Transposable element mobility and chromosomal rearrangement in the fungal pathogen Cryptococcus during human infection

环境中存在的致病真菌已成为对人类健康日益普遍的威胁。新型隐球菌和密切相关的物种加蒂隐球菌是危及生命的真菌性脑膜炎的主要原因，澳大利亚是少数两个物种普遍存在的国家之一。尽管新生梭状芽胞杆菌在免疫功能低下的患者（如艾滋病患者）中是一种越来越常见的感染原因，但大约四分之一的感染者没有明显的免疫系统缺陷。对于艾滋病患者来说，在没有抗逆转录病毒治疗的情况下，隐球菌感染是无法治愈的，需要终生服用抗真菌药物来控制感染。在感染过程中，隐球菌不仅受到免疫系统和抗真菌药物的作用，还受到宿主体内高温、营养受限环境的影响。拟议的研究将揭示隐球菌如何在这种环境中进化，使感染持续存在，尽管医疗干预。我认为隐球菌基因组中存在的自然发生的可移动遗传元件在长期感染期间引起染色体重排，从而产生基因缺失和复制，从而促进生存。通过表征这些变化和与之相关的基因，该研究将确定参与发病机制的新基因，并将增加我们对感染过程的理解。该项目的预期结果是详细了解隐球菌感染过程中移动元件运动和染色体重排的作用，以及它们如何影响致病过程的基因。从这项研究中获得的基础知识将有助于在临床环境中对抗感染的研究，提供新的药物靶点，并有助于促进更有效治疗方法的发展。

Pathogenic fungi present in the environment have emerged as an increasingly common threat to human health. Cryptococcus neoformans and the closely related species Cryptococcus gattii are the leading causes of life-threatening fungal meningitis, and Australia is one of the few countries where both species are prevalent. Although C. neoformans is an increasingly common cause of infection in immunocompromised patients such as those suffering from AIDS, approximately one in four infected individuals has no apparent immune system defect. For patients with AIDS, in the absence of antiretroviral therapy cryptococcal infection is incurable and requires lifelong treatment with antifungal medication to keep the infection in check. During infection, Cryptococcus is under tremendous stress enforced not only by the immune system and the presence of antifungals, but also by the high temperature, nutrient limiting environment encountered in the host. The proposed research will reveal how Cryptococcus evolves in this environment to enable persistence of infection despite medical intervention. I propose that naturally occurring mobile genetic elements present in the Cryptococcus genome cause chromosomal rearrangements during long term infection to produce gene deletions and duplications that facilitate survival. By characterising these changes and the genes associated with them, the research will identify novel genes involved in pathogenesis and will increase our understanding of the infection process. The expected outcome of this project is a detailed understanding of the roles mobile element movement and chromosomal rearrangement play in Cryptococcus during infection, and how these affect genes that contribute to the pathogenic process. The fundamental knowledge gained from this study will facilitate studies designed to combat infections in the clinical setting, provide new drug targets and help foster the development of more effective therapies.