Visceral Leishmanasis in Bihar State, Indian

描述(申请人提供)：最近利什曼病的分布和发病率有所扩大。内脏利什曼病尤其麻烦，因为它导致了大多数死亡。印度、尼泊尔、孟加拉国、苏丹和巴西占全球报告的VL病例的90%。在印度数百万面临风险的人中，比哈尔邦占病例的近90%，紧随其后的是西孟加拉邦、恰尔肯德邦和东北方邦。这个拟议的热带医学研究中心分为3个项目，将研究影响印度比哈尔邦个人和社区内脏利什曼病流行、分布和发病的流行病学、临床、免疫学和遗传因素。组成TMRC的各个项目也旨在提供新的数据，这些数据将更广泛地适用于其他主要全球疾病焦点的控制计划的持续发展，包括开发新的疫苗和诊断辅助工具。这三个主要项目的主题是：项目1：印度比哈尔邦内脏利什曼病的临床和流行病学研究：该项目的目标是提供指导印度比哈尔邦消除或控制内脏利什曼病的努力所需的流行病学和临床证据，并提供流行病学数据，为未来的控制计划提供更广泛的信息，包括开发新型疫苗和诊断辅助工具。项目2：印度比哈尔邦调节性T细胞亚群和细胞因子在人类VL发病中的作用。该项目是一项重点研究，将调查调节性T细胞和抑制性细胞因子在人类内脏利什曼病发病机制中的作用，以期开发基于免疫的治疗方法，逆转与活动性疾病相关的免疫抑制。项目3：印度比哈尔邦内脏利什曼病的遗传风险因素。这个项目将解决导致内脏利什曼病遗传易感性低的遗传因素，目的是确定基因/机制/途径。 在疾病的发病机制中起作用。TMRC将汇集独特的 流行病学家、临床医生、免疫学家和分子遗传学家解决内脏问题 利什曼病是这一致命疾病的全球主要疫源地之一。 项目1：印度比哈尔邦内脏利什曼病的临床和流行病学研究(Singh，S.P.) 项目1描述(申请人提供)：报告：内脏利什曼病(VL)是一种寄生虫病，如果不治疗，是致命的。印度次大陆有数十万人受到影响。大多数人都很穷，依靠公共资金或慈善机构接受治疗。疾病控制的基础是早期诊断和治疗，以及控制传播疾病的沙蝇。到目前为止，控制努力只是暂时缓解，主要流行病定期反弹。这是因为我们对疾病传播动力学的理解存在差距。这项研究旨在确定这些因素，并评估通过寄生虫基因组测序产生的新诊断方法和候选疫苗。这项研究将提供新的知识和工具，使地区政府能够在2015年前实现疾病控制的目标。 项目描述：VL在印度的分销情况参差不齐。村庄和家庭一级疾病传播的决定因素尚未得到很好的了解。亚临床感染被认为在疾病传播中起着重要作用，但亚临床感染的标志物尚未得到验证。我们不完全理解为什么只有一小部分感染者会患上临床疾病。为了更好地了解疾病的动态和传播，这项研究将(1)连续两年对5万人进行详尽的人口调查，使用家庭访谈、CIS技术、遥感数据和多水平建模，以确定将允许更好地针对控制干预措施的生态风险标记；(2)嵌套病例对照研究，以记录家庭和个人水平的VL的可改变的危险因素(例如营养)和危险标记(临床、遗传、免疫学)，每年两轮的血清调查使我们能够记录发生的利什曼感染，并对VL的全面发展进行为期3年的纵向跟踪；(3)针对标准的Western印迹和定性的kDNA PCR和新的Quantiferon T细胞反应分析对现有的感染标记(rK39 ELISA、直接凝集试验、LST)进行评估；(4)用定性和定量的聚合酶链式反应、酶联免疫吸附试验和T细胞分析评价新的(杜氏利什曼原虫复杂特异体基因)标记；(5)在患者和地方病对照中对新的候选疫苗的免疫图谱进行评估。这一结果将为印度次大陆疾病控制的政策和实践提供参考，并增加全球对VL疾病的了解。

DESCRIPTION (provided by applicant): There has been a recent expansion in the distribution and the incidence of leishmaniasis. Visceral leishmaniasis is particularly troublesome as it causes most fatalities. India, Nepal, Bangladesh, Sudan and Brazil harbor 90% of the worldwide reported VL cases. Amongst the millions at risk in India, the state of Bihar accounts for nearly 90% of cases, followed by the states of West Bengal, Jharkhand and Eastern Uttar Pradesh. This proposed Tropical Medicine Research Center is divided into 3 projects that will address epidemiological, clinical, immunological and genetic factors that influence the prevalence, distribution and pathogenesis of visceral leishmaniasis in individuals and communities in Bihar State in India. The individual projects that make up this TMRC are also designed to provide new data that will be more broadly applicable to the continuing development of control programs in the other major global foci of disease, including development of novel vaccines and diagnostic aids. Themes of the three major projects are: Project 1: Clinical and epidemiological studies of Visceral Leishmaniasis in Bihar, India: Goals of this project are to provide the epidemiological and clinical evidence that is required to guide efforts to eliminate or control visceral leishmaniasis in the state of Bihar, India, and to provide epidemiological data that will more broadly inform future control programs including development of novel vaccines and diagnostic aids. Project 2: The role of regulatory T cell subsets and cytokines in the pathogenesis of human VL in Bihar, India. This project is a focused study that will investigate the role of regulatory T cells and suppressive cytokines in the pathogenesis of human visceral leishmaniasis, with a view toward