US-Brazil Research Collaboration on Strain Variation in TB

描述（由申请人提供）：结核病（TB）是巴西的一个主要公共卫生问题。该ICIDR提案建立在Ellner、Dietze、Rodrigues和Palaci博士之间的现有合作基础上，将加强维托里亚巴西国家结核病研究所（NDI）的科学基础设施和培训能力，并提供解决结核病问题所必需的信息。我们的假设是，结核分枝杆菌（MTB）的菌株变异是家庭接触者肺结核感染传播程度、从感染进展为疾病的风险以及既往分枝杆菌感染/疫苗接种所提供保护的决定因素。我们的研究小组在结核分枝杆菌中发现了一组同义单核苷酸多态性（SNP）标记，并使用它们构建了该物种的明确进化树，从而可以精确确定不同临床菌株之间的相关性，并确定可能共享表型性状的菌株家族。我们还发现了临床MTB菌株之间基因组多样性的新机制。总体而言，这些发现揭示了MTB中迄今未被怀疑的多态性程度，这可能允许其通过抗原变异和其其他细胞功能的变化来适应宿主免疫应答。在巴西维托里亚进行的一项新颖的家庭接触设计将用于实现以下目标：目标1。确定某些临床菌株是否更具传染性或在感染患者中导致更多疾病进展，而其他菌株是否具有相反的表型，并确定具有不同表型的菌株与宿主免疫系统相互作用的方式是否存在差异。目标二。确定菌株与先天免疫系统相互作用的方式是否不同，以及宿主差异影响这种相互作用的程度。目标3。确定对MTB的适应性免疫是菌株特异性的程度，并发现可以在未来有效对抗所有MTB菌株的疫苗中组合的主要菌株或细菌因子。该计划在来自美国和巴西的领先流行病学家，免疫学家，分子生物学家和微生物学家之间建立了合作，这将使用创新的流行病学研究设计，对人类结核病生物学和免疫学的关键方面进行前沿研究和培训。

DESCRIPTION (provided by applicant): Tuberculosis (TB) is a major public health concern in Brazil. This ICIDR proposal builds on a pre-existing collaboration between Drs. Ellner, Dietze, Rodrigues and Palaci and will enhance the scientific infrastructure and training capabilities of the Nucleo de Doengas Infecciosas (NDI) in Vitoria Brazil and provide information essential to address the TB problem. Our hypothesis is that strain variation in Mycobacterium tuberculosis (MTB) is a determinant of the extent of transmission of infection in household contacts with pulmonary TB, the risk of progressing from infection to disease, and the protection conferred by prior mycobacterial infection/vaccination. Our group has discovered a set of synonymous single nucleotide polymorphism (SNP) markers in MTB and used them to construct an unequivocal evolutionary tree of the species making it possible to precisely determine how different clinical strains are related, and to identify strain families likely to share phenotypic traits. We also have discovered new mechanisms for genomic diversity among clinical MTB strains. Overall, these discoveries have uncovered a hitherto unsuspected degree of polymorphism in MTB that may allow it to adapt to host immune responses by antigenic variation and changes in its other cellular functions. A novel household contact design conducted in Vitoria, Brazil will be used to accomplish the following: Aim 1. To determine whether some clinical strains are more transmissible or cause more disease progression in infected patients, whereas other strains have the opposite phenotype, and to determine whether strains with different phenotypes diverge in the way they interact with the host immune system. Aim 2. To determine if strains vary in the way that they interact with the innate immune system and the degree to which host differences influence this interaction. Aim 3. To determine the degree to which adaptive immunity to MTB is strain-specific, and to discover the principal strains or bacterial factors that could be combined in a future vaccine effective against all MTB strains. This program creates a collaboration among leading epidemiologists, immunologists, molecular biologists and microbiologists from the U.S. and Brazil that will enable cutting edge research and training on crucial aspects of tuberculosis biology and immunology in human populations using an innovative epidemiological study design.