Leprosy Bacillus: From Genotype to Phenotype to Tools

描述(由申请人提供)：尽管多年来多种药物疗法(MDT)覆盖全球，而且发病率大幅下降，但麻风新病例的发现率仍然居高不下。这一事实清楚地表明，单靠治疗并不能阻止麻风病的传播，并突显了我们对这一疾病理解上的重大差距；我们不知道麻风病是如何传播的，我们也没有充分开发或评估有前景的工具来检测临床前麻风病，这是一个可能的传播源，或追踪社区内的个别分离株。在之前的支持下，该联盟确定了麻风分枝杆菌特有的蛋白质和多肽，有望在麻风流行地区进行细胞介导的免疫分析，并在麻风分枝杆菌基因组中存在足够的遗传多样性，以追踪全球和局部的单个分离株。在巴西麻风病流行地区继续开发这些工具，并随后通过新成立的IDEA(麻风病诊断和流行病学检测倡议)全球网络解决传播和早期诊断问题，是拟议研究的主要重点。此外，作为疾病易感性的生物标志物，特别是神经损伤和残疾，保护性和致病细胞因子将被确定，目的是识别能够在麻风病患者中诱导与对照组相比具有区别性T细胞表型的抗原。该计划是基础研究事业的巅峰，将为麻风病控制项目带来评估化疗干预对疾病发病率影响的手段，并为根除这种困扰人类最贫困人口的疾病指明方向。

DESCRIPTION (provided by applicant): New case detection rates in leprosy remain obstinately high despite years of global coverage with multiple drug therapy (MDT) and a major decrease in prevalence. This fact demonstrates clearly that treatment alone does not block transmission of leprosy and underscores major gaps in our comprehension of the disease; we do not know how leprosy is transmitted and we have not fully developed or assessed promising tools for detecting preclinical leprosy, a possible source of transmission, or tracing individual isolates within communities. Under previous support, this consortium identified Mycobacterium leprae specific proteins and peptides, promising in cell mediated immune assays in leprosy endemic regions, and sufficient genetic diversity within M. leprae genomes to trace individual isolates, globally and locally. The continuing development of these tools in leprosy endemic regions of Brazil, and subsequently through the newly formed IDEAL (Initiative for Diagnostic and Epidemiological Assays for Leprosy) global network, to address transmission and early diagnosis, are the major foci of the proposed research. Also, as biomarkers for disease susceptibility, notably nerve damage and disability, both protective and disease inducing cytokines will be determined with the aim of identifying antigens able to induce a discriminating T cell phenotype in leprosy patients compared to controls. This program, the culmination of a career in basic research, will bring to leprosy control programs the means to assess the effects of chemotherapeutic intervention on disease incidence, and point the way to eradication of a disease that afflicts the most impoverished of humanity.