Human Genetics of Tuberculosis

项目摘要 由结核分枝杆菌(Mtb)引起的结核病(TB)是一大健康问题。大约四分之一的 世界人口受到感染，但只有少数人在初次感染期间或以后感染期间患上结核病。 二次感染或潜伏的结核分枝杆菌重新激活。遗传流行病学证据有力地表明，结核病是 是由人类的遗传基因决定的。自2000年以来，人们一直在剖析其分子基础。我们发现了2个 结核病背后的先天性免疫错误的类型，均损害干扰素-γ免疫：(I)罕见的免疫错误， 例如在少数结核病患者中发现的常染色体隐性完全IL-12Rβ1和TYK2缺陷，以及(Ii)a 选择性扰乱IL-23的TYK2错义P1104A变异体纯合性所致的常见IEI 依赖干扰素-γ免疫，占欧洲结核病病例的1%。这些发现提供了证据 在特定种族中，人类结核病既有罕见的单基因病因，也有常见的单基因病因的原则，以及 证实依赖于TYK2的干扰素-γ的产生是对结核分枝杆菌保护性免疫所必需的。然而，广大的 大多数结核病患者缺乏遗传病因。我们假设结核病是不同物种集合的结果 单基因或双基因IEI的，具有不完全或很少完全外显的，并且有相当大的比例 不同祖先的种群。为了发现这些变异，我们的项目将结合一个候选基因 方法侧重于罕见和常见的编码TYK2变体，并在全基因组范围内搜索罕见和常见的 其他基因的变异。将在海地招募结核病患者，重点是家庭患者 至少有两个受结核病影响的兄弟姐妹，和/或有复发形式的结核病，因为这些患者更有可能携带 是啊。我们的项目还将利用我们之前在海地和世界各地招募的结核病患者(&gt；1500人)， 遵循以下策略：(I)基于下一代测序(&gt；900)的全面遗传研究 具有已有的完整外显子组测序数据的样本)，以使用 不同遗传假设(遗传异质性或同质性， 单基因或双基因遗传)，以及(Ii)深入的功能研究，以生化表征蛋白质 由新发现的候选变异体编码，并在 分子和细胞水平。我们还将测试这些IEI的效果是否会受到结核分枝杆菌菌株的影响 在海地患者中进行了一项特定的宿主-病原体相互作用研究。我们的初步数据表明，这 方法是卓有成效的，因为我们已经确定了强有力的候选基因类型，包括两种双等位基因功能丧失 TYK2、TNF、BTN2A2和PDCD1的罕见变异以及IL10RA和IL10RA的单或双等位基因常见变异 HL A-DRB1。我们寻找控制单基因或双基因IEI的罕见而常见的变异 高外显性结核病的发展将破译人类对结核分枝杆菌的保护性免疫机制。 这种方法还将为新的预防或治疗方法铺平道路，旨在从基因上挽救 有结核病风险或患有结核病的患者的免疫反应不足。

Project Summary Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a major health problem. About a quarter of the world population is infected, yet only a minority develop TB, either during primary infection, or later during secondary infection or reactivation of latent Mtb. Genetic epidemiological evidence strongly suggests that TB is driven by human genetic predisposition. Its molecular basis has been dissected since 2000. We discovered 2 types of inborn errors of immunity (IEI) underlying TB, both impairing interferon (IFN)-γ immunity: (i) rare IEI, such as autosomal recessive complete IL-12Rβ1 and TYK2 deficiencies, found in a few TB patients, and (ii) a common IEI due to homozygosity for the TYK2 missense P1104A variant that selectively disrupts IL-23- dependent IFN-γ immunity, accounting for up to 1% of European TB cases. These findings provided proof of principle that there are both rare and common monogenic etiologies of human TB, in specific ethnicities, and established that TYK2-dependent IFN-γ production is essential for protective immunity to Mtb. However, the vast majority of TB patients lack a genetic etiology. We hypothesize that TB is the consequence of a diverse collection of monogenic or digenic IEI, with incomplete or more rarely complete penetrance, and in a sizeable proportion of populations of diverse ancestries. To discover these variants, our project will combine a candidate gene approach focused on rare and common coding TYK2 variants with a genome-wide search for rare and common variants in other genes. TB patients will be recruited in Haiti with a specific focus on patients belonging to families with at least two TB-affected siblings, and/or with recurrent forms of TB, as these patients are more likely to carry IEI. Our project will also take advantage of our previously recruited TB patients in Haiti and worldwide (>1,500), following a strategy combining: (i) a comprehensive genetic study based on next generation sequencing (>900 samples with whole exome sequencing data already available) to search for candidate TB-causing variants using cutting-edge computational analyses under different genetic hypotheses (genetic heterogeneity or homogeneity, monogenic or digenic inheritance), and (ii) in-depth functional studies to biochemically characterize the proteins encoded by the newly discovered candidate variants, and to validate their causal role immunologically at the molecular and cellular levels. We will also test whether the effects of these IEI may be influenced by Mtb strains using a specific host-pathogen interaction study in Haitian patients. Our preliminary data indicate that this approach is fruitful, as we already identified strong candidate genotypes, including both bi-allelic loss-of-function rare variations in TYK2, TNF, BTN2A2, and PDCD1, and mono- or bi-allelic common variations in IL10RA and HLA-DRB1. Our search for rare and common variants underlying monogenic or digenic IEI that govern the development of TB with high penetrance will decipher mechanisms of protective immunity to Mtb in humans. This approach will also pave the way to new preventive or therapeutic approaches, aiming to rescue genetically deficient immune responses in patients at risk of, or with TB.