Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
Department of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia.
PLoS Pathog. 2020 Mar 4;16(3):e1008332. doi: 10.1371/journal.ppat.1008332. eCollection 2020 Mar.
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.
链球菌属的病原体在人类宿主感染过程中栖息在许多不同的环境小生境中，细菌必须根据可用营养物质调整其代谢。尽管它们缺乏柠檬酸循环，但一些链球菌在缺乏现成碳水化合物来源的小生境中繁殖。相反，它们依靠碳水化合物的掠夺来获取能量，这些能量是从宿主那里获得的。在这里，我们发现肺炎链球菌的一个双组分系统（TCS07）对宿主细胞上存在的蛋白质上的糖缀合结构作出反应。使用下一代 RNA 测序，我们发现未表征的 TCS07 调控子编码了对宿主糖加工和释放的糖转运蛋白以及细胞内碳水化合物分解代谢酶很重要的蛋白质。我们发现功能性 TCS07 等位基因是在糖缀合模型蛋白胎球蛋白上生长所必需的。一致地，我们看到糖降解途径的 TCS07 依赖性激活。因此，我们确定了负责感知宿主衍生糖的分子成分，并将其与降解糖所需的蛋白质的诱导联系起来。此外，我们将 TCS07 调控子与小鼠模型中的毒力联系起来，从而确立了宿主衍生糖代谢对体内感染的重要性。最后，对来自链球菌属的菌株进行比较系统发育基因组分析表明，TCS07 及其大部分调控子在利用宿主糖生长的物种中特异性保守。
