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

Abstract

Author summary Worldwide, Streptococcus pneumoniae is the most common cause of community acquired pneumonia with high mortality rates. Interestingly, S. pneumoniae strictly relies on carbohydrate scavenging for energy acquisition, which are obtained from the host. This is a critical step in pathogenesis and a common mechanism among Streptococcal species. In this study, we discover an uncharacterized two-component system that responds to the carbohydrate structures present on the host cells. These are important findings as we describe the molecular mechanism responsible for sensing these host derived glycans, and how this mechanism is linked to virulence, thus highlighting that glycan metabolism is important for infection in vivo, thereby posing a novel target for intervention. Our phylogenetic analysis reveals that the two-component system and the genetic regulon co-occur and are specifically conserved among Streptococcal species capable of degrading host-glycans. 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.