The LiaFSR-SpxA2 regulatory axis governs bile salt resistance and virulence in group B Streptococcus

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Streptococcus agalactiae, also known as Group B Streptococcus (GBS), colonizes the intestinal tract, where it must overcome bile salt-mediated membrane disruption to establish infection. However, it is unclear the specific molecular mechanisms underlying this resistance. In this study, a Himar1 transposon screen identified a bile salt hypersensitive spxA2 (SAHN016_RS09865) mutant. To elucidate how SpxA2 mediates bile salt stress adaptation and promotes GBS pathogenesis, we constructed the spxA2 deletion mutant ΔspxA2 by homologous recombination. We found that deletion of spxA2 significantly compromises membrane stability, as evidenced by a markedly increased negative surface charge and decreased hydrophobicity in the ΔspxA2 mutant. Under bile salt stress, the ΔspxA2 mutant exhibited severe membrane depolarization and compromised membrane integrity. Genetic and transcriptional analyses further revealed that the LiaFSR two-component system as the upstream regulator that significantly upregulated spxA2 transcription in response to bile salt stress, defining a novel LiaFSR-SpxA2 regulatory pathway playing a role in bile salt resistance in GBS. Importantly, this LiaFSR-SpxA2 regulatory axis plays a role in colonization and virulence in a tilapia infection model. Collectively, our work defines the LiaFSR-SpxA2 axis as a central regulator of membrane homeostasis that is critical for GBS to overcome innate host defenses, thereby facilitating intestinal colonization and the progression to systemic disease.

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