Table 1.

Copper detoxification strategies of intracellular pathogens and their association with survival and virulence.

Pathogen	Locus/Gene	Function	Infection model	Phenotype of mutant during infection, relative to wild-type	Reference
Transportation
M. tuberculosis	mctB	Mycomembrane channel; efflux	Inhalational; guinea pig	Reduced bacterial burdens in lungs and lymph nodes	[63]
	ctpV	Putative inner membrane protein; efflux	Inhalational; mouse, guinea pig	Reduced lung damage and immune response, decreased mortality of mice	[64]
	ricR	Transcriptional repressor of Cu responsive regulon; Cu homeostasis	Inhalational; mouse	Mutant with constitutive repression of ricR regulon has reduced bacterial burden in lungs	[65]
S. Typhimurium	copA and golT	Inner membrane P1B-type ATPases; efflux	Peritoneal macrophages	Decreased survival of ΔcopA ΔgolTin wildtype but not ATP7aLysMcre macrophages	[27]
			RAW264.7 macrophages	Decreased survival of ΔcopA ΔgolT	[48]
			Competitive intraperitoneal challenge; mouse	Decreased survival of ΔcopA ΔgolT in livers and spleens	[27]
*E. coli	copA	Inner membrane P1B− type ATPase; efflux	RAW264.7 macrophages	Decreased survival of mutant	[26]
S. pneumoniae	copA	Inner membrane P1B− type ATPase; efflux	Intratracheal, intraperitoneal, and intravenous; mouse	Decreased survival in blood, decreased mortality of mice	[49,66]
			A549 lung epithelial cells	Decreased adherence and invasion	[49]
Sequestration
Uropathogenic E. coli	ybt	Cu-binding siderophore (yersiniabactin); sequestration, detoxification	Urinary tract infection; mouse and human	Uropathogenic E. coli expressing ybt during infection has enhanced Cu resistance Cu(II)-Ybt forms during infection	[45]
			RAW264.7 macrophages	Decreased survival of mutant in Cu-replete macrophages	[47]
Oxidation
S. Typhimurium	cueO	Multicopper oxidase; detoxification	Oral gavage; mouse	Decreased burdens in liver and spleen	[67]

^*Non-pathogenic, but provided as a model Gram-negative organism.