MRC AMED - Study of the T cell Response During Cryptococcal Meningitis Using New Tools

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，而在世界各地，危及生命的侵袭性真菌感染造成的死亡人数超过了疟疾和某些类型的癌症。这些危及生命的侵袭性真菌感染尤其令人担忧，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免疫治疗。然而，与细菌和病毒相比，真菌的研究很少，世界上只有少数研究小组拥有了解免疫系统如何处理真菌的专业知识。真菌感染的大脑和中枢神经系统（脑膜炎）是最致命的形式的侵袭性真菌疾病。最常见的真菌性脑感染是隐球菌性脑膜炎，由新型隐球菌引起，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较弱的人。隐球菌性脑膜炎不易治疗；每5个患者中就有4个死于此病。因此，迫切需要新的治疗战略和诊断方法，这反过来又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绩效。我们研究的目标是更好地了解免疫系统如何发展针对新型隐球菌的长期特异性保护。为此，我们开发了动物模型，使我们能够追踪对新生C.产生特异性反应的免疫细胞，使我们能够观察它们在感染期间的行为，并了解它们需要什么来预防疾病，这些研究在人类身上尚不可行。这项工作将是一个合作项目，将在伯明翰（英国）和东北（日本）进行，以利用我们的综合资源和专业知识。作为一个团队，我们最有能力回答关于长期抗真菌免疫如何发展的基本问题，这反过来将帮助我们确定对隐球菌脑膜炎最有效的治疗方法，从而帮助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 our research is to better understand how the immune system develops long-term specific protection against Cryptococcus neoformans. For this, we have developed animal models that allow us to track immune cells that specifically react to C. neoformans, allowing us to observe their behaviour during infection and understand what they need to protect against disease, research which is not yet feasible to perform in humans. This work will be a collaborative project that will take place in Birmingham (UK) and Tohoku (Japan), in order to take advantage of our combined resources and expertise. As a team, we are best positioned to answer fundamental questions about how long-term antifungal immunity develops, which in turn will help us to determine what treatments will work best for cryptococcal meningitis thus helping to reduce the impact of this devastating disease on human health.