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Human Neutrophil-Mediated Nonoxidative Antifungal Activity against Cryptococcus neoformans

机译：人类嗜中性粒细胞介导的新型隐球菌抗氧化抗真菌活性

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It has long been appreciated that polymorphonuclear leukocytes (PMN) kill Cryptococcus neoformans, at least in part via generation of fungicidal oxidants. The aim of this study was to examine the contribution of nonoxidative mechanisms to the inhibition and killing of C. neoformans. Treatment of human PMN with inhibitors and scavengers of respiratory burst oxidants only partially reversed anticryptococcal activity, suggesting that both oxidative and nonoxidative mechanisms were operative. To define the mediators of nonoxidative anticryptococcal activity, PMN were fractionated into cytoplasmic, primary (azurophil) granule, and secondary (specific) granule fractions. Incubation of C. neoformans with these fractions for 18 h resulted in percents inhibition of growth of 67.4 ± 3.4, 84.6 ± 4.4, and 29.2 ± 10.5 (mean ± standard error, n = 3), respectively. Anticryptococcal activity of the cytoplasmic fraction was abrogated by zinc and depletion of calprotectin. Antifungal activity of the primary granules was significantly reduced by pronase treatment, boiling, high ionic strength, and magnesium but not calcium. Fractionation of the primary granules by reverse phase high-pressure liquid chromatography on a C4 column over an acetonitrile gradient revealed multiple peaks with anticryptococcal activity. Of these, peaks 1 and 6 had substantial fungistatic and fungicidal activity. Peak 1 was identified by acid-urea polyacrylamide gel electrophoresis (PAGE) and mass spectroscopy as human neutrophil proteins (defensins) 1 to 3. Analysis of peak 6 by sodium dodecyl sulfate-PAGE revealed multiple bands. Thus, human PMN have nonoxidative anticryptococcal activity residing principally in their cytoplasmic and primary granule fractions. Calprotectin mediates the cytoplasmic activity, whereas multiple proteins, including defensins, are responsible for activity of the primary granules.
机译：长期以来，人们一直认识到，多形核白细胞（PMN）至少部分通过杀真菌氧化剂的产生杀死新型隐球菌。这项研究的目的是检查非氧化机制对 C的抑制和杀伤作用。新甲虫。用呼吸道爆发性氧化剂的抑制剂和清除剂治疗人PMN只能部分逆转抗隐球菌活性，这表明氧化和非氧化机制均有效。为了确定非氧化抗隐球菌活性的介体，将PMN分为细胞质，初级（嗜酸性）颗粒和次级（特异性）颗粒部分。 C的孵化。具有这些馏分的新甲虫18小时分别导致67.4±3.4、84.6±4.4和29.2±10.5的生长抑制百分比（平均值±标准误差， n = 3）。锌和钙卫蛋白的消耗消除了细胞质部分的抗隐球菌活性。链霉蛋白酶处理，煮沸，高离子强度和镁而不是钙可显着降低初级颗粒的抗真菌活性。在C 4 色谱柱上通过乙腈梯度在反相高压液相色谱上分离初级颗粒，发现多个峰具有抗隐球菌活性。在这些峰中，峰1和峰6具有显着的抑真菌和杀真菌活性。峰1通过酸-尿素聚丙烯酰胺凝胶电泳（PAGE）和质谱鉴定为人中性粒细胞蛋白（防御素）1至3。通过十二烷基硫酸钠-PAGE分析峰6显示了多个谱带。因此，人PMN具有非氧化抗隐球菌活性，主要存在于它们的细胞质和初级颗粒级分中。钙卫蛋白介导细胞质的活性，而包括防御素在内的多种蛋白质则负责初级颗粒的活性。

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