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PepO is a target of the two-component systems VicRK and CovR required for systemic virulence of Streptococcus mutans.
Virulence ( IF 5.2 ) Pub Date : 2020-05-19 , DOI: 10.1080/21505594.2020.1767377
Lívia A Alves 1 , Tridib Ganguly 2 , Érika N Harth-Chú 1 , Jessica Kajfasz 2 , José A Lemos 2 , Jacqueline Abranches 2 , Renata O Mattos-Graner 1
Affiliation  

Streptococcus mutans, a cariogenic species, is often associated with cardiovascular infections. Systemic virulence of specific S. mutans serotypes has been associated with the expression of the collagen- and laminin-binding protein Cnm, which is transcriptionally regulated by VicRK and CovR. In this study, we characterized a VicRK- and CovR-regulated gene, pepO, coding for a conserved endopeptidase. Transcriptional and protein analyses revealed that pepO is highly expressed in S. mutans strains resistant to complement immunity (blood isolates) compared to oral isolates. Gel mobility assay, transcriptional, and Western blot analyses revealed that pepO is repressed by VicR and induced by CovR. Deletion of pepO in the Cnm+ strain OMZ175 (OMZpepO) or in the Cnm- UA159 (UApepO) led to an increased susceptibility to C3b deposition, and to low binding to complement proteins C1q and C4BP. Additionally, pepO mutants showed diminished ex vivo survival in human blood and impaired capacity to kill G. mellonella larvae. Inactivation of cnm in OMZ175 (OMZcnm) resulted in increased resistance to C3b deposition and unaltered blood survival, although both pepO and cnm mutants displayed attenuated virulence in G. mellonella. Unlike OMZcnm, OMZpepO could invade HCAEC endothelial cells. Supporting these phenotypes, recombinant proteins rPepO and rCnmA showed specific profiles of binding to C1q, C4BP, and to other plasma (plasminogen, fibronectin) and extracellular matrix proteins (type I collagen, laminin). Therefore this study identifies a novel VicRK/CovR-target required for immune evasion and host persistence, pepO, expanding the roles of VicRK and CovR in regulating S. mutans virulence.

中文翻译:

PepO 是变形链球菌全身毒力所需的双组分系统 VicRK 和 CovR 的靶标。

变形链球菌是一种致龋菌,通常与心血管感染有关。特定变形链球菌血清型的全身毒力与胶原蛋白和层粘连蛋白结合蛋白 Cnm 的表达有关,Cnm 受 VicRK 和 CovR 转录调节。在这项研究中,我们鉴定了 VicRK 和 CovR 调节基因 pepO,它编码保守的内肽酶。转录和蛋白质分析表明,与口服分离株相比,pepO 在对补体免疫具有抗性的变形链球菌菌株(血液分离株)中高度表达。凝胶迁移率测定、转录和蛋白质印迹分析表明,pepO 被 VicR 抑制并被 CovR 诱导。Cnm+菌株 OMZ175 (OMZpepO) 或 Cnm-UA159 (UApepO) 中 pepO 的缺失导致对 C3b 沉积的敏感性增加,以及与补体蛋白 C1q 和 C4BP 的低结合。此外,pepO 突变体在人血液中的离体存活率降低,杀死大蜡螟幼虫的能力受损。OMZ175 (OMZcnm) 中 cnm 的失活导致对 C3b 沉积的抵抗力增加,血液存活率不变,尽管 pepO 和 cnm 突变体在大蜡螟中表现出毒力减弱。与 OMZcnm 不同,OMZpepO 可以侵入 HCAEC 内皮细胞。支持这些表型的是,重组蛋白 rPepO 和 rCnmA 显示出与 C1q、C4BP 以及其他血浆(纤溶酶原、纤连蛋白)和细胞外基质蛋白(I 型胶原、层粘连蛋白)结合的特异性特征。因此,本研究确定了免疫逃避和宿主持久性所需的新型 VicRK/CovR 靶标 pepO,扩大了 VicRK 和 CovR 在调节变形链球菌毒力方面的作用。
更新日期:2020-05-19
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