the development of immune-based therapies that will reverse the immunosuppression associated with active disease. Project 3: Genetic risk factors for Visceral Leishmaniasis in Bihar, India. This project will address genetic factors that underly genetic susceptibility to visceral leishmaniasis, with the purpose of identifying genes/ mechanisms/ pathways that contribute to the pathogenesis of disease. The TMRC will bring together a unique combination of epidemiologists, clinicians, immunologists and molecular geneticists to tackle the problem of visceral leishmaniasis in one of the major global foci of this fatal disease. PROJECT 1: Clinical and epidemiological studies of Visceral Leishmaniasis in Bihar, India (Singh, S. P.) PROJECT 1 DESCRIPTION (provided by applicant): Lay statement: Visceral leishmaniasis (VL) is a parasitic disease that is fatal if untreated. Several hundred thousand people are affected in the Indian subcontinent. Most are poor and depend on public funds or charity for treatment. Disease control is based on early diagnosis and treatment, and control of sandflies that transmit disease. Control efforts to date have given only temporary reprieve, with periodic rebound of major epidemics. This is because there are gaps in our understanding of the dynamics of disease transmission. This study is designed to identify these factors, and to evaluate novel diagnostics and vaccine candidates that have arisen through genomic sequencing of the parasite. The study will provide new knowledge and tools to allow regional governments to achieve their aim of disease control by 2015. Project description: VL in India is patchy in distribution. The determinants of disease transmission at a village and household level are not well understood. Subclinical infection is thought to play a significant role in disease transmission, but markers of subclinical infection have yet to be validated. We don't fully understand why only a small proportion of infected subjects develop clinical disease. To gain a better understanding of disease dynamics and transmission, this study will undertake (1) an exhaustive population survey of 50,000 persons for two consecutive years using household interviews, CIS technology, remote sensing data and multi-level modelling, to identify the ecological risk markers that will permit better targeting of control interventions; (2) a nested case control study to document the modifiable risk factors (e.g. nutritional) and risk markers (clinical, genetic, immunological) for VL at household and individual level, with two annual rounds of sero-survey allowing us to document incident leishmanial infections, and a 3-year longitudinal follow-up to document development of full blown VL; (3) evaluation of existing (rK39 ELISA, Direct Agglutination Test, LST) markers of infection against standard Western blot and qualitative kDNA PCR and new Quantiferon assays for T cell responses; (4) evaluation of novel (Leishmania donovanicomplex specific genes) markers using qualitative and quantitative PCR, ELISA and T-cell assays; and (5) immune profiling of novel vaccine candidate in patients and endemic controls. The results will inform policy and practice for disease control in the Indian sub-continent, and add to global understanding of VL disease.