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

在寻求新的抗微生物策略的过程中，一个仍然未被探索的领域是开发增强免疫系统活性的药剂（“免疫调节剂”）。这些药物可以作为常规抗生素的替代或辅助。这个学生奖学金的重点是人类鞘氨醇-1-磷酸（S1 P）途径，免疫功能的关键调节因子和这种治疗策略的可行目标。S1 P通路的调节可以使用选择性S1 P受体（S1 PR）激动剂或S1 P裂解酶（S1 PL）抑制剂来实现，S1 P裂解酶是一种通过催化其不可逆降解来控制S1 P水平的酶。独特的是，S1 P靶向治疗具有实现有益的免疫调节的潜力，同时直接抑制病原体。例如，某些S1 PR激动剂将免疫调节活性与直接抗微生物活性联合收割机组合。此外，我们最近的特点是细菌编码的S1 PLs，所需的类鼻疽伯克霍尔德氏菌，类鼻疽的病原体的发病机制。S1 PL直向同源物也存在于其他细菌物种中，包括分枝杆菌。这种细菌S1 PLs的抑制剂有望削弱毒力，从而将免疫调节与抗毒力活性相结合。通过位于微生物学和细胞生物学之间的多学科研究计划，学生将致力于验证S1 P途径作为治疗感染性疾病的可行治疗靶点。具体来说，学生将：1）进行细菌S1 PL的生化表征，并使用最近描述的S1 PL抑制剂对细菌酶进行第一次抑制剂研究。2)确定细菌S1 PLs和S1 P通路调节在巨噬细胞胞内感染期间的影响。特别是，学生将研究鞘氨醇稳态，细胞内钙动员和溶酶体功能之间的联系（基于来自Edd-Evans小组的观察，即鞘氨醇/S1 P水平的变化改变溶酶体功能）。3）评估最新一代S1 P途径调节剂的活性（选择性S1 PR激动剂和S1 PL抑制剂）在相关的体内（幼虫）和体外感染模型中，有和没有co-常规抗生素的管理。该项目提供微生物学和细胞生物学前沿的出色培训机会，并将从监督团队的互补专业知识中受益，包括分子细菌学和宿主-病原体相互作用（Brown;埃克塞特）、鞘脂-溶酶体生物学和溶酶体钙成像（Edgard-Evans;卡迪夫）以及S1 PL的酶表征（Campopiano;爱丁堡）。该项目还受益于获得诺华最新一代S1 P通路调节剂，包括第一个记录的S1 PL特异性抑制剂。获得这些化合物将加快临床转化。

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.