Candidalysin: a key mediator of Candida vaginitis immunopathology

念珠菌溶素：念珠菌阴道炎免疫病理学的关键介质

• 批准号: 9767658
• 负责人: Brian M Peters
• 金额: $ 38万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767658
• 关键词: Affect; Age; Alleles; Amino Acids; Candida; Candida albicans; Candidiasis; Cells; Chronic; Cleaved cell; Clinical; Clinical Management; Complex; Data; Disease; Engineering; Epithelial Cells; Etiology; Exhibits; Female of child bearing age; Foundations; Genetic; Health; Human; Hyphae; Immune response; Immunity; Immunologic Deficiency Syndromes; In Vitro; Infection; Inflammasome; Inflammation; Inflammatory; Integration Host Factors; Interleukin-1 beta; Interleukin-18; Knockout Mice; Link; Mediating; Mediator of activation protein; Medical Care Costs; Molecular; Mus; Mutagenesis; Mycoses; Mycotoxins; Onset of illness; Oral mucous membrane structure; Outcome; Pain; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Peptide Hydrolases; Peptides; Population; Protein Isoforms; Proteins; Quality of life; Recurrence; Research; Role; Signal Pathway; Signal Transduction; Symptoms; Testing; Therapeutic; Toxin; Vagina; Vaginitis; Variant; Virulence Factors; Vulvovaginal Candidiasis; Woman; Yeasts; cell injury; delta opioid receptor; experience; fungus; genetic variant; immunopathology; improved; in vivo; molecular targeted therapies; mouse model; neutrophil; novel; polypeptide; prevent; promoter; reproductive; symptomatology; transcriptome sequencing; vaginal fluid; vaginal mucosa; whole genome

Candida albicans, the primary causative agent of fungal vaginitis, will affect 75% of all women of reproductive age at least once in their lifetime. Long believed to result from immunodeficiency, a growing body of evidence strongly suggests that vaginitis is now considered to be an immunopathology, in which the host response actually drives disease symptoms. Lack of a comprehensive understanding of the host and fungal factors that initiate symptomatic disease high remains a barrier to progress in better treating and managing this most prevalent human fungal infection. Guided by strong preliminary data, we have identified the newly described fungal toxin Candidalysin as the major virulence factor governing vaginitis pathogenesis. Therefore, the objective of this proposal is to determine if variation in expression or activity of Candidalysin in clinical isolates governs C. albicans pathogenicity at the vaginal mucosa. These aims will test our central hypothesis that variation in Candidalysin activity partly underlies the variable symptomatology of Candida vaginal colonization and identification of host signaling engaged by Candidalysin may elucidate new molecular therapeutic targets. Under the first aim, we will determine amino acid residues that contribute to reduced pathogenicity of a variant Candidalysin observed in clinical isolates. We will also determine differential host responses to wild-type and variant Candidalysin at the vaginal mucosa. The second aim will focus on identifying prevalent genetic mechanisms (promoter sequences, Kex proteases) that control Candidalysin expression and function. We will confirm these by functional level by allelic transfers between strong and weak Candidalysin expressing strains. The third aim seeks to identify host factors elicited by Candidalysin that may drive immunopathology in vivo and determine if blockade of these signaling mechanisms can alleviate symptomatic disease. The outcomes of this project will provide foundational information regarding function of Candidalysin isoforms, genetic checkpoints of Candidalysin expression, and identify promising new pathways that may be exploited for the clinical management of vaginitis.

白色念珠菌是真菌性阴道炎的主要病原体， 一生中至少有一次衰老。长期以来被认为是由免疫缺陷引起的，越来越多的证据表明， 强烈表明阴道炎现在被认为是一种免疫病理学，其中宿主反应 实际上驱动了疾病症状。缺乏对宿主和真菌因素的全面了解， 高起始症状性疾病仍然是更好地治疗和管理这一最 流行的人类真菌感染。在强有力的初步数据的指导下，我们已经确定了新描述的 真菌毒素溶菌素是控制阴道炎发病的主要毒力因子。 因此，本建议的目的是确定在细胞中，拟南芥溶素的表达或活性的变化是否与细胞中的表达或活性有关。 临床分离株控制C.白色念珠菌在阴道粘膜的致病性。这些目标将考验我们的中央 假丝酵母菌溶素活性变化是假丝酵母菌变异性的部分基础的假说 阴道定殖和鉴定宿主信号转导所涉及的拟南芥素可能阐明新的分子 治疗目标在第一个目标下，我们将确定有助于减少的氨基酸残基。 在临床分离株中观察到的变异体放线菌素的致病性。我们还将确定差异宿主 在阴道粘膜对野生型和变异型的曲马多来霉素的反应。第二个目标将侧重于 鉴定控制拟南芥溶血素的普遍遗传机制（启动子序列、Kex蛋白酶） 表达和功能。我们将通过强和弱之间的等位基因转移来证实这些功能水平 溶藻素表达菌株。第三个目的是确定由拟南芥溶素引起的宿主因子， 驱动体内免疫病理学，并确定阻断这些信号传导机制是否可以减轻 症状性疾病该项目的成果将提供关于 拟南芥素异构体，拟南芥素表达的遗传检查点，并确定有前途的新途径 可用于阴道炎的临床治疗。