Visceral Leishmaniasis in Bihar State, India

描述（由申请人提供）：内脏利什曼病（VL）仍然是印度的主要健康问题。为了了解VL的复杂发病机制，TMRC研究了流行病学，免疫学和疾病遗传学中的关键问题。我们开发了长期研究活动所需的资源、基础设施和人力。我们实现了所有3个项目的主要目标，获得了有趣的成果，这些成果大多已被带到相关领域的科学界。在TRMC II中，我们希望以TMRC I的结果为基础，更好地了解人类宿主/病原体关系的演变。因此，屯门公路资源中心第二期分为四个主要项目和四个核心设施。项目1将研究疾病进展的决定因素和潜伏感染在传播中的作用，并将研究无症状感染者在临床和公共卫生层面的作用。通过产生这些证据，我们希望能够为控制计划以及临床决策提供信息，以减少流行地区的疾病传播。我们还将研究其他NTD在VL合并感染中的作用。项目2是对白蛉病媒的研究，以改进目前病媒控制工作的不足。该项目将测试一些假设，挑战与比哈尔邦的VL白蛉媒介P. argentipes相关的现行惯例。VL免疫调节项目3将继续开展工作，旨在了解导致未经治疗的VL严重进展和致命结局的免疫抑制途径。在TMRC I中，我们证明了活性VL的全血具有产生抗原特异性IFNg和IL-10的能力，其在防止寄生虫杀死中具有生物活性。我们想知道如何破坏IL-10的活性。项目4将携带TMRC I进行的GWAS的主要发现，以确定HLA II类分子的分子和细胞作用，这将对治疗干预和疫苗设计产生重大影响。除了这些项目外，还将有一个科学和行政核心A;一个数据管理和生物统计核心B;一个人口监测系统（DSS）核心C，分两个阶段覆盖Muzaffarpur的125 000多人;以及一个分子分型和诊断核心D。 公共卫生相关性：TMRC II将充分利用TMRC 1 5年来开发的资源，该资源为发展中国家带来了尖端科学技术，以消除致命的致病性疾病。流行病学、免疫学、遗传学、生物统计学等领域的国际专家，加上沿着能够进入现场和获得临床样本，因此很有可能实现解开VL复杂性的目标。 项目1：疾病进展的决定因素和潜伏感染在传播中的作用 项目负责人：Kansal，S.，MD （申请人提供的描述）：项目1“疾病进展的决定因素和潜伏感染在传播中的作用”将研究一系列因素，这些因素将有助于理解为什么在印度次大陆只有有限数量的杜氏利什曼原虫感染者发展为内脏利什曼病（VL）。项目1还将有助于评估无症状感染者（未发展为疾病的人）在L中的作用。Donovani传输。该项目将联合收割机结合现场和实验室工作。将在高传播地区进行两次利什曼病感染的血清学调查，以确定研究地区最近的无症状血清转换者和对照者（详见核心C）。同样，VL病例和对照（即健康的家庭接触者）也将被确定并纳入不同的研究。项目1分为4个具体目标。目的1将检查HLA型与血清转换和疾病进展的相关性，控制在以前的危险因素研究中确定的几个混杂因素。目标2将使用最近开发的定量PCR评估不同亚群（即血清转化者和血清阴性个体）中的寄生虫负荷，并评估其对VL进展的影响，同时考虑遗传和环境因素。目标3将在两项病例对照研究中检查与其他被忽视的热带病（NTD）合并感染与VL之间的关联。(1)一项比较利什曼原虫血清阳性与一般人群的不匹配病例对照研究和（2）一项比较VL病例与社区对照的匹配病例对照研究将用于评估丝虫或地蠕虫L的影响。Donovani合并感染进展为VL。最后，目标4将通过以下方式研究无症状感染者的作用：（1）验证改良的基于SLA的Quantiferon，以检测无症状个体的细胞免疫应答;（2）选择待纳入异种诊断实验的个体（外周血单核细胞（PBMC）培养阳性）（详情见项目2）。 公共卫生相关性：该项目产生的结果对个人和公共卫生都很重要。确定从VL感染进展为疾病的危险因素可能有助于二级预防。无症状感染在L. Donovani传播可能对目前的VL控制策略产生重大影响。

DESCRIPTION (provided by applicant): Visceral leishmaniasis (VL) remains a major health problem in India. To understand the complex pathogenesis of VL, TMRC examined key questions in epidemiology, immunology and genetics of disease. We developed the resources, infrastructure and manpower necessary for long term research activities. We achieved the major objectives of all 3 projects, obtaining interesting results that have mostly been brought to the scientific community working in related fields. In TRMC II we want to build on the results of TMRC I, to gain greater understanding of the evolution of the human host/pathogen relationship. TMRC II has therefore been divided into 4 major projects with 4 core facilities. Project 1 will be on the determinants of disease progression and role of latent infection in transmission and will study the role of asymptomatic infection in VL at clinical and public health levels. By generating this evidence we expect to be able to inform control programs, as well as clinical decision-making, to decrease spread of disease in the endemic region. We will also be investigating the role of other NTDs in coinfection with VL. Project 2 constitutes studies of the sand fly vector to improve currently inadequate vector control efforts. This project will test a number of hypotheses, challenging current conventions related to the sand fly vector of VL in Bihar, P. argentipes. Project 3 on immune regulation in VL will continue work aimed at understanding the ever evading immunosuppressive pathways that account for severe progression and fatal outcome of untreated VL. In TMRC I, we demonstrated that whole blood of active VL has the capacity to produce antigen specific IFNg and IL-10, which is biologically active in preventing parasite killing. We want to learn how to subvert the activity of IL-10. Project 4 will carry forwad major findings from a GWAS undertaken