Fungal Ras-mediated invasive growth mechanisms

真菌 Ras 介导的侵袭性生长机制

基本信息

项目摘要

DESCRIPTION (provided by applicant): Aspergillus fumigatus is the major causative agent of invasive aspergillosis, a severe and life-threatening disease of immunocompromised patients. A. fumigatus is a ubiquitous and adept pathogen, able to adapt quickly to the mammalian lung environment and to effectively handle the stresses encountered while growing within the human host. Because of the multi-factorial nature of fungal growth, attempts to identify individual A. fumigatus virulence determinants are often unsuccessful. However, previous studies have consistently proven that filamentous fungal pathogens must be able to coordinate proper hyphal morphogenesis in order to invade tissue and cause high mortality rates. Unfortunately, our knowledge of the molecular mechanisms supporting sustained polarized growth and the establishment and progression of invasive disease is incomplete. To elucidate these mechanisms, better models of the signaling pathways and protein interactions that regulate fungal morphogenesis must be developed. Ras proteins orchestrate multiple fungal morphogenetic processes in pathogenic fungi. Regulation of these processes by Ras plays an essential role in fungal virulence, making fungal Ras signaling an invaluable tool for probing fungal pathogenesis and identifying new targets for novel therapeutics. Although many aspects of Ras signaling pathways are often considered too highly conserved to serve as antimicrobial targets in eukaryotic pathogens, we have identified novel, fungal-specific protein domains that define fundamental differences between fungal and human Ras proteins. These include two areas of significant divergence between fungal Ras proteins and their human counterpart, H-ras: 1) the Invariant Arginine Domain (IRD), a novel domain conserved in the RasA homologs of every available fungal genome but not present in H-ras, and 2) an extended hypervariable region (HVR) in filamentous fungi. Our preliminary data show that the IRD and HVR are required for Ras function during hyphal growth and morphogenesis, revealing fungal-specific aspects of Ras signaling. The overall objectives of this proposal are to fully define the impact of these fungal-specific protein domains to Ras biology, using mutations of these domains to identify novel Ras pathway interactions critical for polarized morphogenesis and virulence. Using mutational and biochemical analyses, Aim 1 or this proposal will define the contribution of the IRD and HVR to A. fumigatus Ras biology. These studies will address how mutation of the IRD and HVR affect RasA GTPase activity, activation, localization and interaction downstream effectors. Complementing our Aim 1 studies, Aim 2 utilizes an unbiased proteomics screen to identify novel, fungal-specific Ras interactions contributing to Ras-mediated growth and virulence. Because Ras signaling is essential for fungal virulence, identification and characterization of fundamental differences between human and Ras pathways carries the long-term potential of uncovering novel antifungal therapies.
描述(由申请方提供):烟曲霉菌是侵袭性曲霉病的主要病原体,侵袭性曲霉病是免疫功能低下患者的严重和危及生命的疾病。A.烟曲霉是一种普遍存在的和熟练的病原体,能够快速适应哺乳动物的肺环境,并有效地处理在人类宿主中生长时遇到的压力。由于真菌生长的多因素性质,试图鉴定单个A。烟曲霉毒力决定因子通常是不成功的。然而,以前的研究一直证明,丝状真菌病原体必须能够协调适当的菌丝形态发生,以侵入组织并导致高死亡率。不幸的是,我们对支持持续极化生长和侵袭性疾病的建立和进展的分子机制的认识是不完整的。为了阐明这些机制,必须开发更好的调节真菌形态发生的信号通路和蛋白质相互作用的模型。Ras蛋白在致病真菌中协调多种真菌形态发生过程。Ras对这些过程的调控在真菌毒力中起着至关重要的作用,使真菌Ras信号转导成为探索真菌发病机制和确定新疗法新靶点的宝贵工具。虽然Ras信号通路的许多方面通常被认为过于保守,不能作为真核病原体中的抗菌靶标,但我们已经确定了新的真菌特异性蛋白结构域,这些结构域定义了真菌和人类Ras蛋白之间的根本差异。这些包括真菌Ras蛋白和它们的人类对应物H-ras之间的两个显著差异的领域:1)不变精氨酸结构域(IRD),一种在每个可用的真菌基因组的Rasa同源物中保守但不存在于H-ras中的新结构域,和2)丝状真菌中的延伸高变区(HVR)。我们的初步数据表明,IRD和HVR是所需的Ras功能在菌丝生长和形态建成,揭示真菌特异性方面的Ras信号。本提案的总体目标是充分界定 这些真菌特异性蛋白质结构域Ras生物学,使用这些结构域的突变,以确定新的Ras途径的相互作用,极化形态和毒力的关键。使用突变和生化分析,目标1或本建议将定义IRD和HVR对A的贡献。烟曲霉生物学这些研究将解决IRD和HVR的突变如何影响Rasa GT3活性、激活、定位和相互作用下游效应物。补充我们的目标1的研究,目标2利用一个公正的蛋白质组学筛选,以确定新的,真菌特异性的Ras相互作用,促进Ras介导的生长和毒力。由于Ras信号传导对真菌毒力至关重要,因此人类和Ras途径之间的根本差异的鉴定和表征具有发现新型抗真菌疗法的长期潜力。

