Prevalence, risk factors and consequences of complex M. Tuberculosis infections

描述(由申请人提供) 摘要：结核病是一种全球性的传染病，2006年全球结核病发病人数超过900万例，死亡170万例。多药耐药(MDR)和广泛耐药(XDR)结核病的出现以及艾滋病毒和结核病流行的融合对有效的结核病控制构成威胁。此外，有证据表明，以前的结核分枝杆菌感染对再次感染的免疫力有限，一个人可能同时携带一种以上不同的结核分枝杆菌菌株，不同的结核分枝杆菌血统的毒力特征不同，以及结核分枝杆菌在一个宿主内具有多样性。这些因素中的每一个都加剧了结核分枝杆菌感染宿主内的复杂性，并给个人治疗和人群疾病控制带来了并发症。我提议在秘鲁利马和南非皮特马里茨堡开始治疗结核病的个人中进行一项观察性研究，以评估复杂的结核分枝杆菌感染的流行率、风险因素和后果。我将1)在初始诊断时估计多菌株结核分枝杆菌感染的特定部位流行率和个体间的克隆异质性；2)确定多菌株感染和克隆异质性的宿主和菌株相关危险因素；3)评估多菌株感染和克隆异质性对标准一线治疗方案的早期反应的影响；以及4)建立数学模型来检验多菌株感染和克隆异质性对个体和群体水平的影响。 公共卫生相关性：最近的研究表明，结核分枝杆菌感染比人们以前认识到的更加复杂：一个人可以被一种以上的菌株感染，每种菌株都可以在感染过程中进化。目前对复杂感染的流行情况、与复杂感染有关的病原体和宿主因素、或复杂感染对个人治疗结果的影响或对控制疾病在社区传播的战略的执行情况知之甚少。这里提出的研究将评估秘鲁利马和南非Pietermaritzburg的结核病患者治疗前复杂感染的流行率以及复杂感染对早期治疗反应的影响。这些结果将与开发数学模型相联系，这些模型旨在评估复杂的结核分枝杆菌感染对结核病控制新战略的预测绩效的影响。这项研究的总体目标是更多地了解结核病的自然历史，并利用这些知识来改善个人及其社区的健康。

DESCRIPTION (Provided by the applicant) Abstract: Tuberculosis (TB) is an infectious disease of global importance; in 2006, there were more than 9 million incident cases and 1.7 million deaths attributable to TB. The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB and the convergence of HIV and TB epidemics are threats to effective TB control. Furthermore, evidence exists that previous M. tuberculosis infection confers limited immunity to re-infection, that an individual can simultaneously harbor more than one distinct strain of M. tuberculosis, that distinct lineages of M. tuberculosis differ in their virulence characteristics, and that M. tuberculosis diversifies within a host. Each of these factors contributes to the within-host complexity of M. tuberculosis infection and presents complications for the treatment of individuals and the control of disease in populations. I propose an observational study among individuals starting treatment for TB in Lima, Peru and Pietermaritzburg, South Africa to evaluate the prevalence, risk factors and consequences of complex M. tuberculosis infection. I will 1) estimate the site-specific prevalence of multiple-strain M. tuberculosis infection and clonal heterogeneity among individuals at the time of initial diagnosis; 2) determine the host- and strain-related risk factors for multiple-strain infection and clonal heterogeneity; 3) evaluate the effect of multiple-strain infection and clonal heterogeneity on early response to standard first-line treatment regimens; and 4) develop mathematical models to examine the individual- and population-level effects of multiple-strain infection and clonal heterogeneity. Public Health Relevance: Recent studies indicate that M. tuberculosis infections are more complex than had previously been appreciated: an individual can be infected by more than one strain and each strain can evolve during the course of infection. Little is currently known about the prevalence of complex infections, the pathogenand host-factors related to complex infections, or the effect of complex infections on the treatment outcomes of individuals or on the performance of strategies to control disease spread in communities. The studies proposed here will assess the pre-treatment prevalence of complex infections and the impact of complex infection on early treatment response in TB patients in Lima, Peru and Pietermaritzburg, South Africa. These results will be linked to the development of mathematical models designed to assess the effect of complex M. tuberculosis infection on the projected performance of new strategies for TB control. The overall goal of this study is to learn more about the natural history of TB and to use this knowledge to improve the health of individuals and their communities.