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: 8386577
• 负责人: Xiaorong Lin
• 金额: $ 34.06万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8386577
• 关键词: Affect; Animal Model; Candida albicans; Candidate Disease Gene; Cell Adhesion; Cell Shape; Cells; Cellular Morphology; Coupled; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans infection; Cues; Data; Development; Disease; Environment; Exhibits; Extracellular Protein; Flocculation; Functional RNA; Gene Expression; Genes; Genetic; Genome; Goals; Growth; Human; Hyphae; In Vitro; Infection; Insertional Mutagenesis; Investigation; Knowledge; Lead; Link; Mating Types; Measures; Mediating; Microbe; Modeling; Molecular; Molecular Genetics; Morphogenesis; Mus; Mutation; Mycoses; Partner in relationship; Pathogenicity; Pathway interactions; Phenotype; Pheromone; Play; Property; Research; Resistance; Role; Selection Criteria; Serotyping; Signal Pathway; Signal Transduction; Testing; Therapeutic; Therapeutic Intervention; Virulence; Virulent; Vision; Work; Yeasts; Zinc Fingers; base; dimorphism; disorder control; fungus; genetic element; genetic manipulation; insight; microbial; mortality; mutant; novel; overexpression; pathogen; promoter; research study; response; therapeutic target; trait; transcription factor

DESCRIPTION (provided by applicant): This proposal is to identify and characterize factors in the fungus Cryptococcus neoformans that can be used as targets to compromise its pathogenicity. Cryptococcus is a dimorphic fungus: it generally causes diseases when it is in the yeast form and it is less virulent when it is in the filamentous form (pseudohyphae or hyphae). As the ability to regulate growth form in response to host cues is an essential requirement for many eukaryotic microbes to cause diseases, activating appropriate regulatory circuits for development is likely to be critical for the survival and propagation of Cryptococcus under host conditions. Unfortunately, the molecular bases underlying the link between dimorphism and virulence in Cryptococcus remain an enigma. Filamentation in Cryptococcus has historically been considered to be coupled with mating, which is suppressed under host conditions. Preliminary studies performed in the applicant's lab indicate that genetic manipulation can confer Cryptococcus filamentous growth under conditions that are host physiologically relevant. Znf2, a zinc finger transcription factor, is a master regulator of filamentation and it also dictates cell adhesion (flocculation). Importantly, Znf2 negatively impact Cryptococcus pathogenicity. Thus, Znf2 provides a link to understand the molecular bases of dimorphism and virulence in Cryptococcus. The central hypothesis of this proposal is that Znf2 mediates the ability of Cryptococcus to cause disease by controlling cell morphotype and other features normally associated with morphogenesis. Guided by strong preliminary data, the hypothesis will be tested by pursuing the following specific aims: 1). Establish the relationship between ZNF2 expression, the ability to undergo filamentation, cell adhesion, and Cryptococcus virulence. 2). Characterize additional determinants of filamentation and Znf2 targets, and determine their roles in virulence. The focus on factors that regulate the inherent ability to undergo filamentation in order to understand dimorphism and virulence in Cryptococcus represents a substantial departure from current approaches that are centered on the signaling pathways that lead to mating. Research based on this new vision is expected to generate mechanistic insights into novel virulence determinants in Cryptococcus. Given the divergence of Cryptococcus from other environmentally-acquired dimorphic pathogens (different phyla) that also show a similar inverse association between filamentation and virulence, it is highly likely that this research will identify conserved determinants necessary for fungal dimorphism. As Cryptococcus is both a clinically important pathogen and is amenable to genetic and molecular studies, this research will contribute to a broader understanding of cell-shape determination and the impact of morphotype on the survival of microbial pathogens. The long-term goals are to understand the fundamental requirements for morphogenesis and pathogenicity that are common to fungal pathogens, and to harness such knowledge to develop preventative and therapeutic measures against invasive mycoses.

描述（由申请人提供）：该提案旨在鉴定和表征真菌新型隐球菌中的因子，这些因子可用作损害其致病性的目标。隐球菌是一种二形性真菌：当它处于酵母形式时通常会引起疾病，而当它处于丝状形式（假菌丝或菌丝）时，其毒性较低。由于响应宿主信号调节生长形式的能力是许多真核微生物引起疾病的基本要求，因此激活适当的发育调节电路可能对于隐球菌在宿主条件下的生存和繁殖至关重要。不幸的是，隐球菌二态性和毒力之间联系的分子基础仍然是个谜。 隐球菌的丝状结构历来被认为与交配有关，而交配在宿主条件下受到抑制。在申请人的实验室中进行的初步研究表明，基因操作可以在与宿主生理相关的条件下赋予隐球菌丝状生长。 Znf2 是一种锌指转录因子，是丝状形成的主要调节因子，它还决定细胞粘附（絮凝）。重要的是，Znf2 对隐球菌的致病性有负面影响。因此，Znf2 为理解隐球菌二态性和毒力的分子基础提供了一个联系。该提议的中心假设是 Znf2 通过控制细胞形态类型和通常与形态发生相关的其他特征来介导隐球菌引起疾病的能力。在强有力的初步数据的指导下，将通过追求以下具体目标来检验该假设：1）。建立 ZNF2 表达、丝状形成能力、细胞粘附和隐球菌毒力之间的关系。 2）。表征丝状化和 Znf2 靶标的其他决定因素，并确定它们在毒力中的作用。为了了解隐球菌的二态性和毒力，重点关注调节丝化固有能力的因素，这与当前以导致交配的信号通路为中心的方法有很大不同。基于这一新愿景的研究有望产生对隐球菌新型毒力决定因素的机制见解。鉴于隐球菌与其他环境获得的二态性病原体（不同门）的差异，这些病原体也显示出丝状和毒力之间类似的负相关性，因此这项研究很可能将确定真菌二态性所需的保守决定因素。由于隐球菌既是临床上重要的病原体，又适合进行遗传和分子研究，因此这项研究将有助于更广泛地了解细胞形状决定以及形态类型对微生物病原体生存的影响。长期目标是了解真菌病原体常见的形态发生和致病性的基本要求，并利用这些知识来制定针对侵袭性真菌病的预防和治疗措施。