Host-glycan metabolism is regulated by a species-conserved two-component system in Streptococcus pneumoniae

Pathogens of the Streptococcus genus inhabit many different environmental niches during the course of an infection in a human host and the bacteria must adjust their metabolism according to available nutrients. Despite their lack of the citric-acid cycle, some streptococci proliferate in niches devoid of a readily available carbohydrate source. Instead they rely on carbohydrate scavenging for energy acquisition, which are obtained from the host. Here we discover a two-component system (TCS07) of Streptococcus pneumoniae that responds to glycoconjugated structures on proteins present on the host cells. Using next-generation RNA sequencing we find that the uncharacterized TCS07 regulon encodes proteins important for host-glycan processing and transporters of the released glycans, as well as intracellular carbohydrate catabolizing enzymes. We find that a functional TCS07 allele is required for growth on the glycoconjugated model protein fetuin. Consistently, we see a TCS07-dependent activation of the glycan degradation pathway. Thus, we pinpoint the molecular constituents responsible for sensing host derived glycans and link this to the induction of the proteins necessary for glycan degradation. Furthermore, we connect the TCS07 regulon to virulence in a mouse model, thereby establishing that host-derived glycan-metabolism is important for infection in vivo. Finally, a comparative phylogenomic analysis of strains from the Streptococcus genus reveal that TCS07 and most of its regulon is specifically conserved in species that utilize host-glycans for growth.链球菌属（Streptococcus）病原菌在人体宿主感染过程中会定植于多种不同的生态位，此类细菌必须根据可获取的营养物质调整自身代谢。尽管缺乏三羧酸循环，部分链球菌仍能在缺乏易获取碳水化合物来源的生态位中增殖，转而通过从宿主处搜寻获取碳水化合物来获取能量。本研究中，我们发现了肺炎链球菌（Streptococcus pneumoniae）的双组分系统（TCS07），该系统可响应宿主细胞表面蛋白上的糖缀合物结构。借助下一代RNA测序技术，我们发现未被表征的TCS07调节子所编码的蛋白质，对宿主糖链加工、释放糖链的转运蛋白以及胞内碳水化合物分解代谢酶均发挥重要作用。我们证实，具备功能的TCS07等位基因是在糖缀合物模型蛋白胎球蛋白上增殖所必需的。与之相符的是，我们观察到糖链降解通路的激活依赖于TCS07。综上，我们精准定位了负责感知宿主来源糖链的分子组分，并将其与糖链降解必需蛋白的诱导表达关联起来。此外，我们还在小鼠模型中将TCS07调节子与毒力关联起来，从而证实宿主来源的糖代谢对体内感染至关重要。最后，对链球菌属菌株开展的比较基因组系统发育分析显示，TCS07及其大部分调节子仅在以宿主糖链为营养进行增殖的物种中保守存在。