Candida albicans Adhesion and Candidiasis

白色念珠菌粘附和念珠菌病

• 批准号: 8208855
• 负责人: JANET F STAAB
• 金额: $ 20.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8208855
• 关键词: Address; Adhesions; Affinity Chromatography; Animal Model; Bacteria; Bacterial Adhesins; Binding; Biochemical; Biochemistry; Biological Assay; Blood; Blood Circulation; Bypass; Candida albicans; Candidiasis; Cell Surface Proteins; Cell surface; Cells; Cellular Immunity; Cessation of life; Comorbidity; Cytotoxic Chemotherapy; Defect; Development; Disease; Disease Management; Disseminated candidiasis; Drug or chemical Tissue Distribution; Endothelial Cells; Enzymes; Epithelial Cells; Epithelium; Extracellular Matrix; Family; Family member; Fungal Proteins; Gastrointestinal tract structure; Goals; HIV Infections; Individual; Infection; Integration Host Factors; Intestinal Mucosa; Intravenous; Keratin; Laboratories; Lead; Life; Lysine; Mediating; Membrane Proteins; Methodology; Methods; Modeling; Molecular Biology; Mucous Membrane; Mus; Oral mucous membrane structure; Organism; Oryza; Outcome; Population; Proteins; Reaction; Recombinants; Research; Research Project Grants; Resources; Rhizopus; Risk; Role; Sampling; Staging; Stream; Surface; Tissues; Transglutaminases; Virulence; Virulence Factors; Yeasts; antiretroviral therapy; base; covalent bond; crosslink; fungus; improved; insight; interdisciplinary approach; keratinocyte; link protein; mouse model; neutrophil; novel; oropharyngeal thrush; pathogen; receptor

DESCRIPTION (provided by applicant): C. albicans normally resides in the gastrointestinal tract of healthy individuals as harmless, commensal yeast. Conditions that cause defects in cell mediated immunity, and/or deficiencies in neutrophils and loss of mucosal barrier function allow C. albicans to over grow, cause mucosal disease such as oropharyngeal candidiasis (OPC) , or enter the blood stream, and cause disseminated infection. C. albicans-host mucosal interactions are thus of primary importance in mediating risks for both OPC and invasive disease. Previously we identified a C. albicans protein, Hyphal Wall Protein 1 (Hwp1), which mediates a unique interaction between C. albicans filamentous cells and the surface of buccal epithelial cells (BECs). This interaction is in the form of a covalent bond between Hwp1 and an unidentified BEC surface co-substrate protein, catalyzed by a member of the family of transglutaminases (TGs). We also determined that Hwp1 was needed for systemic candidiasis in the intravenous mouse model, but the role of the fungal protein in this infection model was not revealed. The long- term goal of this research is to better understand how the adhesin and virulence factor, Hwp1, is involved C. albicans' ability to interact with host cells. This proposal is based on the hypothesis that host TG-mediated reactions that utilize Hwp1 as a substrate are essential for mucosal and disseminated candidiasis. The Aims of this proposal are: (1) To determine the identity of the host lysine donor proteins that participate with Hwp1 in stabilized adhesion to epithelial and endothelial cell surfaces. (2) To determine the role of Hwp1 in translocation of C. albicans across the intestinal mucosa. (3) To determine the role of TG2 in disseminated candidiasis. The aims proposed here will provide insights into the mechanism of fungal-host interactions that can lead to disease. Further understanding of candidiasis has the potential to generate improved disease management strategies. PUBLIC HEALTH RELEVANCE: The yeast Candida albicans is often found as a cause of serious blood stream infections. The ability of C. albicans to cause disease is not well understood but is likely associated with the organism's ability to bind to host tissues. In this research grant, we proposed to examine how a particular C. albicans protein allows the fungus to bind tightly to host cells and what host factors may influence this binding.

描述（由申请人提供）： C.白色念珠菌通常作为无害的肠道酵母存在于健康个体的胃肠道中。引起细胞介导的免疫缺陷和/或嗜中性粒细胞缺陷和粘膜屏障功能丧失的病症允许C.白色念珠菌过度生长，引起粘膜疾病，如口咽念珠菌病（OPC），或进入血流，引起播散性感染。C.因此，白色念珠菌-宿主粘膜相互作用在介导OPC和侵袭性疾病的风险方面是最重要的。之前我们发现了一个C。白念珠菌菌丝壁蛋白1（Hyphal Wall Protein 1，Hwp 1）是一种介导白念珠菌与白念珠菌之间独特相互作用的蛋白质。白色念珠菌的丝状细胞和颊上皮细胞（BECs）的表面。这种相互作用是在Hwp 1和一个身份不明的BEC表面共底物蛋白，由一个家庭的成员的转谷氨酰胺酶（TG）催化的共价键的形式。我们还确定了Hwp 1是静脉注射小鼠模型中系统性念珠菌病所需的，但真菌蛋白在该感染模型中的作用尚未揭示。这项研究的长期目标是更好地了解粘附素和毒力因子Hwp 1是如何参与C。白色念珠菌与宿主细胞相互作用的能力。这一建议是基于这样的假设，即宿主TG介导的反应，利用Hwp 1作为底物是必不可少的粘膜和播散性念珠菌病。本研究的目的是：（1）确定与Hwp 1一起参与稳定粘附于上皮和内皮细胞表面的宿主赖氨酸供体蛋白的身份。(2)探讨Hwp 1在C.白色念珠菌穿过肠粘膜。(3)确定TG 2在传播性念珠菌病中的作用。这里提出的目标将提供深入了解真菌-宿主相互作用的机制，可能导致疾病。进一步了解念珠菌病有可能产生改进的疾病管理策略。 公共卫生相关性： 酵母菌白色念珠菌经常被发现是严重的血液感染的原因。C.白色念珠菌引起疾病的原因还不清楚，但可能与生物体与宿主组织结合的能力有关。在这项研究基金中，我们建议研究一个特定的C。白念珠菌蛋白允许真菌紧密结合宿主细胞，以及什么宿主因素可能影响这种结合。