Wang L
Ko ER
Gilchrist JJ
Pittman KJ
Rautanen A
Pirinen M
Thompson JW
Dubois LG
Langley RJ
Jaslow SL
Salinas RE
Rouse DC
Moseley MA
Mwarumba S
Njuguna P
Mturi N
Wellcome Trust Case Control Consortium
Kenyan Bacteraemia Study Group
Williams TN
Scott JA
Hill AV
Woods CW
Ginsburg GS
Tsalik EL
Ko DC
Sci Adv. 2017;3e1602096
Sepsis is a deleterious inflammatory response to infection with high mortality. Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients. Pathway-based genome-wide association analysis of nontyphoidal Salmonella bacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway. Measurement of the pathway's substrate, methylthioadenosine (MTA), in two cohorts of sepsis patients demonstrated increased plasma MTA in nonsurvivors. Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation. A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death. Furthermore, mice infected with Salmonella had prolonged survival when MTA was administered before infection, suggesting that manipulating MTA levels could regulate the severity of the inflammatory response. Our results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of disease and lead to new biomarkers for patient stratification and potential therapeutic targeting.
