Manganese acquisition is essential for virulence of Enterococcus faecalis
Manganese acquisition is essential for virulence of Enterococcus faecalis
复制标题
DOI：
10.1371/journal.ppat.1007102
复制
发表时间：
2018-09-01
期刊：
影响因子：
6.7
通讯作者：
Lemos, Jose A.
中科院分区：
文献类型：
--
作者：
Colomer-Winter, Cristina;Flores-Mireles, Ana L.;Lemos, Jose A.
锰（Mn）是一种必需的微量营养素，由于被称为营养免疫的主动宿主防御机制，在感染期间不易被病原体获得。为了克服这种营养限制，细菌利用高亲和力转运蛋白，使它们能够与宿主金属结合蛋白竞争。尽管锰在细菌发病机制中的作用已经确定，但锰在大肠杆菌病理生理学中的相关性知之甚少。粪便。在这里，我们确定和特点的主要锰收购系统的E。粪便。我们发现，ABC型通透酶EfaCBA和两个Nramp型转运蛋白，名为MntH1和MntH2，共同工作，以促进锰限制条件下的细胞生长。EfaCBA、MntH1和MntH2（Delta efa Delta mntH1 Delta mntH2菌株）的同时灭活导致细胞Mn含量急剧降低（> 95%），离体体液（血清和尿液）严重生长缺陷，大蜡螟菌毒力显著丧失，兔心内膜炎和鼠导管相关尿路感染（CITTI）模型中毒力几乎完全丧失。尽管在体外或离体条件下以及在无脊椎动物模型中EfaCBA、MntH1和MntH2存在功能冗余，但efaCBA和mntH2（Delta efa Delta mntH2菌株）的双重失活足以促使对钙卫蛋白（一种锰和锌螯合宿主抗菌蛋白）的最大敏感性，并使哺乳动物模型中的毒力丧失。有趣的是，EfaCBA似乎在全身感染期间起着突出的作用，而MntH2在CRTTI期间更重要。EfaCBA和MntH2在这些网站中的不同作用可以归因于，至少部分地，从心脏或膀胱分离的细胞中的efaA和mntH2的差异表达。总的来说，这项研究表明，锰的收购是必不可少的致病E。faecalis和验证锰吸收系统作为有前途的目标，为新的抗菌剂的发展。
Manganese (Mn) is an essential micronutrient that is not readily available to pathogens during infection due to an active host defense mechanism known as nutritional immunity. To overcome this nutrient restriction, bacteria utilize high-affinity transporters that allow them to compete with host metal-binding proteins. Despite the established role of Mn in bacterial pathogenesis, little is known about the relevance of Mn in the pathophysiology of E. faecalis. Here, we identified and characterized the major Mn acquisition systems of E. faecalis. We discovered that the ABC-type permease EfaCBA and two Nramp-type transporters, named MntH1 and MntH2, work collectively to promote cell growth under Mn-restricted conditions. The simultaneous inactivation of EfaCBA, MntH1 and MntH2 (Delta efa Delta mntH1 Delta mntH2 strain) led to drastic reductions (> 95%) in cellular Mn content, severe growth defects in body fluids (serum and urine) ex vivo, significant loss of virulence in Galleria mellonella, and virtually complete loss of virulence in rabbit endocarditis and murine catheter-associated urinary tract infection (CAUTI) models. Despite the functional redundancy of EfaCBA, MntH1 and MntH2 under in vitro or ex vivo conditions and in the invertebrate model, dual inactivation of efaCBA and mntH2 (Delta efa Delta mntH2 strain) was sufficient to prompt maximal sensitivity to calprotectin, a Mn-and Zn-chelating host antimicrobial protein, and for the loss of virulence in mammalian models. Interestingly, EfaCBA appears to play a prominent role during systemic infection, whereas MntH2 was more important during CAUTI. The different roles of EfaCBA and MntH2 in these sites could be attributed, at least in part, to the differential expression of efaA and mntH2 in cells isolated from hearts or from bladders. Collectively, this study demonstrates that Mn acquisition is essential for the pathogenesis of E. faecalis and validates Mn uptake systems as promising targets for the development of new antimicrobials.