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

我们假设沙门氏菌通过SASP分泌组中的未知蛋白引起宿主衰老反应来重新编程感染生态位。通过识别这些蛋白质，该项目旨在在病原体颠覆细胞衰老的新兴领域开辟新的天地，并利用获得的知识来阐明有助于抗击AMR伤寒传播的诊断生物标记物。目的1：鉴定和鉴定沙门氏菌诱导的宿主细胞分泌组在感染培养的人细胞过程中的特征。目标2：利用马拉维伊丽莎白女王中心医院急性伤寒患者的临床标本验证宿主分泌组。通过用产毒沙门氏菌攻击培养的人类细胞，该项目将复制伤寒的感染机制。蛋白质组学将能够识别宿主分泌体中的“衰老生物标志物”，并使用一系列基于人类细胞的技术来研究它们在感染中的作用(目标1)。马拉维利物浦惠康信托临床研究计划的实地工作将使用伤寒参与者的临床样本来研究和验证东道主的反应，以最大限度地提高影响和临床重要性(目标2)。学生利用一个新的和令人兴奋的合作，由伤寒领域的专家支持，包括首席主管Daniel Humphreys博士(谢菲尔德)、副主任Melita Gordon教授(马拉维)和詹姆斯·梅林博士(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.