title: A putative P-type ATPase required for virulence and resistance to haem toxicity in Listeria monocytogenes.
abstract: Regulation of iron homeostasis in many pathogens is principally mediated by the ferric uptake regulator, Fur. Since acquisition of iron from the host is essential for the intracellular pathogen Listeria monocytogenes, we predicted the existence of Fur-regulated systems that support infection. We examined the contribution of nine Fur-regulated loci to the pathogenicity of L. monocytogenes in a murine model of infection. While mutating the majority of the genes failed to affect virulence, three mutants exhibited a significantly compromised virulence potential. Most striking was the role of the membrane protein we designate FrvA (Fur regulated virulence factor A; encoded by frvA [lmo0641]), which is absolutely required for the systemic phase of infection in mice and also for virulence in an alternative infection model, the Wax Moth Galleria mellonella. Further analysis of the ΔfrvA mutant revealed poor growth in iron deficient media and inhibition of growth by micromolar concentrations of haem or haemoglobin, a phenotype which may contribute to the attenuated growth of this mutant during infection. Uptake studies indicated that the ΔfrvA mutant is unaffected in the uptake of ferric citrate but demonstrates a significant increase in uptake of haem and haemin. The data suggest a potential role for FrvA as a haem exporter that functions, at least in part, to protect the cell against the potential toxicity of free haem.
authors.affiliation: Alimentary Pharmabiotic Centre, Department of Microbiology, University College Cork, Cork, Ireland.
authors.forename: Heather P
authors.initials: HP
authors.lastname: McLaughlin
authors.forename: Qiaobin
authors.initials: Q
authors.lastname: Xiao
authors.forename: Rosemarie B
authors.initials: RB
authors.lastname: Rea
authors.forename: Hualiang
authors.initials: H
authors.lastname: Pi
authors.forename: Pat G
authors.initials: PG
authors.lastname: Casey
authors.forename: Trevor
authors.initials: T
authors.lastname: Darby
authors.forename: Alain
authors.initials: A
authors.lastname: Charbit
authors.forename: Roy D
authors.initials: RD
authors.lastname: Sleator
authors.forename: Susan A
authors.initials: SA
authors.lastname: Joyce
authors.forename: Richard E
authors.initials: RE
authors.lastname: Cowart
authors.forename: Colin
authors.initials: C
authors.lastname: Hill
authors.forename: Phillip E
authors.initials: PE
authors.lastname: Klebba
authors.forename: Cormac G M
authors.initials: CG
authors.lastname: Gahan
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D001681:Biological Assay; D019295:Computational Biology; D024881:Drug Resistance, Bacterial / Q000187:drug effects* / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D005798:Genes, Bacterial / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D006418:Heme / Q000633:toxicity*; D006706:Homeostasis / Q000187:drug effects; D007501:Iron / Q000378:metabolism; D008089:Listeria monocytogenes / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity*; D008088:Listeriosis / Q000382:microbiology; D051379:Mice; D008969:Molecular Sequence Data; D009036:Moths / Q000187:drug effects / Q000382:microbiology; D016254:Mutagenesis, Insertional / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014774:Virulence / Q000187:drug effects / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D012097:Repressor Proteins; C068477:ferric uptake regulating proteins, bacterial; D006418:Heme; D007501:Iron; D000251:Adenosine Triphosphatases