The genetic basis of invasive meningococcal disease

侵袭性脑膜炎球菌病的遗传基础

• 批准号: MR/X023990/1
• 负责人: Vanessa Sancho Shimizu
• 金额: $ 76.13万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX023990%2F1
• 关键词: genetic; basis; invasive; meningococcal; disease

Invasive meningococcal disease (IMD) is a rare disease affecting children and young adults due to bacterial infection by Neisseria meningitidis. Life-threatening infection of the blood, and/or brain lead to IMD. Although most people carry this bacteria in their nose, the majority do not develop IMD. We know that genetic mutations of specific immune pathways make individuals more susceptible to IMD. Patients with these mutations are unable to produce factors that help kill the bacteria. These mutations however are only present in a small number of IMD patients. We thus put forward the idea that other genetic mutations may exist in IMD patients. To identify new genes in IMD, we sequenced DNA from ~700 children with life-threatening bacterial infections, including 250 IMD patients. The sequences from these patients revealed mutations in other protective immune signaling pathways known to be involved in sensing invading bacteria. Here, we propose to test whether these new mutations affect the way a cell responds to the bacteria in an experimental infection. We will use cells from the lining of the airway, and blood cells. We chose to carry out these experiments in these cell types as airway cells are important for the entry of bacteria into the nose, and the blood cells will model the 'invasive' stage of disease when the bacteria replicates in the blood leading to life-threatening infection. Finally, we will test some of these mutations in a zebrafish model of bacterial infection where we may visualize how the body responds to infection in real-time. Understanding the role ofthese genes will improve our understanding of why certain individuals develop life-threatening infections and may lead to better treatment and prevention of childhood infections.

侵袭性脑膜炎球菌病(IMD)是一种罕见的疾病，由脑膜炎奈瑟菌的细菌感染影响儿童和年轻人。危及生命的血液和/或大脑感染会导致IMD。虽然大多数人在鼻子里携带这种细菌，但大多数人不会患上IMD。我们知道，特定免疫途径的基因突变使个人更容易患上IMD。具有这些突变的患者无法产生有助于杀死细菌的因子。然而，这些突变只存在于一小部分IMD患者中。因此，我们提出了IMD患者可能存在其他基因突变的观点。为了确定IMD中的新基因，我们对约700名患有危及生命的细菌感染的儿童进行了DNA测序，其中包括250名IMD患者。来自这些患者的序列揭示了其他保护性免疫信号通路的突变，这些信号通路已知参与感知入侵细菌。在这里，我们建议测试这些新的突变是否影响细胞在实验感染中对细菌的反应方式。我们将使用呼吸道衬里的细胞和血细胞。我们选择在这些细胞类型中进行这些实验，因为呼吸道细胞对于细菌进入鼻子很重要，当细菌在血液中复制导致危及生命的感染时，血细胞将模拟疾病的“侵袭性”阶段。最后，我们将在细菌感染的斑马鱼模型中测试其中一些突变，在那里我们可以实时可视化身体对感染的反应。了解这些基因的作用将提高我们对为什么某些人会患上危及生命的感染的理解，并可能导致更好地治疗和预防儿童感染。