The link between dimorphism and virulence in Cryptococcus
隐球菌二态性和毒力之间的联系
基本信息
- 批准号:9529008
- 负责人:
- 金额:$ 6.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:
项目摘要
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.
新生隐球菌引起的隐球菌病每年夺走数十万人的生命。
这种真菌病的死亡率高得令人无法接受(10-70%)。目前的抗真菌治疗
隐球菌病极其有限,而且没有疫苗可用。因此,迫切需要了解
可以被新型抗真菌药物或疫苗选择性靶向的隐球菌计划。隐球菌能
假定不同的形态类型:酵母形态被认为是致病的,丝状形态是相关的
毒力减弱。因此,理解形态变化的分子基础和它们的
可以利用对隐球菌毒力的影响来抗击这种致命的疾病。在这个过程的第一阶段
研究项目中,我们建立了作为连接形态和毒力潜势的调节剂的锌氟化合物。
隐球菌。ZNF2的缺失锁定了酵母形式的细胞,并增强了隐球菌的毒力。相反,
ZNF2过表达促进菌丝生长。过表达ZNF2的隐球菌细胞诱导保护性
哺乳动物宿主中的防御反应是无毒的。更重要的是,ZNF2免疫
过表达细胞,无论是活的或热灭活的,都可以为宿主提供100%的保护
随后受到致命性野生型H99感染的挑战。这种保护很少被观察到
对抗这种致命的真菌病原体。因此,激活znf2是一种很有希望的方法。
危害隐球菌的致病性,并提供了一种研究宿主免疫的工具。假设ZnF2是
隐球菌菌丝形态发生的决策者及其富含分泌蛋白的调节子
包括黏附蛋白,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。因此,对于
在这个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
可以在Aim 1中诱导保护性宿主免疫反应。在Aim 2中,我们将确定Znf2调节电路
(激活物、抑制物和/或受体),并评估它们在隐球菌毒力中的作用。我们假设
激活和/或抑制这种有效的抗毒力因子的抑制物可以被利用来
在感染期间损害隐球菌的致病性。我们的初步数据表明,ZnF2可以
在感染过程中被人为地强烈激活,但在野生型细胞中其激活被抑制。我们期待着
研究项目第二阶段取得的成果将使我们更接近我们的长期目标:
了解以隐球菌为基础的形态发生和致病性的基本要求
基因模型,并利用这些知识来制定预防和治疗措施
侵袭性真菌病。
项目成果
期刊论文数量(13)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Morphogenesis in fungal pathogenicity: shape, size, and surface.
- DOI:10.1371/journal.ppat.1003027
- 发表时间:2012
- 期刊:
- 影响因子:6.7
- 作者:Wang L;Lin X
- 通讯作者:Lin X
Total synthesis and biological evaluation of an antifungal tricyclic o-hydroxy-p-quinone methide diterpenoid.
- DOI:10.1021/jo4013964
- 发表时间:2013-09-20
- 期刊:
- 影响因子:0
- 作者:Huang J;Foyle D;Lin X;Yang J
- 通讯作者:Yang J
Non-coding RNAs in the development and pathogenesis of eukaryotic microbes.
- DOI:10.1007/s00253-013-5160-y
- 发表时间:2013-09
- 期刊:
- 影响因子:5
- 作者:Chacko, Nadia;Lin, Xiaorong
- 通讯作者:Lin, Xiaorong
Glucosamine stimulates pheromone-independent dimorphic transition in Cryptococcus neoformans by promoting Crz1 nuclear translocation.
- DOI:10.1371/journal.pgen.1006982
- 发表时间:2017-09
- 期刊:
- 影响因子:4.5
- 作者:Xu X;Lin J;Zhao Y;Kirkman E;So YS;Bahn YS;Lin X
- 通讯作者:Lin X
The link between morphotype transition and virulence in Cryptococcus neoformans.
- DOI:10.1371/journal.ppat.1002765
- 发表时间:2012
- 期刊:
- 影响因子:6.7
- 作者:Wang L;Zhai B;Lin X
- 通讯作者:Lin X
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Xiaorong Lin其他文献
Xiaorong Lin的其他文献
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{{ truncateString('Xiaorong Lin', 18)}}的其他基金
Develop and Assess mRNA Lipid Nanoparticle Vaccines Against Cryptococcosis
开发并评估针对隐球菌病的 mRNA 脂质纳米颗粒疫苗
- 批准号:
10616313 - 财政年份:2023
- 资助金额:
$ 6.97万 - 项目类别:
Define the molecular bases for cryptococcal adaptation to host conditions by the RAM pathway
通过 RAM 途径定义隐球菌适应宿主条件的分子基础
- 批准号:
10627371 - 财政年份:2023
- 资助金额:
$ 6.97万 - 项目类别:
Investigating a signaling molecule that cooperates with quorum sensing to induce biofilm formation in C. neoformans
研究与群体感应配合诱导新型隐球菌生物膜形成的信号分子
- 批准号:
10550504 - 财政年份:2022
- 资助金额:
$ 6.97万 - 项目类别:
Systematic investigation of GPI-anchored mannoproteins in Cryptococcus neoformans
新型隐球菌中 GPI 锚定甘露糖蛋白的系统研究
- 批准号:
10117186 - 财政年份:2020
- 资助金额:
$ 6.97万 - 项目类别:
Defining the genetic network governing cryptococcal morphological transition
定义控制隐球菌形态转变的遗传网络
- 批准号:
10403545 - 财政年份:2018
- 资助金额:
$ 6.97万 - 项目类别:
Defining the genetic network governing cryptococcal morphological transition
定义控制隐球菌形态转变的遗传网络
- 批准号:
10170231 - 财政年份:2018
- 资助金额:
$ 6.97万 - 项目类别:
Defining the genetic network governing cryptococcal morphological transition
定义控制隐球菌形态转变的遗传网络
- 批准号:
9923532 - 财政年份:2018
- 资助金额:
$ 6.97万 - 项目类别:
Defining the genetic network governing cryptococcal morphological transition
定义控制隐球菌形态转变的遗传网络
- 批准号:
9615729 - 财政年份:2018
- 资助金额:
$ 6.97万 - 项目类别:
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