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

Abstract

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.

The Quorum Sensing Auto-Inducer 2 (AI-2) Stimulates Nitrogen Fixation and Favors Ethanol Production over Biomass Accumulation in Zymomonas mobilis

“…However, specific AI-2-related responses can be found in the expression of genes involved in the composition of cellular membranes and elements associated with various processes, such as bacterial motility, DNA repair, inorganic nutrient metabolism, and carbohydrate degradation. Interestingly, similar scenarios have also been observed during the QS response in additional bacterial species [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45].…”

The pneumococcal social network

“…The expression of several cell–cell communication peptides is responsive to levels of host carbohydrates: SHP144 and SHP939 are induced in mannose and galactose and PhrA in galactose. Further, these peptides, as well as PhrA2 and VP1, are repressed in rich media [ 22 , 43 , 44 , 46 ]. The Rgg144/SHP144 system is core; it is activated when the autoinducing peptide SHP144 is imported into the cell and binds Rgg144.…”

“…Instead, phrA is expressed in the presence of galactose and mannose [ 26 , 45 , 46 ]. GlnR, a regulator of glutamine and glutamate metabolism, also binds the promoter region of tprA activating its expression in the presence of multiple different sugars [ 46 ]. Thus, activation of the TprA/PhrA signaling cascade is regulated by a complex network of different metabolic pathways.…”

“…It is curious that the TprA/PhrA signaling system impacts virulence in the blood, where glucose is in abundance. Perhaps, in this setting, the impact on TprA/PhrA system may be attributed to other pathways and not to galactose and mannose metabolism [ 46 ].…”

“…Interestingly, PhrA2 from a PMEN1 strain can relieve the inhibition of the noncognate regulator TprA in a non-PMEN1 strain. PhrA is normally induced in the presence of galactose, while PhrA2 regulation has not been shown to be dependent on carbon source [ 26 , 46 ]. This crosstalk may allow the induction of PhrA in conditions where PhrA2 is induced and galactose is not the main carbon source.…”