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: 7470088
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470088
• 关键词: Animals; Antifungal Therapy; Attenuated; Biological Assay; Candida albicans; Candidiasis; Cell physiology; Cells; Complex; Condition; 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; Invasive; Investigation; Knockout Mice; Lead; Link; Morphogenesis; Morphology; Multigene Family; Mycoses; NRG1 gene; Natural Immunity; Nature; Neuregulin 1; Nosocomial Infections; Organ Survival; Outcome; PLAB Protein; Pathogenesis; Patients; Pattern; Pattern recognition receptor; Phagocytes; Predisposition; Prevention strategy; Process; Public Health; Range; Rate; 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(申请人提供)：白色念珠菌是念珠菌病最常见的病原体，现在是医院感染的第四大原因，死亡率很高，尽管目前有可用的治疗方法。人类宿主和白色念珠菌有着悠久的联系历史。因此，这种高度的共存导致了寄主的多层防御机制和这种机会性病原体的多层毒力机制的进化。显然，寄主免疫机制和病原菌毒力机制交织在一起，导致了寄主-真菌相互作用的高度复杂性。然而，在白念珠菌致病机制的研究中，宿主免疫和真菌毒力之间的相互作用一直被忽视，而且大多数关于这些主题的研究都是“片面的”。我们已经构建了一种白念珠菌的基因工程菌株(TET-NRG1)，它允许“在体内”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系统性感染的免疫防御机制。本应用程序的具体目标是：i)分析在感染过程的不同阶段以及导致定植(当细胞保持在酵母形态中)或活动性疾病(当允许丝状生长发生)的条件下，我们的白念珠菌tet-NRG1菌株感染期间的免疫反应和保护性免疫机制；ii)研究固有免疫和获得性免疫的机制，通过该机制，该菌株的初次感染可以保护其免受随后与野生型毒力白念珠菌菌株的挑战；以及iii)研究Toll样受体在负责预防初次和二次感染的固有免疫和获得性免疫中的表达模式和作用。与公共卫生相关：白色念珠菌是念珠菌病的主要病原体，是最常见的真菌感染，现在是美国医院感染的第四大原因，死亡率高，经济负担飙升。我们的长期目标是了解宿主免疫和念珠菌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 迫切需要以免疫为基础的预防和治疗系统性念珠菌病的战略。