College of Life Sciences & Medicine, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom.
Infect Immun. 2010 Apr;78(4):1650-8. doi: 10.1128/IAI.00001-10. Epub 2010 Feb 1.
The pathogenicity of the opportunistic human fungal pathogen Candida albicans depends on its ability to escape destruction by the host immune system. Using mutant strains that are defective in cell surface glycosylation, cell wall protein synthesis, and yeast-hypha morphogenesis, we have investigated three important aspects of C. albicans innate immune interactions: phagocytosis by primary macrophages and macrophage cell lines, hyphal formation within macrophage phagosomes, and the ability to escape from and kill macrophages. We show that cell wall glycosylation is critically important for the recognition and ingestion of C. albicans by macrophages. Phagocytosis was significantly reduced for mutants deficient in phosphomannan biosynthesis (mmn4Delta, pmr1Delta, and mnt3 mnt5Delta), whereas O- and N-linked mannan defects (mnt1Delta mnt2Delta and mns1Delta) were associated with increased ingestion, compared to the parent wild-type strains and genetically complemented controls. In contrast, macrophage uptake of mutants deficient in cell wall proteins such as adhesins (ece1Delta, hwp1Delta, and als3Delta) and yeast-locked mutants (clb2Delta, hgc1Delta, cph1Delta, efg1Delta, and efg1Delta cph1Delta), was similar to that observed for wild-type C. albicans. Killing of macrophages was abrogated in hypha-deficient strains, significantly reduced in all glycosylation mutants, and comparable to wild type in cell wall protein mutants. The diminished ability of glycosylation mutants to kill macrophages was not a consequence of impaired hyphal formation within macrophage phagosomes. Therefore, cell wall composition and the ability to undergo yeast-hypha morphogenesis are critical determinants of the macrophage's ability to ingest and process C. albicans.
机会性人类真菌病原体白念珠菌的致病性取决于其逃避宿主免疫系统破坏的能力。使用细胞表面糖基化、细胞壁蛋白合成和酵母-菌丝形态发生缺陷的突变株，我们研究了白念珠菌固有免疫相互作用的三个重要方面：原代巨噬细胞和巨噬细胞系的吞噬作用、巨噬细胞吞噬体中的菌丝形成以及从巨噬细胞中逃逸和杀死的能力。我们表明，细胞壁糖基化对于巨噬细胞识别和摄取白念珠菌至关重要。磷酸甘露聚糖生物合成缺陷（mmn4Δ、pmr1Δ 和 mnt3 mnt5Δ）的突变体的吞噬作用显著降低，而 O-和 N-连接甘露聚糖缺陷（mnt1Δ mnt2Δ 和 mns1Δ）与摄入增加相关与亲本野生型菌株和遗传互补对照相比。相比之下，细胞壁蛋白缺陷（如粘附素（ece1Δ、hwp1Δ 和 als3Δ）和酵母锁定突变体（clb2Δ、hgc1Δ、cph1Δ、efg1Δ 和 efg1Δ cph1Δ）的突变体，与野生型 C. albicans 的摄取情况相似。在菌丝缺陷菌株中，巨噬细胞的杀伤作用被阻断，在所有糖基化突变体中显著降低，在细胞壁蛋白突变体中与野生型相当。糖基化突变体杀伤巨噬细胞的能力降低不是由于巨噬细胞吞噬体中菌丝形成受损所致。因此，细胞壁组成和进行酵母-菌丝形态发生的能力是巨噬细胞摄取和处理白念珠菌的能力的关键决定因素。
