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，一个仍未被探索的领域是提高免疫系统活性的制剂(“免疫调节剂”)的开发。这类药物可用作常规抗生素的替代品或附件。这项研究的重点是人类鞘氨醇-1-磷酸(S1P)途径，它是免疫功能的关键调节因子，也是此类治疗策略的可行靶点。S1P途径的调节可以使用选择性S1P受体(S1PR)激动剂或S1P裂解酶抑制剂(S1PL)，S1P裂解酶是一种通过催化S1P不可逆降解来控制S1P水平的酶。例如，某些S1PR激动剂将免疫调节活性与直接抗菌活性结合在一起。此外，我们最近鉴定了类鼻疽的病原体--假腮腺伯克霍尔德氏菌的致病所需的细菌编码的S1PLs。S1PL同源基因也存在于其他细菌物种中，包括分枝杆菌。这种细菌S1PL的抑制剂预计会削弱毒力，从而将免疫调节与抗毒力活性结合起来。通过一个介于微生物学和细胞生物学之间的多学科研究计划，学生的目标是验证S1P途径作为治疗传染病的可行治疗靶点。具体地说，学生将：1)进行细菌S1PL的生化表征，并使用最近描述的S1PL抑制剂进行针对细菌酶的第一次抑制剂研究。2)明确细菌S1PLs和S1P通路调控在巨噬细胞细胞内感染过程中的作用。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(建立在劳埃德-埃文斯小组的观察基础上，鞘氨醇/S1P水平的变化改变溶酶体功能)。3)评估最新一代S1P途径调节剂(选择性S1PR激动剂和S1PL抑制剂)在相关体内(幼虫)和体外感染模型中的活性，以及联合使用常规抗生素的情况。该项目在微生物学和细胞生物学的前沿提供了出色的培训机会，并将受益于监督小组包括分子细菌学和宿主-病原体相互作用(Brown；Brown；神经鞘脂-溶酶体生物学和溶酶体钙成像(Lloyd-Evans；加的夫)，以及S1PL的酶特性(坎波皮亚诺；爱丁堡)。该项目还受益于从诺华公司获得最新一代S1P途径调节剂，包括第一个已记录的S1PL特异性抑制剂。获得这些化合物将加快临床翻译的步伐。

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.