Specific Monoclonal Antibody Overcomes the Salmonella enterica Serovar Typhimurium's Adaptive Mechanisms of Intramacrophage Survival and Replication.
Specific Monoclonal Antibody Overcomes the Salmonella enterica Serovar Typhimurium's Adaptive Mechanisms of Intramacrophage Survival and Replication.
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DOI：
10.1371/journal.pone.0151352
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Eguchi M
中科院分区：
文献类型：
--
作者：
Aribam SD;Harada T;Elsheimer-Matulova M;Iwata T;Kanehira K;Hikono H;Matsui H;Ogawa Y;Shimoji Y;Eguchi M
沙门氏菌特异性抗体在宿主免疫中起着重要作用，但由于以往对抗体介导的保护作用的研究结果不一致，因此，病原菌特异性抗体清除沙门氏菌的机制仍未完全阐明。这些不一致至少部分归因于使用了针对沙门氏菌抗原的多克隆抗体。在这里，我们开发了一种新的单抗(MAb)-449，并鉴定了其相关免疫原，以保护BALB/c小鼠免受鼠伤寒沙门氏菌的感染。此外，这些数据表明，mAb-449免疫原可能是主要的保护性抗原。利用体外感染研究，我们还分析了mAb-449提供宿主保护的机制。值得注意的是，感染单抗-449处理的鼠伤寒沙门氏菌的巨噬细胞与感染对照免疫球蛋白处理的细菌的巨噬细胞相比，显示出更强的病原体摄取。此外，这些巨噬细胞产生高水平的促炎细胞因子肿瘤坏死因子α和一氧化氮，表明mAb449增强了巨噬细胞的激活。最后，在mAb449激活的巨噬细胞中，细胞内细菌数量显著减少，而在免疫球蛋白处理的对照组中发现相反的情况。基于这些发现，我们认为，尽管鼠伤寒沙门氏菌具有在巨噬细胞内存活和复制的潜力，但宿主产生的特定抗体可以有效地介导巨噬细胞的激活，以清除细胞内的细菌。
Salmonella-specific antibodies play an important role in host immunity; however, the mechanisms of Salmonella clearance by pathogen-specific antibodies remain to be completely elucidated since previous studies on antibody-mediated protection have yielded inconsistent results. These inconsistencies are at least partially attributable to the use of polyclonal antibodies against Salmonella antigens. Here, we developed a new monoclonal antibody (mAb)-449 and identified its related immunogen that protected BALB/c mice from infection with Salmonella enterica serovar Typhimurium. In addition, these data indicate that the mAb-449 immunogen is likely a major protective antigen. Using in vitro infection studies, we also analyzed the mechanism by which mAb-449 conferred host protection. Notably, macrophages infected with mAb-449-treated S. Typhimurium showed enhanced pathogen uptake compared to counterparts infected with control IgG-treated bacteria. Moreover, these macrophages produced elevated levels of pro-inflammatory cytokine TNFα and nitric oxide, indicating that mAb-449 enhanced macrophage activation. Finally, the number of intracellular bacteria in mAb-449-activated macrophages decreased considerably, while the opposite was found in IgG-treated controls. Based on these findings, we suggest that, although S. Typhimurium has the potential to survive and replicate within macrophages, host production of a specific antibody can effectively mediate macrophage activation for clearance of intracellular bacteria.