Bacteria can utilize copper (Cu) as a trace element to support cellular processes; however, excess Cu can intoxicate bacteria. Here, we characterize the cop operon in group B streptococcus (GBS) and establish its role in evasion of Cu intoxication and the response to Cu stress on virulence. Growth of a GBS mutant deficient in the copA Cu exporter was severely compromised under Cu stress conditions. GBS survival of Cu stress reflected a mechanism of CopY derepression of the CopA efflux system. However, neither mutant was attenuated for intracellular survival in macrophages. Analysis of global transcriptional responses to Cu by RNA sequencing (RNA-seq) revealed a stress signature encompassing homeostasis of multiple metals. Genes induced by Cu stress included putative metal transporters for manganese import, whereas a system for iron export was repressed. In addition, copA promoted the ability of GBS to colonize the blood, liver, and spleen of mice following disseminated infection. Together, these findings show that GBS copA mediates resistance to Cu intoxication via regulation by the Cu-sensing transcriptional repressor copY. Cu stress responses in GBS reflect a transcriptional signature that heightens virulence and represents an important part of the bacterium's ability to survive in different environments. IMPORTANCE Understanding how bacteria manage cellular levels of metal ions, such as copper, helps to explain how microbial cells can survive in different stressful environments. We show the opportunistic pathogen group B streptococcus (GBS) achieve homeostasis of intracellular copper through the activities of the genes that comprise the cop operon, and we describe how this helps GBS survive in stressful environments, including in the mammalian host during systemic disseminated infection.
Keywords: CopA; bacterial pathogenesis; copper efflux; group B streptococcus; metal ions; metallobiology.