title: The cop operon is required for copper homeostasis and contributes to virulence in Streptococcus pneumoniae.
abstract: High levels of copper are toxic and therefore bacteria must limit free intracellular levels to prevent cellular damage. In this study, we show that a number of pneumococcal genes are differentially regulated by copper, including an operon encoding a CopY regulator, a protein of unknown function (CupA) and a P1-type ATPase, CopA, which is conserved in all sequenced Streptococcus pneumoniae strains. Transcriptional analysis demonstrated that the cop operon is induced by copper in vitro, repressed by the addition of zinc and is autoregulated by the copper-responsive CopY repressor protein. We also demonstrate that the CopA ATPase is a major pneumococcal copper resistance mechanism and provide the first evidence that the CupA protein plays a role in copper resistance. Our results also show that copper homeostasis is important for pneumococcal virulence as the expression of the cop operon is induced in the lungs and nasopharynx of intranasally infected mice, and a copA(-) mutant strain, which had decreased growth in high levels of copper in vitro, showed reduced virulence in a mouse model of pneumococcal pneumonia. Furthermore, using the copA(-) mutant we observed for the first time in any bacteria that copper homeostasis also appears to be required for survival in the nasopharynx.
authors: Department of Genetics, University of Leicester, Leicester LE1 7RH, UK.
authors: Sulman
authors: S
authors: Shafeeq
authors: Hasan
authors: H
authors: Yesilkaya
authors: Tomas G
authors: TG
authors: Kloosterman
authors: Geetha
authors: G
authors: Narayanan
authors: Michal
authors: M
authors: Wandel
authors: Peter W
authors: PW
authors: Andrew
authors: Oscar P
authors: OP
authors: Kuipers
authors: Julie A
authors: JA
authors: Morrissey
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D015964:Gene Expression Regulation, Bacterial; D006706:Homeostasis; D008168:Lung / Q000382:microbiology; D051379:Mice; D009305:Nasopharynx / Q000382:microbiology; D020411:Oligonucleotide Array Sequence Analysis; D011018:Pneumonia, Pneumococcal / Q000382:microbiology; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism*; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D015032:Zinc / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D027682:Cation Transport Proteins; D012097:Repressor Proteins; C065826:cop protein, Bacteria; D003300:Copper; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases; D015032:Zinc