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

基本信息

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
项目类别：
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

项目摘要

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因，将影响所有生殖妇女中的75％年龄至少一次。长期以来一直认为是由于免疫缺陷而产生的，这是越来越多的证据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疾病症状。缺乏对宿主和真菌因素的全面了解发起症状性疾病高仍然是更好地治疗和管理这一进步的障碍普遍的人类真菌感染。在强大的初步数据的指导下，我们已经确定了新描述的真菌毒素念珠菌素是控制阴道炎发病机理的主要毒力因子。因此，该提案的目的是确定念珠菌素在表达或活性中的变化临床分离株控制着阴道粘膜的白色念珠菌致病性。这些目标将测试我们的中心假设念珠菌素活性的变化部分是念珠菌的可变症状的基础念珠菌素参与的宿主信号传导的阴道定植和鉴定可能阐明新分子治疗靶标。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念珠菌素的致病性。我们还将确定差异主机对阴道粘膜的野生型和变体念珠菌素的反应。第二个目标将集中在鉴定控制念珠菌素的普遍遗传机制（启动子序列，KEX蛋白酶）表达和功能。我们将通过强度和弱之间的等位基因转移来确认这些功能水平念珠菌素表达菌株。第三个目标旨在确定念珠菌素引起的宿主因素在体内驱动免疫病理学，并确定这些信号机制的阻塞是否可以减轻有症状的疾病。该项目的结果将提供有关功能的基本信息念珠菌素同工型，念珠菌素表达的遗传检查点，并确定有希望的新途径这可能被利用用于阴道炎的临床管理。