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首页> 外文期刊>MBio >Streptolysin O and NAD-Glycohydrolase Prevent Phagolysosome Acidification and Promote Group A Streptococcus Survival in Macrophages
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Streptolysin O and NAD-Glycohydrolase Prevent Phagolysosome Acidification and Promote Group A Streptococcus Survival in Macrophages

机译：链球菌溶血素O和NAD-乙醇酸水解酶可防止吞噬酶体酸化并促进巨噬细胞中A组链球菌的存活

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Group A Streptococcus (GAS, Streptococcus pyogenes) is an ongoing threat to human health as the agent of streptococcal pharyngitis, skin and soft tissue infections, and life-threatening conditions such as necrotizing fasciitis and streptococcal toxic shock syndrome. In animal models of infection, macrophages have been shown to contribute to host defense against GAS infection. However, as GAS can resist killing by macrophages in vitro and induce macrophage cell death, it has been suggested that GAS intracellular survival in macrophages may enable persistent infection. Using isogenic mutants, we now show that the GAS pore-forming toxin streptolysin O (SLO) and its cotoxin NAD-glycohydrolase (NADase) mediate GAS intracellular survival and cytotoxicity for macrophages. Unexpectedly, the two toxins did not inhibit fusion of GAS-containing phagosomes with lysosomes but rather prevented phagolysosome acidification. SLO served two essential functions, poration of the phagolysosomal membrane and translocation of NADase into the macrophage cytosol, both of which were necessary for maximal GAS intracellular survival. Whereas NADase delivery to epithelial cells is mediated by SLO secreted from GAS bound to the cell surface, in macrophages, the source of SLO and NADase is GAS contained within phagolysosomes. We found that transfer of NADase from the phagolysosome to the macrophage cytosol occurs not by simple diffusion through SLO pores but rather by a specific translocation mechanism that requires the N-terminal translocation domain of NADase. These results illuminate the mechanisms through which SLO and NADase enable GAS to defeat macrophage-mediated killing and provide new insight into the virulence of a major human pathogen. >IMPORTANCE Macrophages constitute an important element of the innate immune response to mucosal pathogens. They ingest and kill microbes by phagocytosis and secrete inflammatory cytokines to recruit and activate other effector cells. Group A Streptococcus (GAS, Streptococcus pyogenes), an important cause of pharyngitis and invasive infections, has been shown to resist killing by macrophages. We find that GAS resistance to macrophage killing depends on the GAS pore-forming toxin streptolysin O (SLO) and its cotoxin NAD-glycohydrolase (NADase). GAS bacteria are internalized by macrophage phagocytosis but resist killing by secreting SLO, which damages the phagolysosome membrane, prevents phagolysosome acidification, and translocates NADase from the phagolysosome into the macrophage cytosol. NADase augments SLO-mediated cytotoxicity by depleting cellular energy stores. These findings may explain the nearly universal production of SLO by GAS clinical isolates and the association of NADase with the global spread of a GAS clone implicated in invasive infections.
机译：A组链球菌（GAS，化脓性链球菌）作为链球菌性咽炎，皮肤和软组织感染以及危及生命的疾病（例如坏死性筋膜炎和链球菌中毒性休克综合征。在感染的动物模型中，已经证明巨噬细胞有助于宿主抵抗GAS感染。然而，由于GAS可以抵抗巨噬细胞的体外杀伤并诱导巨噬细胞死亡，因此有人认为GAS在巨噬细胞中的细胞内存活可能导致持续感染。使用同基因突变体，我们现在显示GAS孔形成毒素链球菌溶血素O（SLO）及其毒素NAD-糖水解酶（NADase）介导GAS的细胞存活和巨噬细胞的细胞毒性。出乎意料的是，这两种毒素并未抑制含GAS吞噬体与溶酶体的融合，而是阻止了吞噬体的酸化。 SLO具有两个基本功能：吞噬溶酶体膜的渗透和NADase易位到巨噬细胞胞浆中，这两者对于最大化GAS细胞内存活都是必需的。尽管NADase传递到上皮细胞是由结合到细胞表面的GAS分泌的SLO介导的，但在巨噬细胞中，SLO和NADase的来源是吞噬溶酶体内的GAS。我们发现，NADase从吞噬体转移到巨噬细胞胞质不是通过SLO孔简单扩散而是通过需要NADase N末端易位域的特定易位机制发生的。这些结果阐明了SLO和NADase使GAS击败巨噬细胞介导的杀伤机制，并提供了对主要人类病原体毒力的新见解的机制。 >重要性巨噬细胞是对粘膜病原体固有免疫反应的重要组成部分。它们通过吞噬作用摄入并杀死微生物，并分泌炎症细胞因子以募集并激活其他效应细胞。 A组链球菌（GAS，化脓性链球菌）是咽炎和侵袭性感染的重要原因，已被证明可以抵抗巨噬细胞的杀伤。我们发现，GAS对巨噬细胞杀伤的抵抗力取决于GAS成孔毒素链球菌溶血素O（SLO）及其毒素NAD-糖水解酶（NADase）。 GAS细菌通过巨噬细胞吞噬作用而被内在化，但是通过分泌SLO来抵抗杀伤，SLO破坏了吞噬酶体膜，阻止了吞噬酶体酸化，并将NADase从吞噬酶体转移到巨噬细胞胞质中。 NADase通过消耗细胞能量储存来增强SLO介导的细胞毒性。这些发现可能解释了GAS临床分离株几乎普遍产生SLO，以及NADase与涉及侵袭性感染的GAS克隆在全球的传播有关。

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