Fungi on the Brain: Interrogating Host-Pathogen Interactions during Fungal Meningitis

真菌是人类健康不佳的主要原因；每年有数亿人遭受皮肤和粘膜真菌感染，而威胁生命的侵袭性真菌感染在世界各地造成的死亡人数超过疟疾和某些类型的癌症。这些危及生命的侵袭性真菌感染是一个特别令人担忧的问题，因为我们治疗它们的抗真菌药物有限，诊断非常困难，而且没有真菌疫苗。了解如何控制针对真菌的保护性免疫反应可以帮助我们设计针对这些感染的疫苗和基于免疫的治疗方法。然而，与细菌和病毒相比，真菌的研究很少，世界上只有几个研究小组拥有了解免疫系统如何处理真菌的专业知识。大脑和中枢神经系统的真菌感染(脑膜炎)是最致命的侵袭性真菌疾病。最常见的真菌脑感染是由新型隐球菌引起的隐球菌性脑膜炎，主要影响撒哈拉以南非洲低收入和中等收入国家免疫系统减弱的人。隐球菌性脑膜炎不容易治疗；每5名这种疾病患者中就有4人死于这种疾病。因此，迫切需要新的治疗战略和诊断方法，这反过来又有可能通过改善人口健康来改善这些低收入/中等收入国家的社会和经济表现。我的研究目标是更好地了解对隐球菌的免疫力，特别是在大脑中。每个器官都有自己的特殊免疫细胞，参与监视和警告免疫系统中其他细胞的入侵者的存在。小胶质细胞是大脑内部免疫系统的特殊细胞。我们已经知道它们很久了，但它们仍然是神秘的，因为直到最近，我们还没有必要的工具来理解它们。这些新工具包括动物模型，使我们能够从大脑中删除小胶质细胞，这样我们就可以确定小胶质细胞的缺失如何影响疾病的进展和解决。利用我在真菌免疫学和小胶质细胞生物学方面的背景，我用真菌感染的动物模型来适应这些小胶质细胞枯竭的小鼠，使我能够理解小胶质细胞在面对真菌入侵者时所做的事情。回答这个基本问题将帮助我们确定什么治疗方法对真菌中枢神经系统感染最有效，这样我们就可以减少这种毁灭性疾病对人类健康的影响。

Fungi are a major cause of ill-health in humans; hundreds of millions of people suffer from skin and mucosal fungal infections every year, while life-threatening invasive fungal infections cause more deaths around the world than malaria and some types of cancer. These life-threatening invasive fungal infections are a particular cause for concern, because we have limited antifungal drugs to treat them, diagnosis is very difficult and there are no fungal vaccines. Knowledge of how protective immune responses against fungi are controlled can help us to design vaccines and immune-based treatments for these infections. Yet, compared to bacteria and viruses, fungi are poorly studied and only a few research groups in the world have the expertise to understand how the immune system deals with fungi. Fungal infection of the brain and central nervous system (meningitis) is the most lethal form of invasive fungal disease. The most common fungal brain infection is cryptococcal meningitis, caused by the fungus Cryptococcus neoformans, which mostly affects people with weakened immune systems in low and middle-income countries in sub-Saharan Africa. Cryptococcal meningitis is not easily treated; 4 out of every 5 patients with this disease die from it. New treatment strategies and diagnostics are therefore urgently needed, which in turn could potentially improve the social and economic performance of these low/middle-income countries by improving the population's health. The goal of my research is to better understand immunity to Cryptococcus specifically in the brain. Each organ has its own specialised immune cells that are involved in surveillance and alarming other cells of the immune system to the presence of an invader. Microglia are the specialised cells of the brain's internal immune system. We've known about them for a long time but they are still mysterious since, until recently, we didn't have the tools needed to understand them. These new tools include animal models that enable us to delete microglia from the brain so we can determine how the absence of microglia affects disease progression and resolution. Using my background in fungal immunology and microglia biology, I have adapted these microglia-depleting mice with animal models of fungal infection to allow me to understand what microglia do when confronted with a fungal invader. Answering this fundamental question will then help us to determine what treatments will work best for fungal CNS infection so we can reduce the impact of this devastating disease on human health.