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

Abstract

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 TCS07dependent 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.

Carbon catabolite repression on the Rgg2/3 quorum sensing system in Streptococcus pyogenes is mediated by PTSMan and Mga

“…When colonizing the mucosal surface of the human host, which is a glucose‐deplete environment, GAS will need to utilize alternative carbon sources for proliferation. As mannose is typically available in glycans of host proteins decorating the surface of cells, as well as a component of host mucins, it could be available as a carbon source to sustain cellular viability upon degradation (Andreassen et al., 2020) by GAS that are colonizing the mucosal surface. Thus, the presence of mannose could signal to GAS that it is in a host environment that is suitable for colonization, resulting in the promotion of biofilm formation mediated through the QS system (Gogos et al., 2018).…”

The two-component system YesMN promotes pneumococcal host-to-host transmission, and regulates genes involved in zinc homeostasis

“…To confirm that the TCS YesMN impacts pneumococcal shedding, we constructed mutants with unmarked, in-frame deletion of HK yesM ( ΔyesM ), the RR yesN ( ΔyesN ), or both yesMN ( ΔyesMN ). Deletion of yesMN was not associated with impaired growth (18) and all the constructed mutants in the study grew as WT type 4 isolate (data not shown).…”

“…Overexpression of the response regulator (RR) YesN in D39 (Type 2 isolate) leads to an increase in the expression of genes that code for N-linked glycan-metabolizing enzymes. Also, compared to the parental D39, ΔyesMN had a slightly reduced virulence in a lung infection model (18).…”

Pivotal Roles for Ribonucleases in Streptococcus pneumoniae Pathogenesis

“… d Member of the WalRK two-component system regulon ( 55 ). e Member of the TCS07/YesMN two-component system regulon ( 84 ). f Member of the LiaFSR two-component system regulon ( 58 ).…”