Host Immunity and Virulence in Candida albicans Pathogenesis

白色念珠菌的宿主免疫和毒力发病机制

• 批准号: 7629771
• 负责人: Jose L. Lopez-Ribot
• 金额: $ 33.7万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7629771
• 关键词: Animals; Antifungal Therapy; Attenuated; Biological Assay; Candida albicans; Candidiasis; Cell physiology; Cells; Complex; Defense Mechanisms; Development; Disease; Disseminated candidiasis; Economic Burden; Economics; Engineering; Evolution; Exposure to; Face; Filament; Gene Expression; Goals; Hospitals; Human; Immune; Immune response; Immunity; Immunocompromised Host; In Vitro; Infection; Investigation; Knockout Mice; Lead; Link; Morphogenesis; Morphology; Multigene Family; Mycoses; NRG1 gene; Natural Immunity; Nature; Nosocomial Infections; Organ Survival; Outcome; Pathogenesis; Patients; Pattern; Pattern recognition receptor; Phagocytes; Predisposition; Prevention strategy; Process; Public Health; Recording of previous events; Research Personnel; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Series; Serum; Side; Staging; Surface; Systemic infection; TLR2 gene; TLR4 gene; Tetanus Helper Peptide; Tissues; Toll-like receptors; Virulence; Virulent; Yeasts; base; cytokine; fungus; in vivo; insight; member; mortality; mutant; outcome forecast; pathogen; prevent; programs; protective effect; research study; response; secondary infection; sensor

DESCRIPTION (provided by applicant): Candida albicans is the most common etiological agent of candidiasis, now the fourth leading cause of nosocomial infections carrying high levels of mortality despite currently available therapy. The human host and C. albicans have a long history of association. Consequently, this high degree of co-existence has led to the evolution of layers of defense mechanisms in the host and layers of virulence mechanisms in this opportunistic pathogen. It is clear that mechanisms of host immunity and pathogen virulence intertwine, giving rise to the highly complex nature of host-fungus interactions. However, the interplay between host immunity and fungal virulence has traditionally been ignored in the in the study of C. albicans pathogenesis and most investigations into these topics are overwhelmingly "one-sided". We have constructed a genetically engineered strain of C. albicans (tet-NRG1) that allows "in vivo" modulation of morphology and virulence, and here we propose to use this strain to gain insight into the mechanisms involved in immune defense against systemic infection. The specific aims of this application are: i) to analyze the immune response and characterize protective immune mechanisms during infection with our C. albicans tet-NRG1 strain at different stages of the infectious process, and under conditions leading to colonization (when cells are maintained in the yeast morphology) or active disease (when filamentation is allowed to occur); ii) to investigate the mechanisms of innate and adaptive immunity by which primary infection with this strain protects against a subsequent challenge with a wild type virulent C. albicans strain; and iii) to examine the patterns of expression and role of Toll-like receptors in the innate and adaptive immunity responsible for protection against primary and secondary infections. Relevance to public health: Candida albicans is the main causative agent of candidiasis, the most frequent fungal infection and now the fourth leading cause of infections in US hospitals, with high mortality rates and soaring economic burden. Our long term goal is to understand how the interplay between host immunity and candidal virulence determines the outcome of infection. Results are likely to lead to the development of new immune-based strategies for the prevention and treatment of systemic candidiasis that are urgently needed.

描述（由申请人提供）：白色念珠菌是念珠菌病的最常见病因，现在是医生感染的第四个主要原因，尽管目前可用于治疗，但仍具有高水平的死亡率。人类寄主和白色念珠菌的结合历史悠久。因此，这种高度的共存导致了这种机会性病原体中的宿主和毒力机制层中防御机制的演变。很明显，宿主免疫和病原体毒力的机制交织在一起，从而产生了宿主 - 连通相互作用的高度复杂性。然而，在白色念珠菌发病机理的研究中，传统上忽略了宿主免疫力与真菌毒力之间的相互作用，并且对这些主题的大多数研究都非常“单方面”。我们已经构建了白色念珠菌（Tet-NRG1）的基因工程菌株，该菌株允许“体内”调节形态和毒力，在这里我们建议使用这种菌株来深入了解针对全身感染的免疫防御机制。该应用的具体目的是：i）分析免疫反应并表征在感染过程的不同阶段使用白色念珠菌Tet-NRG1菌株感染期间的保护性免疫机制，在传染过程的不同阶段，在导致定殖的条件下（当细胞保持在酵母菌形态中）或活性疾病（当允许发生细丝时）； ii）研究先天和适应性免疫的机制，通过这种菌株的原发性感染可以防止使用野生型毒物白色念珠菌菌株进行随后的挑战；和iii）检查toll样受体在先天和适应性免疫中的表达和作用模式，负责保护原发和继发感染。与公共卫生相关：白色念珠菌是念珠菌病的主要原因，是最常见的真菌感染，现在是美国医院感染的第四个主要原因，具有高死亡率和高昂的经济负担。我们的长期目标是了解宿主免疫与候选毒力之间的相互作用如何决定感染的结果。结果可能会导致新的发展 迫切需要的预防和治疗全身性念珠菌病的免疫策略。

项目成果

Physiologic expression of the Candida albicans pescadillo homolog is required for virulence in a murine model of hematogenously disseminated candidiasis.

在血源性念珠菌病小鼠模型中，白色念珠菌同系物的生理表达是其毒力所必需的。

• DOI: 10.1128/ec.00171-12
• 发表时间: 2012
• 期刊: Eukaryotic cell
• 作者: Uppuluri,Priya;Chaturvedi,AshokK;Jani,Niketa;Pukkila-Worley,Read;Monteagudo,Carlos;Mylonakis,Eleftherios;Köhler,JuliaR;LopezRibot,JoseL
• 通讯作者: LopezRibot,JoseL