Cellular senescence: investigating a novel hijack target of the typhoid pathogen Salmonella Typhi

我们假设沙门氏菌宿主衰老反应通过SASP分泌组中未鉴定的蛋白质来重新编程感染生态位。通过鉴定这些蛋白质，该项目旨在在病原体颠覆细胞衰老的新兴领域开辟新天地，并利用获得的知识阐明诊断生物标志物，以帮助对抗AMR伤寒的传播。目标1：目的2：利用马拉维伊丽莎白女王中央医院急性伤寒患者的临床样本鉴定宿主细胞分泌组，该项目结合了分子细胞生物学、感染学、蛋白质组学和免疫学方法。通过用沙门氏菌的致突变菌株挑战培养的人类细胞，该项目将复制伤寒的感染机制。蛋白质组学将能够鉴定宿主分泌体中的“衰老生物标志物”，并使用一系列基于人类细胞的技术研究它们在感染中的作用（目标1）。马拉维利物浦维康信托基金会临床研究项目的实地工作将使用伤寒参与者的临床样本研究和验证宿主反应，以最大限度地发挥影响和临床重要性（目标2）.该奖学金利用了伤寒领域专家（包括主要导师丹尼尔·汉弗莱斯博士）支持的一项令人兴奋的新合作（谢菲尔德）与共同导师Melita Gordon教授（马拉维）和James Meiring博士（谢菲尔德）。该项目旨在为抗击伤寒和抗菌素耐药性做出贡献，并改善弱势社区的健康和财富。

We hypothesise that Salmonella elicits host senescence responses to reprogramme the infection niche through unidentified proteins in the SASP secretome. By identifying the proteins, the project aims to break new ground in an emerging field on pathogen subversion of cellular ageing and use knowledge gained to elucidate diagnostic biomarkers that can help combat the spread of AMR typhoid. Objective 1: Identify and characterise the Salmonella-induced host cell secretome during infection of cultured human cells.Objective 2: Validate the host secretome using clinical samples from individuals with acute typhoid at the Queen Elizabeth Central Hospital in Malawi.The project combines molecular cell biology, infection, proteomic and immunological approaches. By challenging cultured human cells with toxigenic strains of Salmonella, the project will replicate infection mechanisms underlying typhoid. Proteomics will enable identification of 'senescence biomarkers' in the host secretomes and the investigation of their role in infection using a range of human cell-based techniques (objective 1). Field work at the Malawi Liverpool Wellcome Trust Clinical Research Programme will study and validate the host responses using clinical samples from participants with typhoid fever to maximise impact and clinical importance (objective 2).The studentship takes advantage of a new and exciting collaboration supported by experts in the typhoid field including primary supervisor Dr. Daniel Humphreys (Sheffield) together with co-supervisors Prof. Melita Gordon (Malawi) and Dr. James Meiring (Sheffield). The project aims to contribute to the fight against typhoid and antimicrobial resistance, and improve the health and wealth of vulnerable communities.