Characterizing the Mechanisms of Nonopsonic Uptake of Cryptococci by Macrophages.
Characterizing the Mechanisms of Nonopsonic Uptake of Cryptococci by Macrophages.
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DOI：
10.4049/jimmunol.1700790
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发表时间：
2018-05-15
期刊：
影响因子：
--
通讯作者：
May RC
中科院分区：
文献类型：
--
作者：
Lim J;Coates CJ;Seoane PI;Garelnabi M;Taylor-Smith LM;Monteith P;Macleod CL;Escaron CJ;Brown GD;Hall RA;May RC
致病真菌隐球菌通过吸入进入肺部进入人体宿主，并能够居住在血清调理素受限的利基环境中。在这种情况下，非调理吞噬通过吞噬细胞发生的机制知之甚少。利用来自基因敲除小鼠和人类志愿者的吞噬细胞受体的可溶性抑制剂和巨噬细胞的组合，我们证明了通过甘露糖受体摄取未调理的新生隐球菌和加蒂卡提菌依赖于细胞因子对巨噬细胞的激活。然而，尽管新生葡萄球菌的摄取是通过Dectin-1和Dectin-2两种途径，但C.gattii的摄取主要是通过Dectin-1。有趣的是，Dectin抑制剂还阻止了未被调理的隐球菌在蜡蛾(Galleria Mellonella)幼虫中的吞噬作用，并部分保护了幼虫免受这两种真菌的感染，支持了宿主吞噬细胞在扩大早期疾病建立中的关键作用。最后，我们证明了非调理隐球菌的内化并不伴随着核转位或伴随而来的促炎细胞因子的产生，如κ-α。因此，非调理隐球菌能被哺乳动物吞噬细胞识别，从而最大限度地减少促炎细胞因子的产生，并潜在地促进真菌的发病。
The pathogenic fungus Cryptococcus enters the human host via inhalation into the lung and is able to reside in a niche environment that is serum- (opsonin) limiting. Little is known about the mechanism by which nonopsonic phagocytosis occurs via phagocytes in such situations. Using a combination of soluble inhibitors of phagocytic receptors and macrophages derived from knockout mice and human volunteers, we show that uptake of nonopsonized Cryptococcus neoformans and C. gattii via the mannose receptor is dependent on macrophage activation by cytokines. However, although uptake of C. neoformans is via both dectin-1 and dectin-2, C. gattii uptake occurs largely via dectin-1. Interestingly, dectin inhibitors also blocked phagocytosis of unopsonized Cryptococci in wax moth (Galleria mellonella) larvae and partially protected the larvae from infection by both fungi, supporting a key role for host phagocytes in augmenting early disease establishment. Finally, we demonstrated that internalization of nonopsonized Cryptococci is not accompanied by the nuclear translocation of NF-κB or its concomitant production of proinflammatory cytokines such as TNF-α. Thus, nonopsonized Cryptococci are recognized by mammalian phagocytes in a manner that minimizes proinflammatory cytokine production and potentially facilitates fungal pathogenesis.
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