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，目前是医院感染的第四大原因，尽管目前有治疗方法，但死亡率很高。人类宿主与白色念珠菌有着悠久的联系历史。因此，这种高度共存导致了宿主的多层防御机制和这种机会致病菌的多层毒力机制的进化。很明显，宿主免疫机制和病原体毒力交织在一起，导致宿主-真菌相互作用的高度复杂性。然而，宿主免疫和真菌毒力之间的相互作用在白色念珠菌发病机制的研究中一直被忽视，大多数关于这些主题的研究都是压倒性的“片面”。我们已经构建了一种白色念珠菌的基因工程菌株（tet-NRG1），它允许“体内”调节形态和毒力，在这里我们建议使用该菌株来深入了解涉及免疫防御系统感染的机制。该应用程序的具体目的是：i)在感染过程的不同阶段，以及在导致定植（当细胞保持酵母形态时）或活动性疾病（当允许发生丝化时）的条件下，分析我们的白色念珠菌tet-NRG1菌株感染期间的免疫反应并表征保护性免疫机制；ii)研究先天免疫和适应性免疫的机制，通过这种机制，初次感染该菌株可以防止随后受到野生型强毒白色念珠菌菌株的攻击；iii)研究toll样受体在保护机体免受原发性和继发性感染的先天免疫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，念珠菌病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。结果很可能导致新的发展

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.