Persistence versus Escape: Aspergillus terreus and Aspergillus fumigatus Employ Different Strategies during Interactions with Macrophages
Persistence versus Escape: Aspergillus terreus and Aspergillus fumigatus Employ Different Strategies during Interactions with Macrophages
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DOI：
10.1371/journal.pone.0031223
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发表时间：
2012-02-03
期刊：
影响因子：
3.7
通讯作者：
Brock, Matthias
中科院分区：
文献类型：
--
作者：
Slesiona, Silvia;Gressler, Markus;Brock, Matthias
侵袭性支气管肺曲霉病（IBPA）是一种危及免疫功能低下患者生命的疾病。虽然土曲霉是常见的环境中，A。烟曲霉是目前引起IBPA的主要病原。然而，一旦A. terreus在宿主中建立感染，疾病与A.烟曲霉感染因此，我们假设疾病建立的初始步骤可能在这两个物种之间有根本的不同。由于肺泡巨噬细胞是面对吸入分生孢子的第一批吞噬细胞之一，我们比较了A。Terreus和A.具有肺泡巨噬细胞的烟曲霉分生孢子。A.土生孢子的吞噬速度比A.烟曲霉分生孢子，可能是由于表面上的β-1，3-葡聚糖和半乳甘露聚糖的较高暴露。与此一致，阻断dectin-1和甘露糖受体显著降低了A. terreus，但对A.烟熏。与A. fumigatus、烟曲霉A.土不抑制吞噬溶酶体的酸化，但在体外和免疫活性小鼠中保持活力，没有萌发迹象。A的无能。terreus对巨噬细胞萌发和穿透能力明显低于A.烟熏。用v-ATP酶抑制剂巴弗洛霉素阻断吞噬溶酶体的酸化，A.土发芽率和细胞毒性。重组表达A. nidulans是A. naphthopyrone synthase的同源物。烟曲霉PksP，抑制吞噬溶酶体酸化，并导致增加的发芽，巨噬细胞损伤和毒性皮质类固醇治疗的小鼠。总之，我们表明，A. Terreus和A.烟曲霉已经进化出显著不同的策略以在宿主免疫细胞的攻击下存活。而A. fumigatus阻止吞噬作用和吞噬溶酶体酸化，并通过萌发从巨噬细胞逃逸，A.土生菌被迅速吞噬，但分生孢子在巨噬细胞中甚至在免疫活性宿主中也表现出长期持久性。
Invasive bronchopulmonary aspergillosis (IBPA) is a life-threatening disease in immunocompromised patients. Although Aspergillus terreus is frequently found in the environment, A. fumigatus is by far the main cause of IBPA. However, once A. terreus establishes infection in the host, disease is as fatal as A. fumigatus infections. Thus, we hypothesized that the initial steps of disease establishment might be fundamentally different between these two species. Since alveolar macrophages represent one of the first phagocytes facing inhaled conidia, we compared the interaction of A. terreus and A. fumigatus conidia with alveolar macrophages. A. terreus conidia were phagocytosed more rapidly than A. fumigatus conidia, possibly due to higher exposure of beta-1,3-glucan and galactomannan on the surface. In agreement, blocking of dectin-1 and mannose receptors significantly reduced phagocytosis of A. terreus, but had only a moderate effect on phagocytosis of A. fumigatus. Once phagocytosed, and in contrast to A. fumigatus, A. terreus did not inhibit acidification of phagolysosomes, but remained viable without signs of germination both in vitro and in immunocompetent mice. The inability of A. terreus to germinate and pierce macrophages resulted in significantly lower cytotoxicity compared to A. fumigatus. Blocking phagolysosome acidification by the v-ATPase inhibitor bafilomycin increased A. terreus germination rates and cytotoxicity. Recombinant expression of the A. nidulans wA naphthopyrone synthase, a homologue of A. fumigatus PksP, inhibited phagolysosome acidification and resulted in increased germination, macrophage damage and virulence in corticosteroid-treated mice. In summary, we show that A. terreus and A. fumigatus have evolved significantly different strategies to survive the attack of host immune cells. While A. fumigatus prevents phagocytosis and phagolysosome acidification and escapes from macrophages by germination, A. terreus is rapidly phagocytosed, but conidia show long-term persistence in macrophages even in immunocompetent hosts.