Zinc is an essential trace element for normal bacterial physiology but, divergently, can intoxicate bacteria at high concentrations. Here, we define the molecular systems for Zn detoxification in , also known as group B streptococcus, and examine the effects of resistance to Zn stress on virulence. We compared the growth of wild-type bacteria and mutants deleted for the Zn exporter, , and the response regulator, , using Zn-stress conditions Macrophage antibiotic protection assays and a mouse model of disseminated infection were used to assess virulence. Global bacterial transcriptional responses to Zn stress were defined by RNA sequencing and quantitative reverse transcription-PCR. and enabled to survive Zn... More
Zinc is an essential trace element for normal bacterial physiology but, divergently, can intoxicate bacteria at high concentrations. Here, we define the molecular systems for Zn detoxification in , also known as group B streptococcus, and examine the effects of resistance to Zn stress on virulence. We compared the growth of wild-type bacteria and mutants deleted for the Zn exporter, , and the response regulator, , using Zn-stress conditions Macrophage antibiotic protection assays and a mouse model of disseminated infection were used to assess virulence. Global bacterial transcriptional responses to Zn stress were defined by RNA sequencing and quantitative reverse transcription-PCR. and enabled to survive Zn stress, with the putative CzcD efflux system activated by SczA. Additional genes activated in response to Zn stress encompassed divalent cation transporters that contribute to regulation of Mn and Fe homeostasis. , the - Zn management axis supported virulence in the blood, heart, liver, and bladder. Additionally, several genes not previously linked to Zn stress in any bacterium, including, most notably, for arginine deamination, also mediated resistance to Zn stress, representing a novel molecular mechanism of bacterial resistance to metal intoxication. Taken together, these findings show that responds to Zn stress by regulation of , with additional novel mechanisms of resistance supported by , encoding arginine deaminase. Cellular management of Zn stress in supports virulence by facilitating bacterial survival in the host during systemic infection. , also known as group B streptococcus, is an opportunistic pathogen that causes various diseases in humans and animals. This bacterium has genetic systems that enable zinc detoxification in environments of metal stress, but these systems remain largely undefined. Using a combination of genomic, genetic, and cellular assays, we show that this pathogen controls Zn export through CzcD to manage Zn stress and utilizes a system of arginine deamination never previously linked to metal stress responses in bacteria to survive metal intoxication. We show that these systems are crucial for survival of during Zn stress and also enhance virulence during systemic infection in mice. These discoveries establish new molecular mechanisms of resistance to metal intoxication in bacteria; we suggest these mechanisms operate in other bacteria as a way to sustain microbial survival under conditions of metal stress, including in host environments.
