Population Based Molecular epidemiology of Tuberculosis

描述(申请人提供)：14年多来，我们一直在将结核分枝杆菌基因分型与标准疾病控制信息相结合，以检查旧金山的结核病流行病学。同时，我们已利用三藩市提供的天然实验室来检查该生物体的基本生物学特性，并将这些特性与结核病的流行病学特征联系起来。在这项申请中，我们描述了一组研究，旨在寻求在前一批赠款期间所做的观察，表明结核分枝杆菌的特定地理谱系已经适应了人类群体的遗传差异。这一概念框架为结核分枝杆菌与人类之间的关系提供了一个新的视角。我们观察到的这种关联有几种可能的解释，分为两大类，社会学(流行病学)和生物学。在这项应用中，我们将使用前瞻性研究设计，以比回溯性更详细的方式检查可能导致这种关联的流行病学因素。综上所述，本文所述的研究包括调查合乎逻辑的第二阶段，第一阶段是我们对回顾数据的分析。本申请中描述的研究将利用对结核病病例及其接触者的数据进行更广泛的检查，以确定可以在多大程度上推断流行病学因素，以控制结核分枝杆菌向不同种族/民族的宿主的传播。如果拟议的研究结果表明，这种联系并不完全基于流行病学因素，那么开始寻找生物机制将是合乎逻辑的。因此，调查的第三阶段将是对人类免疫系统中与种族/民族相关的差异的检查。如果观察结果在更密切的审查下站得住脚，我们的合作者将在单独的资金支持下，对该协会可信的免疫学基础进行具体检查。确认或驳斥谱系中的遗传变异与不同人类群体的遗传机制以重要方式相互作用的概念，将对新疫苗的设计和测试，甚至可能对治疗和预防结核病的药物的临床试验具有重要影响。

DESCRIPTION (provided by applicant): For more than 14 years we have been integrating Mycobacterium tuberculosis genotyping with standard disease control information to examine the epidemiology of tuberculosis in San Francisco. Concurrently, we have used the natural laboratory provided by San Francisco to examine basic biological properties of the organism and to relate these properties to epidemiological features of tuberculosis. In this application we describe a set of studies designed to pursue observations made during the previous grant period suggesting that specific geographic lineages of M. tuberculosis have adapted to genetic differences in human populations. This conceptual framework provides a new perspective on the relationship between M. tuberculosis and humans. The association that we have observed has several potential explanations that fall into two main categories, sociological (epidemiological) and biological. In this application we will use a prospective study design to examine the epidemiological factors that possibly underlie the association in much greater detail than was possible retrospectively. Taken in context, the studies described herein comprise the second phase of a logical progression of investigations, the first phase of which was our analysis of retrospective data. The studies described in this application will utilize a more extensive examination of data from tuberculosis cases and their contacts to determine the extent to which epidemiological factors can be inferred to govern the transmission of M. tuberculosis to hosts of different race/ethnicities. If the results of the proposed studies suggest that the association is not entirely based on epidemiological factors, it would then be logical to begin a search for biological mechanisms. Thus, the third phase of the investigation would be an examination of racially/ethnically-associated differences in the human immune system. Specific examination of plausible immunological bases for the association, if the observation holds up under much closer scrutiny, would be conducted by our collaborators under separate funding. Confirming or refuting the concept that genetic variations in lineages interact in important ways with the genetic machinery of different human populations will have important implications for the design and testing of new vaccines and perhaps for clinical trials of drugs for treatment and prevention of tuberculosis.