项目成果

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Jarrod R. Fortwendel其他文献

MOB-mediated regulation of septation initiation network (SIN) signaling is required for echinocandin-induced hyperseptation in emAspergillus fumigatus/em
棘白菌素诱导烟曲霉超分隔需要 MOB 介导的分隔起始网络(SIN)信号调节
  • DOI:
    10.1128/msphere.00695-23
  • 发表时间:
    2024-02-20
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Harrison I. Thorn;Xabier Guruceaga;Adela Martin-Vicente;Ashley V. Nywening;Jinhong Xie;Wenbo Ge;Jarrod R. Fortwendel;Rebecca S. Shapiro
  • 通讯作者:
    Rebecca S. Shapiro
emhapE/em and emhmg1/em Mutations Are Drivers of emcyp51A/em-Independent Pan-Triazole Resistance in an Aspergillus fumigatus Clinical Isolate
emhapE/em 和 emhmg1/em 突变是烟曲霉临床分离株中不依赖于 emcyp51A/em 的泛三唑抗性的驱动因素
  • DOI:
    10.1128/spectrum.05188-22
  • 发表时间:
    2023-05-18
  • 期刊:
  • 影响因子:
    3.800
  • 作者:
    Ana C. O. Souza;Wenbo Ge;Nathan P. Wiederhold;Jeffrey M. Rybak;Jarrod R. Fortwendel;P. David Rogers
  • 通讯作者:
    P. David Rogers

Jarrod R. Fortwendel的其他文献

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{{ truncateString('Jarrod R. Fortwendel', 18)}}的其他基金

Genetic Determinants of Aspergillus host-pathogen interactions
曲霉菌宿主-病原体相互作用的遗传决定因素
  • 批准号:
    10724816
  • 财政年份:
    2023
  • 资助金额:
    $ 29.52万
  • 项目类别:
Unlocking the cidal activity of echinocandins against Aspergillus fumigatus
解锁棘白菌素对烟曲霉的杀灭活性
  • 批准号:
    10378147
  • 财政年份:
    2021
  • 资助金额:
    $ 29.52万
  • 项目类别:
Unlocking the cidal activity of echinocandins against Aspergillus fumigatus
解锁棘白菌素对烟曲霉的杀灭活性
  • 批准号:
    10179720
  • 财政年份:
    2021
  • 资助金额:
    $ 29.52万
  • 项目类别:
Unlocking the cidal activity of echinocandins against Aspergillus fumigatus
解锁棘白菌素对烟曲霉的杀灭活性
  • 批准号:
    10590730
  • 财政年份:
    2021
  • 资助金额:
    $ 29.52万
  • 项目类别:
Non-cyp51A-mutation Mediated Triazole Resistance in Aspergillus fumigatus
非 cyp51A 突变介导的烟曲霉三唑耐药性
  • 批准号:
    10582526
  • 财政年份:
    2020
  • 资助金额:
    $ 29.52万
  • 项目类别:
Non-cyp51A-mutation Mediated Triazole Resistance in Aspergillus fumigatus
非 cyp51A 突变介导的烟曲霉三唑耐药性
  • 批准号:
    9913275
  • 财政年份:
    2020
  • 资助金额:
    $ 29.52万
  • 项目类别:
Non-cyp51A-mutation Mediated Triazole Resistance in Aspergillus fumigatus
非 cyp51A 突变介导的烟曲霉三唑耐药性
  • 批准号:
    10358515
  • 财政年份:
    2020
  • 资助金额:
    $ 29.52万
  • 项目类别:
Fungal Ras-mediated invasive growth mechanisms
真菌 Ras 介导的侵袭性生长机制
  • 批准号:
    9282239
  • 财政年份:
    2014
  • 资助金额:
    $ 29.52万
  • 项目类别:
Fungal Ras-mediated invasive growth mechanisms
真菌 Ras 介导的侵袭性生长机制
  • 批准号:
    8806512
  • 财政年份:
    2014
  • 资助金额:
    $ 29.52万
  • 项目类别:
Fungal Ras-mediated invasive growth mechanisms
真菌 Ras 介导的侵袭性生长机制
  • 批准号:
    8696215
  • 财政年份:
    2014
  • 资助金额:
    $ 29.52万
  • 项目类别:

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