DEALING WITH THERAPY-RESISTANT CRYPTOCOCCOSIS BY TARGETING INTRACELLULAR PATHOGENS

通过针对细胞内病原体来应对治疗耐药的隐球菌病

• 批准号: MR/J008176/1
• 负责人: Robin May
• 金额: $ 48.82万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ008176%2F1
• 关键词: DEALING; THERAPY; RESISTANT; CRYPTOCOCCOSIS; TARGETING

Cryptococcosis is a life-threatening fungal disease that kills more than 600 000 patients per annum worldwide. The majority of these individuals are newly diagnosed HIV-positive patients in the developing world, for whom the prognosis is relatively good, PROVIDED that they survive the cryptococcal infection. In addition, there is a globally increasing incidence of cryptococcal infection in otherwise healthy people, which appears to be due to the occurrence of localized, hypervirulent populations of the fungus. Thus understanding more about the biology of this pathogen, and developing ways to improve treatment of it, is critical.One major problem is that the 'best practice' antifungal treatment available still fails in more than 10% of patients. One reason for this is that, during an infection, some cryptococcal cells 'hide' within white blood cells of the patient. These intracellular fungi are not exposed to high enough levels of antifungal drugs and can thus act as 'reservoirs' of disease. To try and address this problem, our proposal aims to identify drugs that can be used to stimulate the expulsion of intracellular cryptococci from white blood cells, thus exposing them to lethal levels of antifungal drugs in the circulation. Our group has recently discovered just such an expulsion process, which we call vomocytosis, and shown that it can be stimulated by applying different agents, such as the anti-malarial drug chloroquine. In order to move this finding into the clinic, we need to follow two lines of investigation. Firstly, we need to understand the molecular events that happen within infected white blood cells and lead to fungal expulsion. Such information is essential if we are to devise methods of manipulating that process without causing unwanted 'collateral damage' (for instance, dramatically impairing the body's ability to tackle other pathogens that may be infecting at the same time as Cryptococcus). Secondly, we plan to undertake a high-throughput screen to identify new, more effective, compounds that stimulate cryptococcal expulsion. Importantly, we will take a 'new tricks for old drugs' approach, focusing our search on the list of (>1000) compounds that have already been approved by the Food and Drug Administration. These drugs therefore meet minimum safety standards and have already been used to treat other disease conditions. Therefore compounds that we identify can be moved into clinical practice more rapidly and more cheaply than totally new molecules.At the end of the project, we will thus have provided both important new information about a fatal human disease and revealed a set of compounds that might, in the near future, be utilized to help treat that disease.

隐球菌病是一种威胁生命的真菌性疾病，每年在全球范围内造成60多万患者死亡。这些人中的大多数是发展中国家新诊断的HIV阳性患者，对他们来说，预后相对较好，前提是他们能在隐球菌感染后存活下来。此外，在全球范围内，隐球菌感染在其他健康人群中的发病率也在增加，这似乎是由于局部高毒力真菌种群的发生。因此，了解更多关于这种病原体的生物学，并开发改善治疗方法是至关重要的。一个主要问题是，现有的“最佳实践”抗真菌治疗仍然在超过10%的患者中失败。其中一个原因是，在感染期间，一些隐球菌细胞“隐藏”在患者的白色血细胞中。这些细胞内真菌没有暴露于足够高水平的抗真菌药物，因此可以作为疾病的“水库”。为了尝试解决这个问题，我们的建议旨在确定可用于刺激细胞内隐球菌从白色血细胞中排出的药物，从而使它们在循环中暴露于致命水平的抗真菌药物。我们的研究小组最近发现了这样一个排出过程，我们称之为呕吐细胞增多症，并表明它可以通过应用不同的药物来刺激，例如抗疟疾药物氯喹。为了将这一发现应用于临床，我们需要遵循两条调查路线。首先，我们需要了解受感染的白色血细胞内发生的分子事件，并导致真菌排出。如果我们要设计出操纵这一过程而不造成不必要的“附带损害”的方法，这些信息是必不可少的（例如，大大削弱身体对付可能与隐球菌同时感染的其他病原体的能力）。其次，我们计划进行高通量筛选，以确定新的，更有效的，刺激隐球菌驱逐的化合物。重要的是，我们将采取“老药新把戏”的方法，将我们的搜索集中在已经被食品和药物管理局批准的（>1000）化合物的列表上。因此，这些药物符合最低安全标准，并已用于治疗其他疾病。因此，我们发现的化合物可以比全新的分子更快、更便宜地进入临床实践。在项目结束时，我们将提供有关一种致命的人类疾病的重要新信息，并揭示一系列化合物，这些化合物可能在不久的将来用于帮助治疗这种疾病。

项目成果

The Cryptococcus neoformans Titan cell is an inducible and regulated morphotype underlying pathogenesis.

• DOI: 10.1371/journal.ppat.1006978
• 发表时间: 2018-05
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Dambuza IM;Drake T;Chapuis A;Zhou X;Correia J;Taylor-Smith L;LeGrave N;Rasmussen T;Fisher MC;Bicanic T;Harrison TS;Jaspars M;May RC;Brown GD;Yuecel R;MacCallum DM;Ballou ER
• 通讯作者: Ballou ER

Cryptococcal phospholipase B1 is required for intracellular proliferation and control of titan cell morphology during macrophage infection.

• DOI: 10.1128/iai.03104-14
• 发表时间: 2015-04
• 期刊: Infection and immunity
• 影响因子: 3.1
• 作者: Evans RJ;Li Z;Hughes WS;Djordjevic JT;Nielsen K;May RC
• 通讯作者: May RC

Using Flow Cytometry to Analyze Cryptococcus Infection of Macrophages.

使用流式细胞术分析巨噬细胞的隐球菌感染。

• DOI: 10.1007/978-1-4939-6581-6_24
• 发表时间: 2017
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Evans RJ

Cryptococcus neoformans Intracellular Proliferation and Capsule Size Determines Early Macrophage Control of Infection.

• DOI: 10.1038/srep21489
• 发表时间: 2016-02-18
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Bojarczuk A;Miller KA;Hotham R;Lewis A;Ogryzko NV;Kamuyango AA;Frost H;Gibson RH;Stillman E;May RC;Renshaw SA;Johnston SA
• 通讯作者: Johnston SA

Vomocytosis of live pathogens from macrophages is regulated by the atypical MAP kinase ERK5.

• DOI: 10.1126/sciadv.1700898
• 发表时间: 2017-08
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Gilbert AS;Seoane PI;Sephton-Clark P;Bojarczuk A;Hotham R;Giurisato E;Sarhan AR;Hillen A;Velde GV;Gray NS;Alessi DR;Cunningham DL;Tournier C;Johnston SA;May RC
• 通讯作者: May RC