Human Genetic Susceptibility to Tropical Infectious Diseases

描述(由申请人提供)：我们建议研究与严重钩端螺旋体病感染相关的特定和全基因组水平的人类遗传多态。钩端螺旋体病是一种在热带和亚热带地区都很重要的疾病。它的两极分化(5%严重/致命与通常不严重)的临床特征使其成为表型-基因型比较的理想模型。虽然大多数钩端螺旋体病患者恢复顺利，但少数患者出现肝、肾和出血症状，一些患者尽管接受了重症监护和特殊的抗菌治疗，但仍死亡。钩端螺旋体病的啮齿动物模型表明，TLR4功能低下易患严重疾病，但对最有可能存在多因素遗传易感性的人类来说，确认这一发现并探索全基因组相关性将是重要的。候选人是一名儿科传染病内科医生和前疾病控制和预防中心流行病情报服务官员，在热带传染病方面拥有丰富的现场专业知识，寻求获得专注于严重传染病后果遗传易感性的职业技能。他将大大受益于由K24/R01支持的热带医学研究员、内科科学家Joseph Vinetz博士和统计遗传学专家Nicholas Schork博士提供的双重指导，Nicholas Schork博士是斯克里普斯翻译研究部NIH临床翻译科学奖的共同获得者，也是加州大学圣地亚哥分校人类遗传学和基因组学中心的前联合主任。候选人将利用加州大学圣迭戈分校的高级临床研究计划，包括GCRC、基因组学中心和遗传多态实验室，这些计划在NIH资助的持续培训拨款和国际研究项目中发挥作用。我们寻求a)比较TLR2和TLR4(以及适配蛋白)在重度和轻度感染的钩端螺旋体病患者中的基因型，以及b)利用高密度单核苷酸多态性微阵列和单倍型分析来确定全基因组与钩端螺旋体病预后的相关性，以表征与严重疾病相关的基因组变异。这两种方法都是进一步转化研究和改进诊断、治疗和预防策略的有希望的线索。 相关性：该项目将提供一种研究钩端螺旋体病发病机制的方法，并将作为一种极好的研究培训机制，该机制基于以下假设：严重传染病的易感性可归因于先天免疫检测和信号的特定缺陷，也可归因于目前尚未确定的基因组变异。

DESCRIPTION (provided by applicant): We propose to investigate specific and whole-genome level human genetic polymorphisms associated with severe leptospirosis infection. Leptospirosis is a disease of major importance throughout tropical and sub-tropical regions. Its polarized (<5% severe/fatal vs. usually non-severe) clinical features make it an ideal model for phenotype-genotype comparisons. While most patients with leptospirosis recover uneventfully, a minority develop hepatic, renal, and hemorrhagic manifestations, and some die despite intensive care and specific antimicrobial therapy. A rodent model of leptospirosis demonstrates that hypofunctional TLR4 predisposes to severe disease, but confirmation of this finding and exploration of genome-wide associations will be important in humans in whom multifactorial genetic susceptibility are most likely. The candidate is a pediatric infectious disease physician and former Centers for Disease Control and Prevention Epidemic Intelligence Service Officer with substantial field expertise in tropical infectious diseases seeking to acquire career skills focused on genetic susceptibility to severe infectious disease outcomes. He will greatly benefit from dual mentorship provided by Dr. Joseph Vinetz, physician-scientist and K24/R01-supported tropical medicine investigator, and Dr. Nicholas Schork, statistical genetics expert and recent co-recipient of an NIH Clinical Translational Science Award at the Scripps Translational Research Unit/former Co-Director of the UCSD Center for Human Genetics and Genomics. The candidate will take advantage of advanced clinical research programs at UCSD including the GCRC, the Genomics Center, and the Genetic Polymorphism Laboratory which function within ongoing NIH-funded training grants and international research projects. We seek a) to compare TLR2 and TLR4 (and adaptor protein) genotypes among severely and mildly infected leptospirosis patients and b) to determine genome-wide associations with leptospirosis outcome using high-density single nucleotide polymorphism microarray and haplotype analysis to characterize genomic variation associated with severe disease. Both of these approaches are promising leads toward further translational research and improved diagnostic, therapeutic, and preventive strategies. RELEVANCE: This project will provide a means to investigate mechanisms of leptospirosis pathogenesis and will serve as a superb research training mechanism based on the hypothesis that severe infectious disease susceptibility is attributable to specific defects in innate immune detection and signaling and also due to currently uncharacterized genomic variation.