HOST GENETIC VARIATION REGULATING SALMONELLA INVASION AND DISEASE SUSCEPTIBILITY

 描述(申请人提供)：伤寒沙门氏菌引起伤寒，这是一种每年影响2000多万人的严重感染。在过去的二十年里，关于沙门氏菌如何通过操纵宿主细胞途径和宿主细胞如何反应而导致疾病，已经获得了许多知识。然而，在谁被感染和感染的严重程度上存在巨大的差异。人类的遗传变异如何影响宿主信号通路和反应来调节对沙门氏菌感染的易感性，目前还知之甚少。这种自然发生的宿主遗传变异是一种未开发的资源，可以揭示途径的新组成部分，易感性的预测，以及可能的宿主定向治疗靶点。这项研究的长期目标是 是为了了解宿主遗传差异如何改变细胞对沙门氏菌感染的反应性和敏感性，以及这如何影响人类的疾病风险和严重程度。为了实现这一目标，利用Hi-HOST(高通量人类体外药敏试验)平台对沙门氏菌细胞感染特性进行了全基因组关联研究。在高宿主筛查中，对来自数百个基因分型个体的细胞进行了感染读数的精确测量。然后，全基因组关联被用来确定细胞感染表型变异背后的遗传差异。使用Hi 宿主，鉴定并鉴定了三种影响沙门氏菌诱导的细胞死亡和人类败血症的新调节因子。本申请的目的是利用Hi-host和后续研究来定义和表征改变伤寒沙门氏菌入侵和早期存活的宿主遗传差异。宿主遗传差异是机制研究的起点，以确定涉及巨噬细胞吞噬和早期存活的宿主途径是如何改变的。通过将这些细胞研究与动物模型和人类伤寒队列的基因分型相结合，将深入了解遗传差异如何导致谁生病以及为什么。在目标1中，将识别和验证调节伤寒沙门氏菌入侵的常见人类基因变异。在目标2中，将评估伤寒沙门氏菌入侵变异对人群伤寒和动物模型沙门氏菌感染的影响。在目标3中，将描述新发现的调节分子如何调节伤寒沙门氏菌入侵的机制。实现这些目标将导致阐明宿主-病原体相互作用的新机制，并最终广泛了解遗传差异如何决定哪些人有患伤寒和可能由利用类似入侵机制的病原体引起的其他疾病的风险。随着人们对广谱抗菌药耐药性的担忧与日俱增，这项研究可能会利用我们的遗传差异来揭示新的治疗靶点，而不是关注宿主调节。

 DESCRIPTION (provided by applicant): Salmonella enterica serovar Typhi causes typhoid fever, a severe infection that affects more than twenty million people every year. Much knowledge has been gained over the last twenty years concerning how Salmonella causes disease through manipulating host cellular pathways and how host cells respond. However, there is tremendous variation in who gets infected and the severity of infections. How host signaling pathways and responses are affected by human genetic variation to modulate susceptibility to Salmonella infection is poorly understood. This naturally occurring host genetic variation is an untapped resource that could reveal novel components of pathways, prediction of susceptibility, and possibly host-directed therapeutic targets. The long-term goal of this research is to understand how host genetic differences alter the responsiveness and susceptibility of cells to Salmonella infection and how this affects risk and severity of disease in people. In pursuit of this goal, genome-wide association studies (GWAS) of cellular Salmonella infection traits were carried out using a platform called Hi-HOST (High-throughput Human in vitro Susceptibility Testing). In Hi- HOST screens, precise measurements of infection readouts are conducted on cells derived from hundreds of genotyped individuals. Genome-wide association is then used to identify genetic differences that underlie variation in the cellular infection phenotypes. Using Hi HOST, three new regulators that affect Salmonella- induced cell death in cells and sepsis in human populations were identified and characterized. The objective of this application is to use Hi-HOST and subsequent studies to define and characterize host genetic differences that alter S. typhi invasion and early survival. The host genetic differences serve as the starting point for mechanistic studies to determine how host pathways involving macropinocytosis and early survival are altered. By integrating these cellular studies with animal models and genotyping of human typhoid fever cohorts, an in depth understanding will be achieved for how genetic differences contribute to who gets sick and why. In Aim 1, common human genetic variation that modulates S. typhi invasion will be identified and validated. In Aim 2, the impact of variation in S. typhi invasion on typhoid fever in human populations and Salmonella infections in animal models will be assessed. In Aim 3, mechanisms for how the newly identified regulators modulate S. typhi invasion will be characterized. Carrying out these Aims will result in the elucidation of new mechanisms in host-pathogen interactions and ultimately a broad understanding for how genetic differences determine which individuals are at risk for typhoid fever and possibly other diseases caused by pathogens which utilize similar invasion mechanisms. With rising concerns over resistance to broad-spectrum antimicrobials, this study may leverage our genetic differences to reveal new therapeutic targets focused instead on host modulation.