Addressing the Global Burden of Leptospirosis in Two Endemic Countries

解决两个流行国家钩端螺旋体病的全球负担

• 批准号: 9225174
• 负责人: Joseph M. Vinetz
• 金额: $ 42万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9225174
• 关键词: Acute; Address; Affect; Affinity; Agriculture; Antibodies; Antigens; Area; Attention; Biological; Blood; Canis familiaris; Case Fatality Rates; Cattle; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Microbiology; Clinical Research; Collaborations; Communicable Diseases; Communities; Country; Culture Techniques; Databases; Deposition; Detection; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Doctor of Philosophy; Environment; Enzyme-Linked Immunosorbent Assay; Epidemic; Epidemiology; Family suidae; Genbank; Generations; Genome; Geography; Goals; Gold; Human; Infection; International; Leptospira; Leptospirosis; Letters; Lipopolysaccharides; Marsupialia; Medicine; Methods; Microarray Analysis; Military Personnel; Molecular; Monoclonal Antibodies; Outcome; Outcomes Research; Outpatients; Pathogenicity; Peru; Protein Array; Protein Microchips; Proteins; Public Health; Publishing; Research; Risk; Rodent; Rural; Sampling; Serologic tests; Serum; Site; Source; Sri Lanka; Techniques; Testing; Thinking; Time; Translating; Translational Research; Translations; Urine; Water Buffalo; Work; World Health Organization; Zoonoses; base; burden of illness; clinically actionable; clinically relevant; direct application; disorder prevention; field study; follow-up; improved; novel strategies; prevent; programs; prospective; public health relevance; tool; transmission process

 DESCRIPTION (provided by applicant): The proposed U19 ICIDR Program is focused on human infection and disease by Leptospira. Our overall approach is to use fundamental biological scientific methods combined with clinical/field studies in contrasting epidemiological contexts in Peru and Sri Lanka, to develop new, clinically actionable diagnostic tests. Taking into account the local, regional, and international diversity of Leptospira, the proposed research addresses a hitherto insurmountable gap in the field, that of obtaining diagnostic tests for leptospirosis that are inexpensive, sensitive and efficient, yet easily deployable and effective regardless of the underlying transmission dynamics. The improved accuracy and efficiency of these tests will enable timely administration of appropriate therapy, which is vital for improving clinical outcomes. The overall goal of this Program is to develop robust tools and approaches that will effectively quantify the Global Burden of Leptospirosis, addressing several key goals shared by the international leptospirosis research community as articulated by the World Health Organization's Leptospirosis Epidemiology Reference Group (LERG).1, 2 These approaches, which are applicable to all leptospirosis-endemic and epidemic-prone sites, are summarized as follows: 1. Carry out prospective, field-based clinical studies of suspected acute leptospirosis cases in known or suspected highly endemic settings in Peru (Project 1) and Sri Lanka (Project 2) where the diversity of Leptospira is high and includes the most highly pathogenic as well as less pathogenic (but still infectious) Leptospira. These sites will include contrasting urban vs. rural and seasonal vs. perennial leptospirosis risk areas in Peru and Sri Lanka. The projects will focus on both hospitalized cases (more severe disease) and outpatients (generally mild spectrum of disease) with dedicated attention to comprehensively follow up clinical and microbiological/molecular outcomes; 2. Characterize serum and urine samples from field studies with regard to leptospirosis diagnosis using conventional serology (MAT, ELISA),3, 4, 5 routine culture, our published culture-independent molecular techniques (conventional PCR,6, 7 qPCR,8 Multi Locus Sequence Typing (MLST)9, 10); 3. Test newly developed antigen-detection tests (LPS; alternatively, Leptospira proteins) and antibody- based serological tests using protein microarray technology based on our newly developed Leptospira Genome Project database (PATRIC, http://patricbrc.org; deposited in GenBank, http://www.ncbi.nlm.nih.gov/bioproject/?term=leptospira (both accessed March 7, 2014)) against conventional diagnostics (gold standard re-defined as MAT (on paired samples) plus PCR of blood/urine, given the insensitivity of current culture techniques (problems with past gold-standard diagnostics discussed in Refs.11, 12). The expected outcomes of this program are 1) New tools to diagnose leptospirosis and to identify leptospiral infection of humans; 2) Define and optimize the generalizability of these new tools in diverse and representative settings in Peru and Sri Lanka, and beyond (for example, through the U.S. Centers for Disease Control and Prevention that receives samples from all over the world; see Renee Galloway, Letter of Support); and 3) Enhancing research capacity of foreign collaborators by facilitating development of independent creative scientific thinking, hypothesis generation and testing, and new approaches to addressing clinical and translational research problems of highest priority to the endemic country. Additional benefits from this project include clear application to OneHealth medicine because human leptospirosis reflects interactions of humans with zoonotic domestic and agricultural sources such as dogs, cattle, pigs, and water buffalo, wild and peridomestic rodents and marsupials. The tools developed here will have direct application and translation to veterinary and agricultural settings but such work will be beyond the scope of the present project.