in TMRC I to determine the molecular and cellular action of HLA class II molecules, which will have major implications for therapeutic intervention and vaccine design. In addition to these projects, there will be a Scientific and Administrative Core A; a Data Management and Biostatistics Core B; a Demographic Surveillance System (DSS) Core C covering over 125,000 people in Muzaffarpur in 2 phases; and a Molecular Typing and Diagnostics Core D. PUBLIC HEALTH RELEVANCE: TMRCII will fully utilize resources developed over 5 years in TMRC l, which brought cutting edge scientific technologies to a developing nation to eradicate a fatal pathogenic disease. The combination of international experts in the fields of epidemiology, immunology, genetics, biostatisticians, along with access to field sites and clinical samples makes it highly likely that the goal of unraveling the complexity of VL will be achieved. Project 1: Determinants of Diseases Progression and Role of Latent Infection in Transmission Project Leader: Kansal, S., MD (Description as provided by applicant): Project 1 "Determinants of disease progression and role of latent infection in transmission" will study a series of factors that will help understandig why only a limited number of individuals infected with Leishmania donovani develop Visceral Leishmaniasis (VL) on the Indian subcontinent. Project 1 will also contribute to assess the role of asymptomatically infected individuals (those who do not progress to disease) in L. donovani transmission. This project will combine field and laboratory work. Two serological surveys of leishmaniasis infection will be done in high transmission areas to identify recent asymptomatic seroconvertors and controls in the study area (see Core C for details). Similarly, VL cases and controls (i.e. healthy household contacts) will also be identified and included in the different studies. Project 1 is divided in 4 specific aims. Aim 1 will examine the association of HLA-type with seroconversion and disease progression controlling for several confounders identified in the previous risk factor studies. Aim 2 will use a recently developed quantitative PCR to assess parasite load in different subpopulations (i.e. seroconvertors and seronegative individuals) and assess its influence in progression to VL taking into account genetic and environmental factors. Aim 3 will examine the association between co-infections with other Neglected Tropical Diseases (NTD) and VL in two case-control studies. (1) An unmatched case-control study comparing Leishmania seropositives with the general population and (2) a matched case-control study comparing VL cases to community controls will be used to assess the effect of filaria- or geo-helminths L. donovani co-infection on progression to VL. Finally, Aim 4 will contribute to study the role of asymptomatically infected persons by (1) validating a modified SLA-based Quantiferon to detect cellular immune response in asymptomatic individuals and (2) selecting individuals (peripheral blood mononuclear cells (PBMC) culture positive) to be included in the xenodiagnosis experiments (see Project 2 for details) . PUBLIC HEALTH RELEVANCE: Results generated in this project will be of importance for individual as well as for public health. Identifying risk factors for progression from VL infectionto disease may allow for secondary prevention. Evidence on the potential role of asymptomatic infections in L. donovani transmission may have major implications for the current VL control strategy.