Natural History of Leptospirosis

描述（申请人提供）：钩端螺旋体病是一种新出现的传染病，是一种分布在世界各地的人畜共患螺旋体病。我们已经表明，钩端螺旋体病现在已经从其传统的农村基地蔓延，成为城市环境中与周期性降雨相关的流行病的原因。气候条件和日益增长的城市贫困促成了这种新的流行病学模式的出现：每年在相同的季节期间都会发生与高死亡率有关的大规模暴发，影响到城市贫民窟社区内相同的危险群体。应对这些流行病的公共卫生优先事项是处理严重的临床形式，如威尔氏病和严重肺出血综合征，其死亡率为150 %。目前的治疗和控制措施并未对降低这种死亡率产生影响，因此，需要制定新的预防办法。然而，很少有人知道为什么一小部分（5- 15%）的个体会发展成严重的临床结果。我们假设，在高传播环境中，严重的临床结果受到暴露于环境因素时接种量的差异和自然感染后获得性免疫反应的影响。在巴西萨尔瓦多市，我们建立了研究钩端螺旋体病的流行病学和实验室基础设施。在该地点进行的五年监测已确定了1400多例严重钩端螺旋体病病例，因此为研究钩端螺旋体病的自然史提供了独特的机会。我们提出了一项基于社区的纵向研究，旨在：(1)确定环境风险暴露，包括感染期间可能影响接种量的环境风险暴露，是否与感染后发展为严重疾病的风险增加有关；(2)前瞻性地确定在先前感染期间获得的免疫反应是否可以防止致病性钩端螺旋体的再次感染。这些研究应确定严重钩端螺旋体病的潜在预防措施。同时，它们可能提供更广泛适用的惠益，例如开发改进的诊断工具和确定疫苗开发的目标。

DESCRIPTION (provided by applicant): Leptospirosis, a zoonotic spirochaetal disease with worldwide distribution, is an emerging infectious disease. We have shown that leptospirosis has now spread from its traditional rural base to become the cause of cyclic rainfall-associated epidemics in the urban setting. Conditions of climate and growing urban poverty have contributed to the emergence of this new epidemiological pattern: large outbreaks associated with high mortality occur each year during the same seasonal period and affect the same risk groups within urban slum communities. The public health priority in response to these epidemics is to address the severe clinical forms, such as Weil's disease and severe pulmonary haemorrhage syndrome, for which mortality is >15 percent. Current treatment and control measures have not made an impact in reducing this mortality and therefore, new preventative approaches need to be developed. However, little is known regarding why a small proportion (5-15 percent) of individuals progress to develop severe clinical outcomes. We hypothesize that that in high transmission settings, severe clinical outcomes are influenced by differences in the inoculum size during exposure to environmental factors and by acquired immune response after natural infection. In the city of Salvador, Brazil, we have established the epidemiological and laboratory infrastructure to study leptospirosis. Five-year surveillance at this site has identified more than 1400 severe leptospirosis cases, therefore providing a unique opportunity to study the natural history of leptospirosis. We propose a community-based longitudinal study that aims to: (1) Determine whether environmental risk exposures, including those that may influence inoculum size during infection, are associated with an increased risk of developing severe disease after infection, and (2) Determine prospectively whether immunological responses, acquired during a prior infection, protect against re-infection with pathogenic Leptospira. These studies should identify potential preventative measures for severe leptospirosis. At the same time, they may provide more widely applicable benefits such as the development of improved diagnostic tools and identification of targets for vaccine development.