a Department of Oral and Molecular Microbiology , Osaka University Graduate School of Dentistry , Suita , Osaka , Japan.
b Department of Infection Control and Prevention , Osaka University Graduate School of Medicine , Suita , Osaka , Japan.
Virulence. 2017 Nov 17;8(8):1516-1524. doi: 10.1080/21505594.2017.1328333. Epub 2017 Jun 5.
Streptococcus pneumoniae is a leading cause of bacterial meningitis. Here, we investigated whether pneumococcal paralogous zinc metalloproteases contribute to meningitis onset. Findings of codon-based phylogenetic analyses indicated 3 major clusters in the Zmp family; ZmpA, ZmpC, and ZmpB, with ZmpD as a subgroup. In vitro invasion assays of human brain microvascular endothelial cells (hBMECs) showed that deletion of the zmpC gene in S. pneumoniae strain TIGR4 significantly increased bacterial invasion into hBMECs, whereas deletion of either zmpA or zmpB had no effect. In a mouse meningitis model, the zmpC deletion mutant exhibited increased invasion of the brain and was associated with increased matrix metalloproteinase-9 in plasma and mortality as compared with the wild type. We concluded that ZmpC suppresses pneumococcal virulence by inhibiting bacterial invasion of the central nervous system. Furthermore, ZmpC illustrates the evolutional theory stating that gene duplication leads to acquisition of novel function to suppress excessive mortality.
肺炎链球菌是细菌性脑膜炎的主要病因。在这里，我们研究了肺炎链球菌的同工锌金属蛋白酶是否有助于脑膜炎的发生。基于密码子的系统发育分析结果表明，Zmp 家族存在 3 个主要簇；ZmpA、ZmpC 和 ZmpB，ZmpD 为亚群。体外侵袭人脑微血管内皮细胞（hBMEC）的实验表明，肺炎链球菌 TIGR4 株中 zmpC 基因的缺失显著增加了细菌对 hBMEC 的侵袭，而 zmpA 或 zmpB 的缺失则没有影响。在小鼠脑膜炎模型中，zmpC 缺失突变体表现出对大脑的侵袭增加，并伴有血浆基质金属蛋白酶-9 的增加以及与野生型相比的死亡率增加。我们得出结论，ZmpC 通过抑制中枢神经系统的细菌入侵来抑制肺炎链球菌的毒力。此外，ZmpC 说明了基因复制导致获得新功能以抑制过度死亡率的进化理论。
