PATHOGENESIS OF LEPTOSPIROSIS

候选人高锟博士是一名传染病临床医生，长期致力于国际卫生和微生物发病机制的研究。目前，他正在加州大学伯克利分校的Lee Riley博士和康奈尔大学医学院的Warren Johnson博士的指导下接受实地培训，同时在巴西萨尔瓦多建立针对新发病原体的主动监测和社区研究。这些活动的重点是钩端螺旋体病，这是一种螺旋体人畜共患病，在萨尔瓦多进行的调查表明，钩端螺旋体病是城市大规模流行病的新病因。候选人未来的目标是应用综合实验室和基于人群的方法来研究传染病。为此目的，当前的目标是：1)获得实验室技能，以表征致病机制的菌株特异性决定因素；2)获得先进的流行病学和统计工具，以加强未来的实地研究。在拟议的奖励期内，将通过Lee Riley博士实验室的钩端螺旋体病研究项目和加州大学伯克利分校公共卫生学院的课程作业进行培训。钩端螺旋体病可出现多系统并发症，包括黄疸、急性肾功能衰竭、肺出血和严重贫血。导致感染后出现这些并发症的因素尚不清楚。这些因素可能与菌株特异性、宿主易感性或决定感染接种量大小的流行病学因素有关。这个特定的项目将侧重于菌株特定的因素。在动物模型中，粘附和进入非吞噬性宿主细胞与几种细菌的毒力有关。然而，在人类钩端螺旋体病中还没有研究表明这种关联。在鉴定编码毒力因子的基因方面进展甚微。因此，该项目的具体目标是：1)比较从严重、轻度和无症状人类感染中分离的钩端螺旋体菌株的毒力特征，a)使用豚鼠感染模型，b)进行细菌粘附、侵袭和细胞毒性的组织培养试验，以及2)确定介导哺乳动物细胞关联的特定细菌因子。完成拟议奖项的研究目标将为研究基因产物的结构功能和确定所鉴定的基因是否为毒力因子提供基础。到本奖励期结束时，候选人将掌握识别钩端螺旋体病传播和发病机制中的宿主、菌株和接种特异性因素所需的补充性实验室和流行病学技能。这种专注于这种新兴病原体的技能应该使他能够建立自己作为独立调查员的研究重点。

The candidate, Dr. Albert Ko, is an infectious disease clinician whose long-term commitment has focused on research in international health and microbial pathogenesis. At present, he is receiving field training under the direction of Dr. Lee Riley at University of California, Berkeley and Dr. Warren Johnson at Cornell University Medical College, while establishing active surveillance and community-based studies for emerging pathogens in Salvador, Brazil. The focus of these activities has been leptospirosis, a spirochetal zoonoses, which investigations in Salvador have demonstrated to be an emerging cause of large urban epidemics. The candidate's future goal is to apply an integrated laboratory and population-based approach to infectious diseases. For this purpose, immediate objectives are to: 1) obtain the laboratory skills to characterize strain-specific determinants of pathogenesis and 2) acquire the advanced epidemiological and statistical tools that will enhance future field studies. During the proposed award period, training will be performed through a research project on leptospirosis in Dr. Lee Riley's laboratory and course work at the School of Public Health, University of California at Berkeley. In leptospirosis, multisystem complications can develop which include jaundice, acute renal failure, pulmonary hemorrhage and severe anemia. Factors that contribute to the development of these complications after an infection are not known. Such factors may relate to strain-specific characteristics, host susceptibility, or epidemiologic factors that determine infectious inoculum size. This specific project will focus on the strain-specific factors. Adherence and entry into non-phagocytic host cells in vitro have been correlated with virulence of several bacterial organisms in animal models. However, no studies have addressed this association in human leptospirosis. Little progress has been made in identifying the genes encoding virulence factors. The specific aims of this project, therefore, are to: 1) compare virulence characteristics of leptospiral strains isolated from severe, mild, and asymptomatic human infections using a) a guinea pig infection model, and b) tissue culture assays for bacterial adherence, invasion, and cytotoxicity , and 2) identify specific bacterial factors that mediate mammalian cell association. Completion of the research aims of the proposed award will provide the basis to investigate the structure-function of the gene products and determine whether the identified genes are virulence factors. By the end of this award period, the candidate will have developed the complementary laboratory and epidemiological skills needed to identity host, strain and inoculum-specific factors in transmission and pathogenesis of leptospirosis. Such skills focused on this emerging pathogen should enable him to establish his own research focus as an independent investigator.