Table_3_TprA/PhrA Quorum Sensing System Has a Major Effect on Pneumococcal Survival in Respiratory Tract and Blood, and Its Activity Is Controlled by CcpA and GlnR.DOCX

Streptococcus pneumoniae is able to cause deadly diseases by infecting different tissues, each with distinct environmental and nutritional compositions. We hypothesize that the adaptive capabilities of the microbe is an important facet of pneumococcal survival in fluctuating host environments. Quorum-sensing (QS) mechanisms are pivotal for microbial host adaptation. We previously demonstrated that the TprA/PhrA QS system is required for pneumococcal utilization of galactose and mannose, neuraminidase activity, and virulence. We also showed that the system can be modulated by using linear molecularly imprinted polymers. Due to being a drugable target, we further studied the operation of this QS system in S. pneumoniae. We found that TprA controls the expression of nine different operons on galactose and mannose. Our data revealed that TprA expression is modulated by a complex regulatory network, where the master regulators CcpA and GlnR are involved in a sugar dependent manner. Mutants in the TprA/PhrA system are highly attenuated in their survival in nasopharynx and lungs after intranasal infection, and growth in blood after intravenous infection.

肺炎链球菌（Streptococcus pneumoniae）可通过侵染不同组织引发致死性疾病，而这些组织各自具有独特的环境与营养组成。我们推测，该微生物的适应能力是肺炎链球菌在波动的宿主环境中存活的重要方面。群体感应（Quorum-sensing, QS）机制是微生物适应宿主环境的关键调控途径。我们此前的研究证实，TprA/PhrA QS系统对于肺炎链球菌利用半乳糖、甘露糖，维持神经氨酸酶活性以及致病力均不可或缺。我们还发现，该系统可通过线性分子印迹聚合物进行调控。鉴于该系统可作为药物作用靶点，我们进一步探究了该QS系统在肺炎链球菌（S. pneumoniae）中的运作机制。研究发现，TprA可调控半乳糖与甘露糖代谢相关的9个不同操纵子的表达。我们的数据显示，TprA的表达处于复杂调控网络的管控之下，其中全局调控因子CcpA与GlnR以糖依赖的方式参与该调控过程。TprA/PhrA系统的突变株在经鼻内感染后，于鼻咽部与肺部的存活能力显著衰减；经静脉感染后，其在血液中的增殖能力也大幅降低。