 描述（由适用提供）：拟议的U19 ICIDR计划侧重于人类感染和疾病。我们的总体方法是使用基本的生物学科学方法与临床/现场研究结合在秘鲁和斯里兰卡的流行病学环境中，以开发新的，临床上可行的诊断测试。拟议的研究考虑了钩端螺旋体的本地，区域和国际多样性，该研究涉及该领域中迄今无法无法克服的差距，该差距是获得瘦心脏病的诊断测试，这些测试廉价，敏感且高效，既易于部署，却易于部署且有效，无论对基础传输动力学而不管是有效的。这些测试的准确性和效率的提高将使及时进行适当的治疗，这对于改善临床结果至关重要。该计划的总体目标是开发可有效量化钩端螺旋体病的全球负担的强大工具和方法，以解决国际钩端螺旋体病研究界共享的几个关键目标，这是世界卫生组织的钩端螺旋体病流行病学参考小组（Lerg）。1，2这些方法，这些方法适用于所有这些方法，这些方法适用于所有卵巢螺旋体 - 综合孔孔，并刺激了刺激性，并刺激了这些方法： 1.在秘鲁（项目1）和斯里兰卡（Project 2）中，对可疑急性诱导性螺旋病病例进行可疑的急性钩端螺旋病病例进行了前瞻性的，基于现场的临床研究，其中钩端螺旋体的多样性很高，并且包括高致病性和更低的致病性和致病性（但仍然具有感染力）的leptoptospira。这些地点将包括对比秘鲁和斯里兰卡的城市与季节性与季节性与多年生钩端螺旋体病风险区域的对比。这些项目将重点关注住院病例（更严重的疾病）和门诊病人（通常是温和的疾病谱），并专门关注全面跟进临床和微生物/分子结果； 2。表征来自现场研究的血清和尿液样品，用于使用常规血清学（MAT，ELISA），3、4、5常规培养的钩端螺旋体诊断，我们发表的与文化无关的分子技术（常规PCR，6，7 QPCR，8个多基因座序列序列（MLST）9，10）; 3。测试新开发的抗原检测试验（LPS；替代性，钩端螺旋体蛋白）和基于抗体的血清学测试，该测试基于我们新开发的Leptospira基因组项目数据库（PATRIC，http://patricbrc.org; patrrc; rote; http://www.ncbi.nlm.nih.gov/bioproject/?term=leptospira (both accessed March 7, 2014)) against conventional diagnostics (gold standard re-defined as MAT (on paired samples) plus PCR of blood/urine, given the insensitivity of current culture techniques (problems with past gold-standard diagnostics discussed in Refs.11, 12). 该计划的预期结果是1）诊断钩端螺旋体病并鉴定人类钩端螺旋体感染的新工具； 2）定义和优化这些新工具在潜水员中的普遍性，并代表秘鲁和斯里兰卡的环境，例如（例如，通过美国疾病控制和预防中心接收来自世界各地的样本；请参阅Renee Galloway，请参阅Renee Galloway，支持信）； 3）通过支持开发独立的创造性科学思维，假设产生和检验的发展，增强外国合作者的研究能力，以及解决临床和翻译最高优先级国家的研究问题的新方法。该项目的其他好处包括对OneHealth医学的明确应用，因为人钩端螺旋体病反映了人类与人畜共患家的相互作用，例如狗，牛，牛，猪和水牛，野生和生殖的啮齿动物以及少阵容。这里开发的工具将直接应用于兽医和农业环境，但此类工作将超出本项目的范围。