Calcium Signaling in Streptococcus pneumoniae: Implication of the Kinetics of Calcium Transport

ABSTRACT

The kinetics and pharmacological characterization of a Na⁺/Ca²⁺ exchange system, essential for the growth of the extracellular pathogen Streptococcus pneumoniae in high-calcium media, demonstrated that calcium transport, in addition to its role in calcium homeostasis, is involved in the induction of autolysis and of competence for genetic transformation. These responses are expressed respectively in cultures entering the stationary phase and growing with exponential rates. Experimental virulence also appears to be modulated by the kinetics of calcium transport. Calcium transport in S. pneumoniae is electrogenic and shows sigmoidicity, indicating a cooperative mechanism with an inflexion point at 1 mM Ca²⁺. Mutant strains with Hill number values of 4 and 1, compared to 2 in the wild-type strain, were isolated. These changes were associated with altered regulation of competence and autolysis, and also with reduced experimental virulence. By contrast, they could not be related to a specific calcium requirement for growth. This indicates that the cooperativity of Ca²⁺ transport is not involved in vegetative growth, but rather regulates competence and autolysis. Competence and autolysis represent two growth-phase-dependent responses to an oligopeptide-activator exported to the medium, the competence-stimulating peptide. Addition of this activator to noncompetent cells, triggers net and transient ⁴⁵Ca²⁺ influx. One effect of the activator might be to activate a calcium transporter by enhancing its cooperativity. In addition to an increase in intracellular calcium, a transient membrane depolarization induced by electrogenic calcium influx may be part of the signaling mechanism. The competence activator is a quorum-sensing molecule whose synthesis is autoregulated. This regulation might involve calcium-mediated signaling. As an extracellular pathogen, S. pneumoniae probably develops in niches with variable calcium concentration. Interestingly, virulence depends strongly upon the kinetics of Ca²⁺ transport. Regulation of calcium influx may represent a common mechanism of sensing the environment, if the Na⁺/Ca²⁺ exchanger is the target for external mediators including the competence activator.