Molecular Epidemiology of Leprosy

描述（由申请人提供）：2002年期间发现了670 000例新的麻风病例。尽管世界卫生组织在过去10-20年里实施了有效的多药疗法来治疗麻风病人，但造成这种高发病率的因素是什么？就麻风病而言，致病微生物麻风分枝杆菌的潜在传播机制在来源、宿主、传播方式和与宿主的相互作用方面仍不清楚。存在多种假设，但由于无法培养M，答案仍然是推测性的。麻风病在体外，发病缓慢，临床表现广泛。最近获得的M.麻风病是一种适用于麻风病流行病学的宝贵的新资源。该提案提出了一种独特的方法，旨在协调一致地研究多种因素，以便更全面地了解麻风病持续发病的最合理原因。其目标是通过开发和应用敏感，特异和简单的分子方法来推进几个独立实验室的研究工作。本研究的具体目的是：1.通过PCR扩增M.土壤和水中麻风特异性DNA和mRNA;和B）菌株分型，用于与流行地区发现的临床菌株进行比较; 2.通过PCR扩增麻风病人接触者的M.麻风特异性DNA和mRNA; B）用于与指示病例中发现的临床菌株比较的菌株分型;和c）参与感染和免疫的细胞因子的mRNA的证明;和3.通过以下方法评价新发麻风病例的贡献：a）PCR扩增M。麻风特异性DNA和mRNA; B）菌株分型，用于与流行病学相关病例进行比较; c）鉴别由folP和rpo B基因突变引起的原发性和获得性耐药性，folP和rpo B基因分别是氨苯砜和利福平的靶点。证明M的身份是很重要的。通过菌株分型方法确定麻风病在传播链中的分布。应用9个新发现的多态性位点进行菌株分型是这一建议的关键组成部分。据设想，这项研究投资将产生的实际解决方案和知识数据库将对麻风监测和控制流行最严重地区的传播以及对M.麻风病人

DESCRIPTION (provided by applicant): 670,000 new cases of leprosy were detected during the year 2002. What are the factors that contributed to this high incidence even though effective multidrug therapy implemented by the World Health Organization has been used to treat leprosy patients over the last 10-20 years? For leprosy, the underlying mechanisms of transmission of Mycobacterium leprae, the causative organism, are still unclear with respect to the source, reservoir, mode of transmission and interaction with the host. Multiple hypotheses exist, but answers remain speculative owing to the inability to cultivate M. leprae in vitro, the slow onset of disease, and the broad spectrum of clinical manifestations. The recent availability of the genome sequence of an isolate of M. leprae is a valuable new resource applicable to the epidemiology of leprosy. This proposal presents a unique approach aimed at a concerted effort to study multiple factors in order to obtain a more comprehensive understanding of the most plausible causes for continued incidence of leprosy. The objectives are to advance the research endeavors at several independent laboratories through development and application of sensitive, specific and simple molecular methods. The specific aims are: 1.To evaluate the contribution of the extra-human environment in leprosy transmission by: a) PCR amplification of M. leprae specific DNA and mRNA in soil and water; and b) strain typing for comparison with clinical strains found in the endemic region; 2. To evaluate sub-clinical infections in contacts of leprosy patients by: a) PCR amplification of M. leprae specific DNA and mRNA; b) strain typing for comparison with clinical strains found in index cases; and c) demonstration of mRNA of cytokines involved in infection and immunity; and 3. To evaluate the contribution of incident leprosy cases by: a) PCR amplification of M. leprae specific DNA and mRNA; b) strain typing for comparison with epidemiologically linked cases and; c) identification of primary and acquired drug resistance conferred by mutations in folP and rpoB genes, targets of dapsone and rifampicin respectively. It is important to prove identity of M. leprae within the chain of transmission by strain typing methods. The application of nine newly discovered polymorphic loci for strain typing is a key component of this proposal. It is envisioned that the practical solutions and the knowledge database that will emerge from this research investment will have a tangible impact on leprosy surveillance and control of transmission in the most endemic areas and to studies regarding virulence, evolution and pathogenicity of M. leprae.