Orner Erika P, Bhattacharya Somanon, Kalenja Klea, Hayden Danielle, Del Poeta Maurizio, Fries Bettina C
Department of Microbiology and Immunology, Stony Brook University, Stony Brook, NY, United States.
Department of Medicine, Division of Infectious Disease, Stony Brook University, Stony Brook, NY, United States.
Front Microbiol. 2019 Nov 7;10:2513. doi: 10.3389/fmicb.2019.02513. eCollection 2019.
As mother cells generationally age, their cell walls become thicker and cell-wall associated virulence factors are upregulated. Antiphagocytic protein 1 (App1), and laccase enzymes (Lac1 and Lac2) are virulence factors known to contribute to virulence of during infection through inhibition of phagocytic uptake and melanization. Here we show that these cell-wall-associated proteins are not only significantly upregulated in old cells, but also that their upregulation likely contributes to the increased resistance to antifungal and host-mediated killing during infection and to the subsequent accumulation of old cells. We found that old cells melanize to a greater extent than younger cells and as a consequence, old melanized cells are more resistant to killing by amphotericin B compared to young melanized cells. A decrease in melanization of old Δ mutants lead to a decrease in old-cell resilience, indicating that age-related melanization is contributing to the overall resilience of older cells and is being mediated by laccase genes. Additionally, we found that older cells are more resistant to macrophage phagocytosis, but this resistance is lost when is knocked out, indicating that upregulation of in older cells is in part responsible for their increased resistance to phagocytosis by macrophages. Finally, infections with old cells in the model support our conclusions, as loss of the , and gene ablates the enhanced virulence of old cells, indicating their importance in age-dependent resilience.
随着母细胞逐代老化，它们的细胞壁会变厚，与细胞壁相关的毒力因子会上调。抗吞噬蛋白1（App1）和漆酶（Lac1和Lac2）是已知的毒力因子，在感染过程中通过抑制吞噬摄取和黑化作用来促进毒力。在这里，我们表明这些与细胞壁相关的蛋白质不仅在老化细胞中显著上调，而且它们的上调可能有助于在感染期间增加对抗真菌和宿主介导杀伤的抵抗力，并导致老化细胞的后续积累。我们发现老化细胞比年轻细胞的黑化程度更高，因此，与年轻黑化细胞相比，老化黑化细胞对两性霉素B的杀伤更具抵抗力。老化Δ突变体黑化程度的降低导致老化细胞恢复力下降，表明与年龄相关的黑化作用有助于老化细胞的整体恢复力，并且由漆酶基因介导。此外，我们发现老化细胞对巨噬细胞吞噬作用更具抵抗力，但当被敲除时这种抵抗力丧失，表明老化细胞中 的上调部分负责它们对巨噬细胞吞噬作用抵抗力的增加。最后，在 模型中用老化细胞进行感染支持了我们的结论，因为 、 和 基因的缺失消除了老化细胞增强的毒力，表明它们在年龄依赖性恢复力中的重要性。
