Gene regulatory mechanisms of metabolic adaptation in Neisseria meningitidis in ex vivo infection models

脑膜炎奈瑟菌通常作为一种共生细菌生活在人类上呼吸道，但偶尔也会引起危及生命的疾病，如败血症和急性细菌性脑膜炎。脑膜炎球菌毒力的遗传基础仍然是谜，到目前为止，比较基因组学还未能确定脑膜炎奈索菌的经典毒力基因集。然而，最近在体内模拟条件下对携带菌株和侵入菌株的全转录组比较显示，脑膜炎球菌核心基因组中许多代谢基因的调节存在巨大差异。特别是，脑膜炎球菌在全血中的存活对引起侵袭性疾病至关重要，似乎通过严格的反应与细菌代谢状态有关。我们还发现严格反应通路和其他信号网络（包括sigma- E和MisR调控）之间存在串扰的证据。从这些数据中出现了代谢与脑膜炎球菌毒力密切相关的新情况，因此代谢调节的遗传因素可能包括一类新的脑膜炎球菌毒力相关基因。因此，在这个项目中，我们将(i)分析脑膜炎球菌的严格反应途径及其对细菌细胞血流存活的贡献，（ii）表征在载体和侵入菌株的离体条件下发现的差异调节的规则。

Neisseria meningitidis usually lives as a commensal bacterium in the upper airways of humans but occasionally can also cause life threatening diseases such as sepsis and acute bacterial meningitis. The genetic basis of meningococcal virulence is still enigmatic, and so far comparative genomics has failed to identify a classical virulence gene set in N. meningitidis. However, recent whole-transcriptome comparisons of a carriage and an invasive strain under in vivo mimicking conditions revealed large differences in the regulation of numerous metabolic genes from the meningococcal core genome. In particular, meningococcal survival in whole blood which is crucial for causing invasive diseases seems to be linked to the bacterial metabolic status via the stringent response. We also found evidence for a cross-talk between the stringent response pathway and other signalling networks including the sigma- E and the MisR regulons. From these data a new picture is emerging where metabolism is closely linked to meningococcal virulence, and genetic factors of metabolic regulation might therefore comprise a novel class of meningococcal virulence-associated genes. Accordingly, in this project we will (i) analyse the meningococcal stringent response pathway and its contribution to blood stream survival of bacterial cells, and (ii) characterize the regulons found to be differentially regulated under ex vivo conditions in a carriage and an invasive strain.