HOST GENETIC VARIATION REGULATING SALMONELLA INVASION AND DISEASE SUSCEPTIBILITY

调节沙门氏菌入侵和疾病易感性的宿主基因变异

基本信息

批准号：
8941971
负责人：
Dennis Chun-Yone Ko
金额：
$ 18.28万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8941971
关键词：
Affect Alleles Animal Model Cell Death Cell Line Cells Cessation of life Collaborations Complement Disease Disease susceptibility Event Genes Genetic Genetic Variation Genetic screening method Genotype Goals Hospitalization Human Human Genetics Image Immune response In Vitro Individual Infection Intestinal Perforation Knowledge Lead Life Location Measurement Membrane Modeling Outcome Pathway interactions Phenotype Phosphatidylinositols Play Population Predisposition Process Proteins Research Resistance Resources Risk Role Salmonella Salmonella infections Salmonella typhi Scaffolding Protein Sepsis Severities Severity of illness Signal Pathway Testing Therapeutic Intervention Typhoid Fever Variant Zebrafish antimicrobial cohort gene function genetic variant genome wide association study human population study improved inhibitor/antagonist killings new therapeutic target novel pathogen public health relevance response therapeutic target trait

项目摘要

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.

描述（由申请人提供）：伤寒沙门氏菌引起伤寒，这是一种每年影响超过两千万人的严重感染，在过去的二十年里，人们对沙门氏菌如何通过操纵宿主细胞途径引起疾病以及如何引起疾病有了很多了解。然而，人类基因变异如何影响宿主信号通路和反应来调节沙门氏菌感染的易感性，但对于感染者和感染的严重程度存在巨大差异。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、易感性预测以及可能的宿主导向的治疗靶标，这是这项研究的长期目标。目的是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易感性，以及这如何影响人类疾病的风险和严重程度。为了实现这一目标，开展了细胞沙门氏菌感染特征的全基因组关联研究（GWAS）。使用名为 Hi-HOST（高通量人类体外敏感性测试）的平台进行检测。在 Hi-HOST 筛选中，对来自数百个基因分型个体的细胞进行精确的感染读数测量。使用 Hi 来识别细胞感染表型变异背后的遗传差异。 HOST 是影响沙门氏菌诱导的细胞死亡和人类败血症的三种新调节因子，该应用的目的是使用 Hi-HOST 和后续研究来定义和表征改变伤寒沙门氏菌的宿主遗传差异。宿主遗传差异是机制研究的起点，通过将这些细胞研究与人类伤寒的动物模型和基因分型相结合，确定涉及巨胞饮作用和早期存活的宿主途径。目标 1 中，将识别并验证调节伤寒沙门氏菌入侵的常见人类遗传变异。在目标 3 中，将评估伤寒沙门氏菌对人类伤寒的侵袭和动物模型中的沙门氏菌感染，将描述新发现的调节因子如何调节伤寒沙门氏菌侵袭的机制。目标将是阐明宿主与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个体面临伤寒以及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，而人们对耐药性的担忧日益增加。对于广谱抗菌药物，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，而不是专注于宿主调节。