Unravelling the mechanisms of neurological damage during cryptococcal infection of the brain

揭示大脑隐球菌感染期间神经损伤的机制

• 批准号: MR/X032019/1
• 负责人: Rachael Dangarembizi
• 金额: $ 100.25万
• 依托单位: University of Cape Town
• 依托单位国家: 英国
• 项目类别: Research Grant
• 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%2FX032019%2F1
• 关键词: Unravelling; mechanisms; neurological; damage; during

Lay summaryThe burden of infectious diseases of the brain is incapacitating to the socio-economic development of Africa. Some of the diseases are uniquely prevalent in Africa and are usually neglected in both global research and policy creating a need for African neuroscientists to prioritise and develop local solutions for these challenges. Examples of such diseases include fungal infections of the brain such as cryptococcal meningitis which kills more than 200 000 people each year in Sub-Saharan Africa and also causes neurological dysfunction and disability in survivors, most of which are of an economically productive age. Cryptococcal meningitis (CM) is the leading cause of HIV-associated meningitis, which is characterised by debilitating, inflammatory injury of the brain and a very high chance of death, even with treatment. In Sub-Saharan Africa, the number of people who die from CM and its complications is worsened by the unavailability and inaccessibility of safe and effective drugs. Although a lot of work has been done to describe the biology of the fungal pathogen that causes CM, we know very little about how the human body responds to the fungus especially at the level of the brain, which is the most affected organ in those who succumb to the disease. One of the challenges faced by researchers intending to study brain injury in CM is the lack of appropriate experimental models that provide a good representation of the real clinical form of the disease with good enough resolution to help delineate the complex mechanisms underlying brain damage from this fatal condition. Knowledge of these mechanisms is critical to our understanding of how the disease progresses, as well as to our efforts of developing cheaper and safer drugs that can be accessed by most African people. The first part of this study therefore focusses on introducing a new organ-specific, host-specific experimental model that could be used for studying mechanisms underlying brain injury during cryptococcal infection. The proposed model is based on using both rodent and human brain tissue slices which are carefully kept alive in culture then stimulated with Cryptococcus neoformans, the causative fungus for CM. I will investigate the activation of key inflammatory machinery in immune cells of the brain including receptors for pathogen recognition, transcription factors and other chemical communication molecules released when fighting the fungus. Using state-of-the-art scientific techniques, I will also investigate the contribution of each cell type to the brain's response to the fungus. To compliment data obtained using this novel model, the second part of my proposed research aims to use a living rodent model to recapitulate the human form of CM. Using this model we will be able to describe where in the brain the fungus goes after infection and most importantly, to establish if fungal cells indeed block the fluid clearance pathways of the brain which were discovered recently. This research will fill the existing knowledge gap on how the brain is injured in CM. This models and methods would then serve as a platform for studying the mechanisms of other infections of the CNS that are caused by bacteria, parasites and viruses to inform the development of the much-needed new therapies.

脑部传染病的负担使非洲的社会经济发展丧失能力。其中一些疾病在非洲特别普遍，通常在全球研究和政策中被忽视，这就需要非洲神经科学家优先考虑并制定应对这些挑战的当地解决方案。这类疾病的例子包括脑真菌感染，如隐球菌脑膜炎。隐球菌脑膜炎每年在撒哈拉以南非洲造成20多万人死亡，并在幸存者中造成神经功能障碍和残疾，其中大多数人处于经济生产年龄。隐球菌性脑膜炎（CM）是艾滋病毒相关脑膜炎的主要原因，其特点是使人虚弱，大脑受到炎症性损伤，即使接受治疗，死亡率也很高。在撒哈拉以南非洲，由于无法获得安全有效的药物，死于CM及其并发症的人数进一步增加。尽管已经做了大量的工作来描述导致CM的真菌病原体的生物学特性，但我们对人体对真菌的反应知之甚少，尤其是在大脑水平上，大脑是那些死于这种疾病的人受影响最大的器官。研究CM脑损伤的研究人员面临的挑战之一是缺乏适当的实验模型，这些模型不能很好地代表该疾病的真实临床形式，并具有足够的分辨率，以帮助描述这种致命疾病导致的脑损伤的复杂机制。了解这些机制对我们了解这种疾病如何发展至关重要，对我们开发大多数非洲人都能获得的更便宜、更安全的药物也至关重要。因此，本研究的第一部分侧重于引入一种新的器官特异性、宿主特异性实验模型，该模型可用于研究隐球菌感染期间脑损伤的机制。所提出的模型是基于使用啮齿类动物和人类脑组织切片，这些脑组织切片被小心地保存在培养物中，然后用CM的致病真菌隐球菌（Cryptococcus neoformans）刺激。我将研究大脑免疫细胞中关键炎症机制的激活，包括病原体识别受体、转录因子和对抗真菌时释放的其他化学通讯分子。使用最先进的科学技术，我还将研究每种细胞类型对大脑对真菌的反应的贡献。为了补充使用这种新模型获得的数据，我提出的研究的第二部分旨在使用活体啮齿动物模型来概括人类形式的CM。利用这个模型，我们将能够描述感染后真菌在大脑中的位置，最重要的是，确定真菌细胞是否确实阻断了最近发现的大脑液体清除途径。这项研究将填补CM脑损伤机理的现有知识空白。该模型和方法将作为研究其他由细菌、寄生虫和病毒引起的中枢神经系统感染机制的平台，为急需的新疗法的开发提供信息。