Sphingosine-1-Phosphate receptor 1 signalling in bacterial-macrophage interactions: exploring novel anti-bacterial strategies using immunomodulatory t

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In the quest for novel antimicrobial strategies, one area that remains under-explored is the development of agents that enhance immune system activity ("immunomodulators"). Such agents may be used as an alternative or adjunct to conventional antibiotics. This studentship focuses on the human sphingosine-1-phosphate (S1P) pathway, a key regulator of immune function and a viable target for such a therapeutic strategy. Modulation of the S1P pathway can be achieved using either selective S1P receptor (S1PR) agonists or inhibitors of S1P lyase (S1PL), an enzyme that controls S1P levels by catalysing its irreversible degradation.Uniquely, S1P-targeted therapies have the potential to achieve beneficial immunomodulation whilst simultaneously directly inhibiting the pathogen. For example, certain S1PR agonists combine immunomodulatory activity with direct antimicrobial activity. Furthermore, we have recently characterized bacterial-encoded S1PLs that are required for the pathogenesis of Burkholderia pseudomallei, the causative agent of melioidosis. S1PL orthologues also exist in other bacterial species, including mycobacteria. Inhibitors of such bacterial S1PLs would be expected to impair virulence, thus combining immunomodulation with anti-virulence activity.Through a multidisciplinary programme of research that sits at the interface between microbiology and cell biology, the student will aim to validate the S1P pathway as a viable therapeutic target for the treatment of infectious diseases. Specifically, the student will:1) Undertake biochemical characterization of bacterial S1PLs and perform the first inhibitor studies against bacterial enzymes using a recently described S1PL inhibitor. 2) Define the impact of bacterial S1PLs and S1P pathway modulation during intracellular infection of macrophages. In particular, the student will investigate the linkage between sphingosine homeostasis, intracellular calcium mobilisation and lysosomal function (building on observations from the Lloyd-Evans group that changes in sphingosine/S1P levels alter lysosomal function).3) Assess the activity of the latest generation of S1P pathway modulators (selective S1PR agonists and S1PL inhibitor) within relevant in vivo (larval) and in vitro infection models, with and without co-administration of conventional antibiotics.The project offers outstanding training opportunities at the forefront of microbiology and cell biology and will benefit from complementary expertise of the supervisory team encompassing molecular bacteriology & host-pathogen interactions (Brown; Exeter), sphingolipid-lysosome biology & lysosomal calcium imaging (Lloyd-Evans; Cardiff), and enzymatic characterization of S1PLs (Campopiano; Edinburgh). The project also benefits from access to the latest generation of S1P pathway modulators from Novartis, including the first documented specific inhibitor of S1PL. Access to these compounds will fast-track clinical translation.