Population Based Molecular epidemiology of Tuberculosis

描述（由申请人提供）：14年来，我们一直将结核分枝杆菌基因分型与标准疾病控制信息相结合，以检查旧金山结核病的流行病学。同时，我们利用旧金山提供的自然实验室来检查这种有机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。在本申请中，我们描述了一组研究，这些研究旨在追求在以前的资助期间所做的观察，这些观察表明，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。这一概念框架为研究结核分枝杆菌与人类之间的关系提供了新的视角。我们观察到的这种关联有几种可能的解释，可分为两大类，社会学（流行病学）和生物学。在本应用中，我们将采用前瞻性研究设计，以比回顾性研究更详细的方式检查可能构成关联的流行病学因素。在上下文中，本文所述的研究包括调查的逻辑进展的第二阶段，其中第一阶段是我们的回顾性数据分析。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，以确定可以推断的流行病学因素在多大程度上控制结核分枝杆菌向不同种族/民族宿主的传播。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，那么开始寻找生物学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种族/民族相关差异的检查。如果观察结果在更仔细的审查下成立，我们的合作者将在单独的资助下对这种关联的合理免疫学基础进行具体检查。确认或驳斥谱系中的遗传变异以重要方式与不同人群的遗传机制相互作用这一概念，将对新疫苗的设计和测试以及治疗和预防结核病药物的临床试验产生重要影响。

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.