Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, USA.
Department of Cell and Molecular Biology, San Diego State University, San Diego, California, USA.
Infect Immun. 2018 Jun 21;86(7). doi: 10.1128/IAI.00822-17. Print 2018 Jul.
(group B [GBS]) is often a commensal bacterium that colonizes healthy adults asymptomatically and is a frequent inhabitant of the vaginal tract in women. However, in immunocompromised individuals, particularly the newborn, GBS may transition to an invasive pathogen and cause serious disease. Despite the use of the currently recommended intrapartum antibiotic prophylaxis for GBS-positive mothers, GBS remains a leading cause of neonatal septicemia and meningitis. To adapt to the various host environments encountered during its disease cycle, GBS possesses multiple two-component regulatory systems (TCSs). Here we investigated the contribution of a transcriptional regulator containing a LytTR domain, LtdR, to GBS pathogenesis. Disruption of the gene in the GBS chromosome resulted in a significant increase in bacterial invasion into human cerebral microvascular endothelial cells (hCMEC) as well as the greater penetration of the blood-brain barrier (BBB) and the development of meningitis Correspondingly, infection of hCMEC with the Δ mutant resulted in increased secretion of the proinflammatory cytokines interleukin-8 (IL-8), CXCL-1, and IL-6. Further, using a mouse model of GBS vaginal colonization, we observed that the Δ mutant was cleared more readily from the vaginal tract and also that infection with the Δ mutant resulted in increased cytokine production from human vaginal epithelial cells. RNA sequencing revealed global transcriptional differences between the Δ mutant and the parental wild-type GBS strain. These results suggest that LtdR regulates many bacterial processes that can influence GBS-host interactions to promote both bacterial persistence and disease progression.
（GBS）通常是一种共生菌，无症状地定植于健康成人，是女性阴道的常见寄居菌。然而，在免疫功能低下的个体，特别是新生儿中，GBS 可能转变为侵袭性病原体，并导致严重疾病。尽管目前推荐对 GBS 阳性母亲进行产时抗生素预防，但 GBS 仍然是新生儿败血症和脑膜炎的主要原因。为了适应其疾病周期中遇到的各种宿主环境，GBS 拥有多种双组分调节系统（TCS）。在这里，我们研究了含有 LytTR 结构域的转录调节因子 LtdR 对 GBS 发病机制的贡献。在 GBS 染色体中破坏 基因导致细菌侵入人脑血管内皮细胞（hCMEC）的显著增加，以及血脑屏障（BBB）的更大穿透和脑膜炎的发展。相应地，hCMEC 感染 Δ突变体导致促炎细胞因子白细胞介素-8（IL-8）、CXCL-1 和 IL-6 的分泌增加。此外，使用 GBS 阴道定植的小鼠模型，我们观察到 Δ突变体更容易从阴道中清除，并且感染 Δ突变体导致人阴道上皮细胞产生更多的细胞因子。RNA 测序显示 Δ突变体与亲本野生型 GBS 菌株之间存在全局转录差异。这些结果表明，LtdR 调节许多细菌过程，这些过程可以影响 GBS-宿主相互作用，促进细菌的持续存在和疾病进展。
