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The link between dimorphism and virulence in Cryptococcus

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:
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-08-01 至 2018-11-30

项目摘要

项目成果

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中文摘要
翻译
新型隐球菌引起的隐球菌病每年夺去数十万人的生命。
英文摘要
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.
期刊论文(13)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1021/jo4013964
发表时间: 2013-09-20
期刊: The Journal of organic chemistry
影响因子: --
作者: [Huang J, Foyle D, Lin X, Yang J]
通讯作者: Yang J
DOI: 10.1371/journal.ppat.1003027
发表时间: 2012
期刊: PLoS pathogens
影响因子: 6.7
作者: [Wang L, Lin X]
通讯作者: Lin X
DOI: 10.1007/s00253-013-5160-y
发表时间: 2013-09
期刊: APPLIED MICROBIOLOGY AND BIOTECHNOLOGY
影响因子: 5
作者: [Chacko, Nadia, Lin, Xiaorong]
通讯作者: Lin, Xiaorong
DOI: 10.1371/journal.pgen.1006982
发表时间: 2017-09
期刊: PLoS genetics
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
7
    Develop and Assess mRNA Lipid Nanoparticle Vaccines Against Cryptococcosis
    • 批准号:
      10616313
    • 项目类别:
    • 资助金额:
      $16.62万
    • 财政年份:
      2023
    • 负责人:
      Xiaorong Lin
    • 依托单位:
    Define the molecular bases for cryptococcal adaptation to host conditions by the RAM pathway
    • 批准号:
      10627371
    • 项目类别:
    • 资助金额:
      $18.88万
    • 财政年份:
      2023
    • 负责人:
      Xiaorong Lin
    • 依托单位:
    Investigating a signaling molecule that cooperates with quorum sensing to induce biofilm formation in C. neoformans
    • 批准号:
      10550504
    • 项目类别:
    • 资助金额:
      $22.65万
    • 财政年份:
      2022
    • 负责人:
      Xiaorong Lin
    • 依托单位:
    Systematic investigation of GPI-anchored mannoproteins in Cryptococcus neoformans
    • 批准号:
      10117186
    • 项目类别:
    • 资助金额:
      $22.65万
    • 财政年份:
      2020
    • 负责人:
      Xiaorong Lin
    • 依托单位:
    海外基金