chronic Health Evaluation II score which is currently used in hospitals.
The team utilized mice infected with Salmonella to demonstrate that when MTA was administered prior to infection the mice survived longer, suggesting that the methionine salvage pathway could be manipulated. However, more research is needed before diagnosis or treatment can be based on MTA.
Further research is planned, looking into the utility, dosing, pharmacodynamics and mechanism of MTA in animal models. Ko concluded: “It gets very complicated very fast…some people might have too robust of an inflammatory response and some people might not have a robust enough response; as a result their MTA levels will differ, both between individuals and within an individual over the course of an illness. Biomarkers could determine where individuals fall along that continuum and what treatments might work.”
Sources: Wang L, Ko E, Gilchrist JJ et al. Human genetic and metabolite variation reveals that methylthioadenosine is a prognostic biomarker and an inflammatory regulator in sepsis. Science Advances 3(3) (2017); www.sciencedaily.com/releases/2017/03/170308144720.htm