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

真菌是人类健康不良的主要原因;每年有数亿人患有皮肤和粘膜真菌感染，而威胁生命的侵入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。这些威胁生命的侵袭性真菌感染是一个特别值得关注的问题，因为我们有有限的抗真菌药物来治疗它们，诊断非常困难，也没有真菌疫苗。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。脑和中枢神经系统的真菌感染（脑膜炎）是侵袭性真菌疾病中最致命的形式。最常见的真菌性脑感染是隐球菌性脑膜炎，由真菌新型隐球菌引起，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名患者中就有4人死于隐球菌性脑膜炎，因此迫切需要新的治疗战略和诊断方法，从而有可能通过改善人口健康，改善这些低/中收入国家的社会和经济状况。我们研究的目的是更好地了解免疫系统如何对新型隐球菌产生长期特异性保护。为此，我们开发了动物模型，使我们能够跟踪对C反应的免疫细胞。新形式的人，使我们能够观察他们在感染期间的行为，并了解他们需要什么来预防疾病，这是目前尚不可行的研究在人类身上进行。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力如何发展的基本问题，这反过来将有助于我们确定什么样的治疗方法对隐球菌脑膜炎最有效，从而有助于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.