Lorenz Michael C, Bender Jennifer A, Fink Gerald R
Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center, 6431 Fannin, Houston, TX 77030, USA.
Eukaryot Cell. 2004 Oct;3(5):1076-87. doi: 10.1128/EC.3.5.1076-1087.2004.
The opportunistic fungal pathogen Candida albicans is both a benign gut commensal and a frequently fatal systemic pathogen. The interaction of C. albicans with the host's innate immune system is the primary factor in this balance; defects in innate immunity predispose the patient to disseminated candidiasis. Because of the central importance of phagocytic cells in defense against fungal infections, we have investigated the response of C. albicans to phagocytosis by mammalian macrophages using genomic transcript profiling. This analysis reveals a dramatic reprogramming of transcription in C. albicans that occurs in two successive steps. In the early phase cells shift to a starvation mode, including gluconeogenic growth, activation of fatty acid degradation, and downregulation of translation. In a later phase, as hyphal growth enables C. albicans to escape from the macrophage, cells quickly resume glycolytic growth. In addition, there is a substantial nonmetabolic response imbedded in the early phase, including machinery for DNA damage repair, oxidative stress responses, peptide uptake systems, and arginine biosynthesis. Further, a surprising percentage of the genes that respond specifically to macrophage contact have no known homologs, suggesting that the organism has undergone substantial evolutionary adaptations to the commensal or pathogen lifestyle. This transcriptional reprogramming is almost wholly absent in the related, but nonpathogenic, yeast Saccharomyces cerevisiae, suggesting that these large-scale and coordinated changes contribute significantly to the ability of this organism to survive and cause disease in vivo.
机会性真菌病原体白色念珠菌既是一种良性的肠道共生菌，也是一种常常致命的系统性病原体。白色念珠菌与宿主固有免疫系统的相互作用是这种平衡的主要因素；固有免疫缺陷使患者易患播散性念珠菌病。由于吞噬细胞在抵御真菌感染中至关重要，我们利用基因组转录谱分析研究了白色念珠菌对哺乳动物巨噬细胞吞噬作用的反应。该分析揭示了白色念珠菌转录的剧烈重编程，这一过程分两个连续步骤发生。在早期阶段，细胞转变为饥饿模式，包括糖异生生长、脂肪酸降解激活以及翻译下调。在后期阶段，随着菌丝生长使白色念珠菌能够从巨噬细胞中逃脱，细胞迅速恢复糖酵解生长。此外，早期阶段还存在大量非代谢反应，包括DNA损伤修复机制、氧化应激反应、肽摄取系统和精氨酸生物合成。而且，对巨噬细胞接触有特异性反应的基因中有相当一部分没有已知的同源物，这表明该生物体在进化过程中对共生或致病生活方式进行了大量适应性改变。这种转录重编程在相关但无致病性的酵母酿酒酵母中几乎完全不存在，这表明这些大规模且协调的变化对该生物体在体内生存和致病的能力有显著贡献。
