Characterization of novel virulence factors in Candida

念珠菌新型毒力因子的表征

基本信息

项目摘要

Abstract Candida albicans is uniquely associated as a commensal component of the microbiota of most humans, without harm to most of us, yet it causes a range of infections from mild to life- threatening, based on the immune status of the host. The interaction between C. albicans and mammalian phagocytes is critical, and the Candida-macrophage co-culture has become a valuable model to uncover specific adaptations that promote virulence and commensalism. To further probe the novel biology of this interaction, we used transcriptional profiling to identify fungal genes induced upon phagocytosis. While some of these have recognizable functions, mostly in metabolism (a known response to phagocytosis), more than half the induced genes are uncharacterized and not widely conserved. A surprising number of these genes are quite small and missed in early annotations. Given the uniqueness of the C. albicans-human association, this set of genes is likely enriched for adaptations of C. albicans to host niches. In proof of this principle, we have mutated three of these genes and all three have host-relevant phenotypes, with one as a novel cell wall-associated microadhesin required for adhesion to biotic and abiotic surfaces and for virulence in mouse models. We propose that it clusters conventional adhesins into heterogeneous complexes on the cell surface that strengthens binding to substrates. Two others have antioxidant properties, again despite being quite small proteins (68 and 99 amino acids). These are therefore unique mediators of functions appreciated to be critical for Candida virulence (adhesion and oxidative stress resistance). We propose studies to discern the mechanistic details underlying both phenotypes. Based on the successes of our preliminary genetic analysis, we propose a larger-scale effort to generate a mutant library of all of the uncharacterized macrophage-induced genes and test them in multiple in vitro, ex vivo, and in vivo assays. The strength of this proposal is in our expertise in analyzing this critical host-pathogen interaction, our thorough genetic methods and screening protocols, and the use of multiple animal models. The innovative potential is significant given the focus on novel genes and novel biology at the host-pathogen interface. The outcome of this proposal is a deeper and broader understanding of the genetic functions that are required for commensalism and pathogenicity in fungi.
摘要

项目成果

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Michael C Lorenz其他文献

Vertebrate and invertebrate animal infection models of emCandida auris/em pathogenicity
Candida auris(耳念珠菌)致病性的脊椎动物和无脊椎动物感染模型
  • DOI:
    10.1016/j.mib.2024.102506
  • 发表时间:
    2024-08-01
  • 期刊:
  • 影响因子:
    7.500
  • 作者:
    Melissa Martinez;Danielle A Garsin;Michael C Lorenz
  • 通讯作者:
    Michael C Lorenz

Michael C Lorenz的其他文献

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{{ truncateString('Michael C Lorenz', 18)}}的其他基金

Characterization of novel virulence factors in Candida
念珠菌新型毒力因子的表征
  • 批准号:
    10319584
  • 财政年份:
    2019
  • 资助金额:
    $ 32.1万
  • 项目类别:
Characterization of novel virulence factors in Candida
念珠菌新型毒力因子的表征
  • 批准号:
    9765613
  • 财政年份:
    2019
  • 资助金额:
    $ 32.1万
  • 项目类别:
FASEB SRC on Molecular Pathogenesis: Mechanisms of Infectious Disease
FASEB SRC 关于分子发病机制:传染病机制
  • 批准号:
    9331802
  • 财政年份:
    2017
  • 资助金额:
    $ 32.1万
  • 项目类别:
The role of ATO function in fungal pathogenesis
ATO功能在真菌发病机制中的作用
  • 批准号:
    9127551
  • 财政年份:
    2016
  • 资助金额:
    $ 32.1万
  • 项目类别:
Virulence factor identification by comparative transcriptomics in Candida species
通过比较转录组学鉴定念珠菌属毒力因子
  • 批准号:
    8646883
  • 财政年份:
    2013
  • 资助金额:
    $ 32.1万
  • 项目类别:
Virulence factor identification by comparative transcriptomics in Candida species
通过比较转录组学鉴定念珠菌属毒力因子
  • 批准号:
    8493140
  • 财政年份:
    2013
  • 资助金额:
    $ 32.1万
  • 项目类别:
Roles of acetate metabolism in the virulence of Candida albicans
醋酸盐代谢在白色念珠菌毒力中的作用
  • 批准号:
    8137392
  • 财政年份:
    2010
  • 资助金额:
    $ 32.1万
  • 项目类别:
Understanding Immunomodulation by Candida albicans
了解白色念珠菌的免疫调节作用
  • 批准号:
    7382437
  • 财政年份:
    2008
  • 资助金额:
    $ 32.1万
  • 项目类别:
Understanding Immunomodulation by Candida albicans
了解白色念珠菌的免疫调节作用
  • 批准号:
    7634500
  • 财政年份:
    2008
  • 资助金额:
    $ 32.1万
  • 项目类别:
Extracellular pH modulation by Candida albicans in vitro and in vivo
白色念珠菌对细胞外 pH 值的体外和体内调节
  • 批准号:
    8847274
  • 财政年份:
    2007
  • 资助金额:
    $ 32.1万
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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