Division of Infectious Diseases, Department of Medicine, Stony Brook Universitygrid.36425.36, Stony Brook, New York, USA.
Department of Microbiology and Immunology, Renaissance School of Medicine, Stony Brook Universitygrid.36425.36, Stony Brook, New York, USA.
mBio. 2021 Feb 22;13(1):e0019022. doi: 10.1128/mbio.00190-22. Epub 2022 Feb 15.
Replicative aging is an underexplored field of research in medical mycology. Cryptococcus neoformans () and Candida glabrata () are dreaded fungal pathogens that cause fatal invasive infections. The fungal cell wall is essential for yeast viability and pathogenesis. In this study, we provide data characterizing age-associated modifications to the cell wall of and . Here, we report that old yeast cells upregulate genes of cell wall biosynthesis, leading to cell wall reorganization and increased levels of all major components, including glucan, chitin, and its derivatives, as well as mannan. This results in a significant thickening of the cell wall in aged cells. Old-generation yeast cells exhibited drastic ultrastructural changes, including the presence of abundant vesicle-like particles in the cytoplasm, and enlarged vacuoles with altered pH homeostasis. Our findings suggest that the cell wall modifications could be enabled by augmented intracellular trafficking. This work furthers our understanding of the cell phenotype that emerges during aging. It highlights differences in these two fungal pathogens and elucidates mechanisms that explain the enhanced resistance of old cells to antifungals and phagocytic attacks. Cryptococcus neoformans and Candida glabrata are two opportunistic human fungal pathogens that cause life-threatening diseases. During infection, both microorganisms have the ability to persist for long periods, and treatment failure can occur even if standard testing identifies the yeasts to be sensitive to antifungals. Replicative life span is a trait that is measured by the number of divisions a cell undergoes before death. Aging in fungi is associated with enhanced tolerance to antifungals and resistance to phagocytosis, and characterization of old cells may help identify novel antifungal targets. The cell wall remains an attractive target for new therapies because it is essential for fungi and is not present in humans. This study shows that the organization of the fungal cell wall changes remarkably during aging and becomes thicker and is associated with increased intracellular trafficking as well as the alteration of vacuole morphology and pH homeostasis.
复发性衰老在医学真菌学领域是一个研究不足的领域。新型隐球菌（）和光滑念珠菌（）是可怕的真菌病原体，可引起致命的侵袭性感染。真菌细胞壁对酵母的生存和发病机制至关重要。在这项研究中，我们提供了特征描述老化相关修饰的细胞壁和。在这里，我们报告说，年老的酵母细胞上调细胞壁生物合成的基因，导致细胞壁重新组织和增加所有主要成分的水平，包括葡聚糖、几丁质及其衍生物，以及甘露聚糖。这导致老化细胞的细胞壁显著增厚。老一代酵母细胞表现出剧烈的超微结构变化，包括细胞质中存在大量囊泡样颗粒，以及体积增大、pH 稳态改变的液泡。我们的研究结果表明，细胞壁的修饰可能是通过增强细胞内运输来实现的。这项工作进一步加深了我们对衰老过程中出现的细胞表型的理解。它突出了这两种真菌病原体的差异，并阐明了解释老细胞对真菌药物和吞噬作用增强抗性的机制。新型隐球菌和光滑念珠菌是两种机会性人类真菌病原体，可导致危及生命的疾病。在感染过程中，两种微生物都有能力长时间存活，如果标准检测表明酵母对真菌药物敏感，但治疗失败，仍可能发生。复制寿命是通过细胞在死亡前经历的分裂次数来衡量的特征。真菌衰老与增强对真菌药物的耐受性和对吞噬作用的抗性有关，对老细胞的特征描述可能有助于识别新的抗真菌靶点。细胞壁仍然是新疗法的一个有吸引力的目标，因为它对真菌是必需的，而在人类中不存在。这项研究表明，真菌细胞壁的组织在衰老过程中发生了显著变化，变得更厚，并与细胞内运输的增加以及液泡形态和 pH 稳态的改变有关。
