Genetic predisposition and the role of myeloid cells in the susceptibility to mycobacterial infections in human

遗传易感性和骨髓细胞在人类分枝杆菌感染易感性中的作用

• 批准号: 505651847
• 负责人: Professor Dr. Nico Lachmann
• 金额: --
• 依托单位: Klinik für Pädiatrische Pneumologie, Allergologie und Neonatologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/505651847?language=en
• 关键词: Genetic; predisposition; role; myeloid; cells

Infectious diseases remain a devastating public health burden worldwide. Life-threatening bacterial diseases can result from single-gene inborn errors of immunity (IEI). Mendelian susceptibility to mycobacterial disease (MSMD) is a group of IEI characterized by severe infections caused by weakly virulent mycobacteria in otherwise healthy patients. MSMD patients are also vulnerable to tuberculosis and other diseases caused by intra-macrophagic pathogens. Eighteen of the 19 known MSMD-causing genes control the induction and/or the response to interferon gamma (IFN-g), which is the macrophage-activating factor. We hypothesize that these patients suffer from novel single-gene IEI, probably affecting IFN-g mediated immunity. This project capitalizes on a unique collection of 1,200 patients with MSMD. However, the genetic etiology of many MSMD patients remains unknown, with available whole exome sequencing (WES) data. We will search for novel IEI in these patients and validate their disease-causing effects following three specific aims: i) recruitment of MSMD patients (worldwide) and genome-wide (GW) computational approaches to select novel MSMD-causing candidate genes, ii) validation at the molecular and cellular levels of the products of novel MSMD-causing genes and mutant variants, and their connection with those of known genetic etiologies of MSMD, iii) study of myelopoiesis of MSMD-causing genes and variants using in vitro hematopoietic differentiation of iPSCs. Our project is supported by strong preliminary data, with our identification of four exciting candidate etiologies; with autosomal recessive IRF1, TNF, and CCR2 deficiencies; and one X-linked recessive MCTS1 deficiency. While IRF1, CCR2 and TNF deficiencies were predicted to underlie MSMD based on the mouse model, the discovery of MCTS1 deficiency is most surprising. The four disorders affect the myeloid lineage. We have also already generated iPSCs from one IRF1-deficient patient. The unique expertise of the three groups will synergistically tackle the problems of hematopoietic cells (in particular myeloid cells) and MSMD through the in-depth characterization of rare germline mutations occurring in natura in patients with MSMD diagnosis. This integrated program combining WES analyses with in-depth functional studies including by iPSC technology is achievable and highly innovative in the fields of medicine, genetics, immunology, and infection. This project will provide new biological insights into the pathogenesis of mycobacterial diseases (including tuberculosis) clarifying devastating medical problems. Moreover, the clinical implications will help the patients and their families not only in terms of molecular diagnosis, genetic counseling, and prognosis, but also in terms of treatment, as patients with impaired production of IFN-g can be treated with recombinant IFN-g.

传染病仍然是全世界一个毁灭性的公共卫生负担。威胁生命的细菌性疾病可由单基因先天性免疫缺陷（IEI）引起。分枝杆菌病孟德尔易感性（MSMD）是一组以弱毒分枝杆菌在健康患者中引起严重感染为特征的IEI。MSMD患者也容易患结核病和其他巨噬内病原体引起的疾病。在19个已知的msmd致病基因中，有18个控制对巨噬细胞激活因子干扰素γ (IFN-g)的诱导和/或应答。我们假设这些患者患有新型单基因IEI，可能影响IFN-g介导的免疫。该项目利用了1,200名MSMD患者的独特收藏。然而，许多MSMD患者的遗传病因仍然未知，有可用的全外显子组测序（WES）数据。我们将在这些患者中寻找新的IEI，并在以下三个具体目标下验证其致病作用：i)招募MSMD患者（全世界）和全基因组（GW）计算方法来选择新的MSMD致病候选基因，ii)在分子和细胞水平上验证新型MSMD致病基因和突变变体的产物，以及它们与已知MSMD遗传病因的联系，iii)利用iPSCs体外造血分化研究MSMD致病基因和变体的骨髓形成。我们的项目得到了强有力的初步数据的支持，我们确定了四种令人兴奋的候选病因；常染色体隐性IRF1、TNF和CCR2缺陷；和一个x连锁隐性MCTS1缺陷。虽然基于小鼠模型预测IRF1、CCR2和TNF缺陷是MSMD的基础，但MCTS1缺陷的发现最令人惊讶。这四种疾病影响髓系。我们也已经从一位irf1缺陷患者身上生成了iPSCs。这三个小组的独特专业知识将通过深入描述MSMD诊断患者中自然发生的罕见种系突变，协同解决造血细胞（特别是骨髓细胞）和MSMD的问题。这一综合项目将WES分析与包括iPSC技术在内的深入功能研究相结合，在医学、遗传学、免疫学和感染领域具有高度创新性。该项目将为分枝杆菌疾病（包括结核病）的发病机制提供新的生物学见解，阐明毁灭性的医学问题。此外，临床意义将帮助患者及其家属不仅在分子诊断，遗传咨询和预后方面，而且在治疗方面，因为IFN-g产生受损的患者可以用重组IFN-g治疗。