Interplay between the heat shock response and histidine kinase pathways in the thermally dimorphic fungal pathogen Histoplasma capsulatum

热二态性真菌病原体荚膜组织胞浆菌中热休克反应与组氨酸激酶途径之间的相互作用

• 批准号: 9763433
• 负责人: Sinem Beyhan
• 金额: $ 48.75万
• 依托单位: J. CRAIG VENTER INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-14 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763433
• 关键词: Affect; Aspergillus fumigatus; Binding; Biology; Blastomyces; Body Temperature; Body Temperature Changes; Candida albicans; Cells; Cellular Morphology; Chemicals; Client; Coccidioides; DNA Binding; DNA Binding Domain; DNA-Binding Proteins; Data; Development; Disease; Filament; Geldanamycin; Gene Expression; Genes; Genetic Epistasis; Genetic Transcription; Goals; Growth; HSF1; HSP 90 inhibition; Health; Heat shock factor; Heat shock proteins; Heat-Shock Response; Histoplasma; Histoplasma capsulatum; Human; Human body; Immunocompetent; Immunocompromised Host; Immunoprecipitation; Infection; Infectious Agent; Inhalation; Laboratories; Life; Link; MAP Kinase Gene; Maps; Mass Spectrum Analysis; Modeling; Molds; Molecular; Monitor; Morbidity - disease rate; Morphology; Mycoses; Organism; Osmolar Concentration; Paracoccidioides; Pathogenicity; Pathway interactions; Phase; Phenotype; Play; Prevalence; Protein Family; Proteins; Publishing; Regulation; Reproduction spores; Research; Respiratory Tract Infections; Role; Saccharomyces cerevisiae; Saccharomycetales; Sensory; Signal Transduction; Soil; Source; Temperature; Temperature Sense; Therapeutic; Transcript; Virulence; Virulence Factors; Work; Yeasts; base; experimental study; fungus; inhibitor/antagonist; knock-down; macrophage; mortality; mutant; pathogen; pathogenic fungus; predicting response; prevent; programs; protein protein interaction; protein-histidine kinase; response; sensor histidine kinase; trait; transcription factor; transcriptome sequencing; transcriptomics

Project Summary Histoplasma capsulatum is one of several systemic dimorphic fungal pathogens that switch their growth program from an infectious mold form in the soil to a pathogenic yeast form in mammalian hosts. H. capsulatum causes up to 25,000 life-threatening infections per year in the U.S. alone with up to 50% mortality rate, and is the most common cause of fungal respiratory infections in healthy hosts. Infection occurs when the soil is disrupted, facilitating dispersion of hyphal fragments or spores that are inhaled by humans. Spores and hyphal fragments are the primary infectious agents; however, once introduced into the host, the pathogen converts to a budding-yeast form, which survives and replicates within host macrophages. In the laboratory, the switch between the infectious and parasitic states is modeled by changing the growth temperature: cells grow in the filamentous form (hyphal) at room temperature, whereas growth at 37ºC is sufficient to trigger growth in the yeast form and expression of virulence factors. Despite its importance to human health, very little is known about how H. capsulatum senses and responds to human body temperature. Our prior research findings significantly contributed to the understanding of the molecular mechanism used by H. capsulatum to regulate cell morphology and virulence gene expression: we found that four transcriptional regulators, Ryp1,2,3,4, are the core components of a temperature-responsive intersecting regulatory network. In unpublished studies, we comprehensively identified Ryp-interacting proteins with potential regulatory roles. Among the diverse set of Ryp2-interacting proteins, we characterized a heat shock protein, Hsp90, and two proteins, Ssk1 and Skn7, with predicted response regulator domains. We found that Hsp90, Ssk1 and Skn7 regulate yeast phase growth in H. capsulatum. Hsp90 plays a key role in the heat shock response; and response regulators work with sensor histidine kinases and are often involved in sensing environmental signals. In this project, we propose to build upon our previous findings and fully characterize the involvement of the heat shock response and histidine kinase pathways in regulating Ryp proteins, cell morphology and virulence traits in H. capsulatum in response to host temperature. These studies will provide fundamental information on how cells sense temperature and turn on the appropriate virulence pathways in the host. Ultimately, the information obtained from this project can be used to develop therapeutics for H. capsulatum infections and help prevent other dimorphic fungal infections.

项目概要 荚膜组织胞浆菌是几种改变其生长的系统性二态性真菌病原体之一 程序从土壤中的传染性霉菌形式转变为哺乳动物宿主中的致病性酵母形式。 仅在美国每年就会造成多达 25,000 例危及生命的感染，死亡率高达 50%， 健康宿主发生真菌呼吸道感染的最常见原因是土壤受到感染。 破坏，促进人类吸入的菌丝碎片或孢子的分散。 碎片是主要的传染源；然而，一旦引入宿主，病原体就会转化为病毒。 芽殖酵母形式，在实验室的宿主巨噬细胞内存活和复制。 通过改变生长温度来模拟感染和寄生状态：细胞在丝状体中生长 在室温下形成（菌丝），而在 37°C 下生长足以引发酵母形式的生长，并且 毒力因子的表达。 尽管它对人类健康很重要，但我们对荚膜梭菌如何感知和响应知之甚少 我们之前的研究结果有助于理解人体温度。 荚膜梭菌调节细胞形态和毒力基因表达的分子机制：我们发现 四个转录调节因子 Ryp1、2、3、4 是温度响应型交叉蛋白的核心成分 在未发表的研究中，我们全面鉴定了具有潜力的 Ryp 相互作用蛋白。 在多种 Ryp2 相互作用蛋白中，我们鉴定了一种热休克蛋白， Hsp90，以及两种蛋白质，Ssk1 和 Skn7，具有预测的反应调节域。 Ssk1 和 Skn7 调节 H. capsulatum 中的酵母阶段生长，在热休克中发挥关键作用。 响应；和响应调节器与传感器组氨酸激酶一起工作，并且通常参与传感 在这个项目中，我们建议以我们之前的发现为基础，并充分描述环境信号的特征。 热休克反应和组氨酸激酶途径参与调节 Ryp 蛋白、细胞 这些研究将提供荚膜梭菌对宿主温度的响应的形态和毒力特征。 有关细胞如何感知温度并在宿主中开启适当毒力途径的基本信息。 最终，从该项目获得的信息可用于开发荚膜梭菌的治疗方法 感染并有助于预防其他二形性真菌感染。