The link between dimorphism and virulence in Cryptococcus

隐球菌二态性和毒力之间的联系

• 批准号: 9529008
• 负责人: Xiaorong Lin
• 金额: $ 6.97万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9529008
• 关键词: link; between; dimorphism; virulence; Cryptococcus; link; between; dimorphism; virulence; Cryptococcus

Cryptococcus neoformans causes cryptococcosis that claims hundreds of thousands of lives annually. The mortality rates of this fungal disease are unacceptably high (10-70%). Current antifungal treatments for cryptococcosis are extremely limited and no vaccine is available. Thus, there is a critical need to understand cryptococcal programs that could be selectively targeted by novel antifungals or vaccines. Cryptococcus can assume different morphotypes: the yeast form is considered pathogenic and the filamentous form is associated with attenuated virulence. Therefore, understanding the molecular bases for morphological changes and their impact on cryptococcal virulence could be exploited to combat this fatal disease. During the first phase of this research project, we established Znf2 as the regulator bridging morphotype and virulence potential in Cryptococcus. Deletion of ZNF2 locks cells in the yeast form and enhances cryptococcal virulence. Conversely, ZNF2 overexpression promotes hyphal growth. Cryptococcal cells overexpressing ZNF2 elicit protective defense responses in the mammalian host and are avirulent. More importantly, immunization with ZNF2 overexpression cells, either in live or heat-killed form, can offer 100% protection to the host against a subsequent challenge by an otherwise lethal wild-type H99 infection. Such protection is rarely observed against this deadly fungal pathogen. Therefore, activation of Znf2 represents a promising means to compromise cryptococcal pathogenicity and provides a vehicle to study host immunity. Given that Znf2 is the decision-maker for cryptococcal hyphal morphogenesis and its regulon is enriched with secretory proteins including adhesion proteins, we hypothesize that activation of ZNF2 alters cell surface composition and that certain cellular components present in ZNF2 overexpression cells are effective immunogens. Therefore, for the second phase of this research project, we will identify immunogens present in ZNF2 overexpression cells that can elicit protective host immune responses in aim 1. In aim 2, we will determine Znf2 regulatory circuits (activators, repressors, and/or receptors) and assess their roles in cryptococcal virulence. We hypothesize that turning on the activator and/or inhibiting the repressor of this potent anti-virulence factor could be exploited to compromise cryptococcal pathogenicity during infection. Our preliminary data suggest that Znf2 can be strongly activated artificially during infection, but its activation is subdued in wild-type cells. We expect that results obtained from the second phase of the research project will move us closer to our long term goals: to understand the fundamental requirements for morphogenesis and pathogenicity using Cryptococcus as a genetic model, and to harness such knowledge to develop preventative and therapeutic measures against invasive mycoses.

Neoformans的隐孢子会导致隐孢子虫病，每年夺走了数十万人的生命。 这种真菌疾病的死亡率较高（10-70％）。当前的抗真菌治疗 隐球菌病非常有限，没有疫苗可用。因此，迫切需要了解 可以通过新型抗真菌或疫苗选择性靶向的隐球菌程序。加密赛车可以 假设不同的形态：酵母形式被认为是致病性的，丝状形式是相关的 毒力减弱。因此，了解形态变化及其的分子碱基 可以利用对隐球菌毒力的影响来应对这种致命疾病。在第一阶段 研究项目，我们确立了Znf2作为调节器桥接形态和毒力潜力的调节器 隐球菌。 ZnF2的缺失将酵母形式的细胞锁定并增强了加密局的毒力。反过来， ZNF2过表达促进菌丝生长。过表达ZnF2的加密局会引起保护 哺乳动物宿主的国防反应，是无毒的。更重要的是，用ZNF2免疫 过表达的单元，无论是活物或热杀死的形式，都可以为宿主提供100％的保护 随后通过致命的野生型H99感染挑战。很少观察到这样的保护 针对这种致命的真菌病原体。因此，Znf2的激活代表了一种有希望的手段 妥协的隐球菌致病性，并提供了研究宿主免疫力的载体。鉴于Znf2是 隐球菌菌丝形态发生及其调节的决策者富含分泌蛋白 包括粘附蛋白，我们假设Znf2的激活改变了细胞表面的组成，并且 ZNF2过表达细胞中存在的某些细胞成分是有效的免疫原子。因此，对于 该研究项目的第二阶段，我们将确定Znf2过表达细胞中存在的免疫原子 可以在AIM 1中引起保护性宿主免疫反应。在AIM 2中，我们将确定ZNF2调节电路 （激活剂，阻遏物和/或受体）并评估其在加密秒毒力中的作用。我们假设这一点 可以将激活因子打开激活剂和/或抑制该有效抗病毒因子的阻遏物 感染期间的加密局致病性损害。我们的初步数据表明Znf2可以是 在感染过程中，人为地激活了强烈的激活，但其激活在野生型细胞中被柔和。我们期望这一点 从研究项目的第二阶段获得的结果将使我们更接近我们的长期目标： 了解使用隐孢子作为形态发生和致病性的基本要求 遗传模型，并利用这种知识制定预防和治疗措施 侵入性真菌。