Candidalysin: a key mediator of Candida vaginitis immunopathology

白色念珠菌是真菌性阴道炎的主要病原体，将影响75%的育龄妇女 一生中至少衰老一次。长期以来，越来越多的证据被认为是由免疫缺陷引起的 强烈表明阴道炎现在被认为是一种免疫病理，在这种情况下，宿主的反应 实际上会引发疾病症状。缺乏对寄主和真菌因素的全面了解 最初的症状性疾病高发仍然是在更好地治疗和管理这方面取得进展的障碍 普遍存在的人类真菌感染。在强劲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阴道炎发病的主要毒力因子。 因此，这项建议的目的是确定假丝酵母素的表达或活性是否在 临床分离株控制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 假说假说：念珠菌素活性的变化部分是念珠菌可变症状的基础 念珠菌素参与的阴道定植和宿主信号的鉴定可能阐明新的分子 治疗靶点。在第一个目标下，我们将确定有助于减少的氨基酸残基 临床分离株中一种变异型念珠菌素的致病性观察。我们还将确定差异主机 阴道粘膜对野生型和变异型念珠菌素的反应。第二个目标将集中在 确定控制念珠菌素的主要遗传机制(启动子序列、Kex蛋白酶) 表情和功能。我们将通过等位基因在强弱之间的转移从功能水平上证实这些 念珠菌素表达菌株。第三个目标是确定假丝酵母菌引起的宿主因素 在体内推动免疫病理学，并确定阻断这些信号机制是否可以缓解 症状性疾病。该项目的成果将提供有关功能的基本信息 念珠菌素亚型，念珠菌素表达的遗传检查点，并确定有希望的新途径 这可能被用于阴道炎的临床治疗。

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.