Host Immunity and Virulence in Candida albicans Pathogenesis

描述（由申请人提供）：白色念珠菌是念珠菌病最常见的病原体，目前是医院感染的第四大原因，尽管目前有治疗方法，但死亡率仍很高。人类宿主和C.白色念珠菌有着悠久的交往历史。因此，这种高度的共存导致了宿主防御机制的进化和这种机会病原体毒力机制的进化。很明显，宿主免疫和病原体毒力的机制相互干扰，导致宿主-真菌相互作用的高度复杂性。然而，在传统的研究中，宿主免疫和真菌毒力之间的相互作用一直被忽视。白念珠菌的发病机制和大多数调查这些主题是压倒性的“片面”。我们构建了一株C.白色念珠菌（tet-NRG 1），允许“在体内”的形态和毒力的调制，在这里，我们建议使用这种菌株，以深入了解参与免疫防御系统感染的机制。本申请的具体目的是：i）分析免疫应答并表征感染我们的C.白色念珠菌tet-NRG 1菌株在感染过程的不同阶段，并在导致定植（当细胞保持在酵母形态）或活动性疾病（当允许发生增殖）的条件下; ii）研究先天性和适应性免疫的机制，通过该机制，该菌株的初次感染可以保护免受随后的野生型强毒念珠菌的攻击。白色念珠菌菌株;和iii）检查Toll样受体在负责保护免受原发性和继发性感染的先天性和适应性免疫中的表达模式和作用。与公共卫生的相关性：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力和念珠菌毒力之间的相互作用如何决定感染的结果。结果很可能导致新的发展 预防和治疗系统性念珠菌病的免疫策略是迫切需要的。

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.