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

• 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
• 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

 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（由适用提供）：肠道沙门氏菌血清鼠伤寒会引起伤寒，这是一种严重的感染，每年影响超过两千万人。在过去的二十年中，关于沙门氏菌如何通过操纵宿主细胞途径以及宿主细胞的反应如何引起疾病的许多知识已经获得了很多知识。但是，谁被感染和感染的严重程度存在巨大差异。人们对宿主信号通路和反应的影响如何受到人类遗传变异的影响，以调节对沙门氏菌感染的易感性。这种天然存在的宿主遗传变异是一种未开发的资源，可以揭示途径的新成分，易感性的预测以及可能的宿主指导的治疗靶标。这项研究的长期目标 是要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，以及这如何影响人们疾病的风险和严重程度。为了追求这一目标，使用称为Hi-Host（高通量人体体外易感性测试）的平台进行了细胞沙门氏菌感染特征的全基因组关联研究（GWAS）。在Hi-Host筛选中，对感染读数的精确测量是对来自数百个基因分型个体的细胞进行的。然后，全基因组的关联用于确定细胞感染表型差异的遗传差异。使用HI 宿主，鉴定并表征了影响沙门氏菌诱导的细胞和败血症细胞死亡的三个新调节剂。该应用的目的是使用Hi-Host和随后的研究来定义和表征改变Typhi入侵和早期生存的宿主遗传差异。宿主遗传差异是机械研究的起点，以确定如何改变涉及大型细胞增多症和早期生存的宿主途径。通过将这些细胞研究与动物模型和人伤寒同龄人的基因分型整合在一起，将对遗传差异如何促进谁生病以及原因，深入了解。在AIM 1中，将鉴定和验证调节伤寒链球菌侵袭的常见人遗传变异。在AIM 2中，斑疹伤寒链球菌入侵对AIM 3中人群和沙门氏菌感染伤寒的变异的影响，新鉴定的调节器如何调节斑杆菌入侵的机制。执行这些目标将导致宿主 - 病原体相互作用中新机制的阐明，并最终对遗传差异的广泛理解确定哪些人面临伤寒风险，以及利用类似侵袭机制的病原体引起的其他疾病。由于对对广谱抗微生物的抗性的关注，这项研究可能会利用我们的遗传差异来揭示专注于宿主调节的新治疗靶标。