The Pore-Forming Toxin Listeriolysin O Is Degraded by Neutrophil Metalloproteinase-8 and Fails To Mediate Listeria monocytogenes Intracellular Survival in Neutrophils
The Pore-Forming Toxin Listeriolysin O Is Degraded by Neutrophil Metalloproteinase-8 and Fails To Mediate Listeria monocytogenes Intracellular Survival in Neutrophils
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DOI：
10.4049/jimmunol.1301302
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发表时间：
2014-01-01
影响因子：
4.4
通讯作者：
Seveau, Stephanie
中科院分区：
文献类型：
--
作者：
Arnett, Eusondia;Vadia, Stephen;Seveau, Stephanie
成孔毒素李斯特菌溶血素 O (LLO) 是兼性细胞内病原体单核细胞增生李斯特菌分泌的主要毒力因子。这种毒素通过破坏内化囊泡，将细菌释放到其复制生态位（细胞质）中，促进单增李斯特氏菌在巨噬细胞和多种非吞噬细胞中的细胞内存活。中性粒细胞是先天免疫细胞，在控制感染中发挥重要作用，但尚不清楚 LLO 是否可以赋予中性粒细胞中单核细胞增生李斯特菌生存优势。我们报道 LLO 可以增强人类中性粒细胞的吞噬效率，但无法保护单核细胞增生李斯特菌免受细胞内杀伤。为了解释中性粒细胞中单核细胞增多性李斯特菌存活的缺失，我们假设中性粒细胞脱粒导致形成吞噬体中 LLO 中和分子的释放。支持这一点的是，单核细胞增生利斯特氏菌是中性粒细胞脱颗粒的有效诱导剂，因为它的毒力因子（例如LLO）促进颗粒胞吐作用。在与单核细胞增生李斯特菌相互作用的最初几分钟内，颗粒可以在吞噬体关闭之前与细菌相互作用位点的质膜融合。此外，颗粒产品可直接降解 LLO，不可逆地抑制其活性。储存在次级颗粒中的基质金属蛋白酶-8 被鉴定为一种降解 LLO 的内切蛋白酶，并且阻断中性粒细胞蛋白酶可增加单增李斯特菌的细胞内存活率。总之，我们提出，在吞噬过程中，基质金属蛋白酶 8 降解 LLO 可保护中性粒细胞膜免于穿孔，并有助于将单核细胞增生李斯特菌维持在杀菌性吞噬体中，使其无法逃脱。
The pore-forming toxin listeriolysin O (LLO) is a major virulence factor secreted by the facultative intracellular pathogen Listeria monocytogenes. This toxin facilitates L. monocytogenes intracellular survival in macrophages and diverse nonphagocytic cells by disrupting the internalization vesicle, releasing the bacterium into its replicative niche, the cytosol. Neutrophils are innate immune cells that play an important role in the control of infections, yet it was unknown if LLO could confer a survival advantage to L. monocytogenes in neutrophils. We report that LLO can enhance the phagocytic efficiency of human neutrophils and is unable to protect L. monocytogenes from intracellular killing. To explain the absence of L. monocytogenes survival in neutrophils, we hypothesized that neutrophil degranulation leads to the release of LLO-neutralizing molecules in the forming phagosome. In support of this, L. monocytogenes is a potent inducer of neutrophil degranulation, since its virulence factors, such as LLO, facilitate granule exocytosis. Within the first few minutes of interaction with L. monocytogenes, granules can fuse with the plasma membrane at the bacterial interaction site before closure of the phagosome. Furthermore, granule products directly degrade LLO, irreversibly inhibiting its activity. The matrix metalloproteinase-8, stored in secondary granules, was identified as an endoprotease that degrades LLO, and blocking neutrophil proteases increased L. monocytogenes intracellular survival. In conclusion, we propose that LLO degradation by matrix metalloproteinase-8 during phagocytosis protects neutrophil membranes from perforation and contributes to maintaining L. monocytogenes in a bactericidal phagosome from which it cannot escape.