Group A Streptococcus AdcR Regulon Participates in Bacterial Defense against Host-Mediated Zinc Sequestration and Contributes to Virulence.

Colonization by pathogenic bacteria depends on their ability to overcome host nutritional defenses and acquire nutrients. The human pathogen group A streptococcus (GAS) encounters the host defense factor calprotectin (CP) during infection. CP inhibits GAS growth by imposing zinc (Zn) limitation. However, GAS counterstrategies to combat CP-mediated Zn limitation and the relevance of CP-GAS interactions to bacterial pathogenesis remain unknown. Here, we report that GAS upregulates the AdcR regulon in response to CP-mediated Zn limitation. The AdcR regulon includes genes encoding Zn import (), Zn sparing (), and Zn scavenging systems (, , and ). Each gene in the AdcR regulon contributes to GAS Zn acquisition and CP resistance. The Δ and Δ mutant strains were the most susceptible to CP, whereas the Δ, Δ, and Δ mutant strains displayed less CP sensitivity during growth However, the Δ mutant strain did not display an increased CP sensitivity. The varied sensitivity of the mutant strains to CP-mediated Zn limitation suggests distinct roles for individual AdcR regulon genes in GAS Zn acquisition. GAS upregulates the AdcR regulon during necrotizing fasciitis infection in WT mice but not in mice lacking CP. This suggests that CP induces Zn deficiency in the host. Finally, consistent with the results, several of the AdcR regulon genes are critical for GAS virulence in WT mice, whereas they are dispensable for virulence in mice, indicating the direct competition for Zn between CP and proteins encoded by the GAS AdcR regulon during infection.