Regulatory cross-talk supports resistance to Zn intoxication in Streptococcus

Sullivan, Matthew J. ORCID:, Goh, Kelvin G. K. and Ulett, Glen C. (2022) Regulatory cross-talk supports resistance to Zn intoxication in Streptococcus. PLoS Pathogens, 18 (7). ISSN 1553-7374

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Metals such as copper (Cu) and zinc (Zn) are important trace elements that can affect bacterial cell physiology but can also intoxicate bacteria at high concentrations. Discrete genetic systems for management of Cu and Zn efflux have been described in several bacterial pathogens, including streptococci. However, insight into molecular cross-talk between systems for Cu and Zn management in bacteria that drive metal detoxification, is limited. Here, we describe a biologically consequential cross-system effect of metal management in group B Streptococcus (GBS) governed by the Cu-responsive copY regulator in response to Zn. RNAseq analysis of wild-type (WT) and copY-deficient GBS subjected to metal stress revealed unique transcriptional links between the systems for Cu and Zn detoxification. We show that the Cu-sensing role of CopY extends beyond Cu and enables CopY to regulate Cu and Zn stress responses that effect changes in gene function for central cellular processes, including riboflavin synthesis. CopY also supported GBS intracellular survival in human macrophages and virulence during disseminated infection in mice. In addition, we show a novel role for CovR in modulating GBS resistance to Zn intoxication. Identification of the Zn resistome of GBS using TraDIS revealed a suite of genes essential for GBS growth in metal stress. Several of the genes identified are novel to systems that support bacterial survival in metal stress and represent a diverse set of mechanisms that underpin microbial metal homeostasis during cell stress. Overall, this study reveals a new and important mechanism of cross-system complexity driven by CopY in bacteria to regulate cellular management of metal stress and survival.

Item Type: Article
Additional Information: Data Availability: GEO and NCBI Data Deposits as described in manuscript have the following accession numbers: GSE167894 for WT S. agalactiae 874391 control condition; GSE161127 for WT S. agalactiae 874391 Zn condition; GSE167898 for 'delta'covR S. agalactiae 874391 control condition; GSE167899 for 'delta'covR S. agalactiae 874391 Zn condition; GSE167896 for 'delta'copY S. agalactiae 874391 control condition; GSE167031 for 'delta'copY S. agalactiae 874391 Zn condition ( TraDIS reads are deposited in the Sequence Read Archive (SRA) under BioProject ID: PRJNA674399 (
Uncontrolled Keywords: parasitology,microbiology,immunology,molecular biology,genetics,virology ,/dk/atira/pure/subjectarea/asjc/2400/2405
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 17 Aug 2022 12:32
Last Modified: 23 Oct 2022 06:35
DOI: 10.1371/journal.ppat.1010607


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