DEALING WITH THERAPY-RESISTANT CRYPTOCOCCOSIS BY TARGETING INTRACELLULAR PATHOGENS

点击翻译按钮获取中文摘要

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.