PhD in Infection and Immunity: Sepsis and the newborn’s immune system - Linking microbiome metabolites to protective immunity

Sepsis occurs across all ages, striking over 30 million people worldwide and is the final common pathway in the vast majority of deaths from infection. In extremely vulnerable populations, especially pre-term infants, this can lead to high morbidity rates. The development of a healthy immune system that is effective at protecting against infection is dependent on beneficial bacteria, known as the microbiota, that colonize the gut. This intestinal microbiota produces a range of metabolites as a consequence of digesting our diet that are bioactive and signal to the host immune system. Hence elucidating microbiome metabolite-host protective pathways in sepsis is critical for not only identifying metabolites that can be used as a signature of infection-immune health but also for predicting the likely outcome of infection and the possibility for therapeutic enhancement.
This project will be part of new well-funded (~£6M) multidisciplinary team science driven initiative – named Project Sepsis, that innovatively combines state-of-the-art mass-spectroscopy and transcriptomics with computer-based genomics and metabolomics approaches to decode the communication and metabolic changes of the systemic immune response to infection. The central goal is to more rapidly and, most critically using only a single drop of blood detect infection and identify innovative therapeutic modalities. We have decoded a tripartite immune-metabolic signature that is capable of classifying sepsis with high accuracy (Smith et al Nature Commun. 2014;5:4649). The metabolic pathway includes genomic markers for enzymes, receptors and transporters of metabolites. To date we have not tested whether the metabolites associated with the metabolic pathway are also detectably present in the blood of infected patients. Importantly several of the receptors are known G-protein coupled receptors for microbial metabolites.

For this project doctoral training will involve combining hypothesis and data driven science, applying mass spectroscopic, genomic and computing science methodologies. These investigations undertaken by the successful applicant will test the idea of whether, in early human life, pre-term babies coordinately contribute microbiota derived lipids for signaling the hosts immune activated cognate receptors in infection. The successful candidate will be fully-integrated into the Project-Sepsis programme of work and would expect to publish doctoral research in top tier journals.