title: High-affinity Zn2+ uptake system ZnuABC is required for bacterial zinc homeostasis in intracellular environments and contributes to the virulence of Salmonella enterica.
abstract: To investigate the relevance of zinc in host-pathogen interactions, we have constructed Salmonella enterica mutant strains in which the znuA gene, which encodes the periplasmic component of the ZnuABC high-affinity Zn2+ transporter, was deleted. This mutation does not alter the ability of Salmonella to grow in rich media but drastically reduces its ability to multiply in media deprived of zinc. In agreement with this phenotype, ZnuA accumulates only in bacteria cultivated in environments poor in zinc. In spite of the nearly millimolar intracellular concentration of zinc, we have found that znuA is highly expressed in intracellular salmonellae recovered either from cultivated cells or from the spleens of infected mice. We have also observed that znuA mutants are impaired in their ability to grow in Caco-2 epithelial cells and that bacteria starved for zinc display decreased ability to multiply in phagocytes. A dramatic reduction in the pathogenicity of the znuA mutants was observed in Salmonella-susceptible (BALB/c) or Salmonella-resistant (DBA-2) mice infected intraperitoneally or orally. This study shows that the amount of free metals available for bacterial growth within the infected animal is limited, despite the apparent elevated concentration of free metals within cells and in plasma and suggests that Salmonella exploits the ZnuABC zinc transporter to maximize zinc availability in such conditions. These results shed new light on the complex functions of zinc in vertebrate and bacterial physiology and pave the way for a better comprehension of pathogenic mechanisms in Salmonella infections.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Roma, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Ammendola
authors.forename: Paolo
authors.initials: P
authors.lastname: Pasquali
authors.forename: Claudia
authors.initials: C
authors.lastname: Pistoia
authors.forename: Paola
authors.initials: P
authors.lastname: Petrucci
authors.forename: Patrizia
authors.initials: P
authors.lastname: Petrarca
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rotilio
authors.forename: Andrea
authors.initials: A
authors.lastname: Battistoni
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D001692:Biological Transport; D027682:Cation Transport Proteins / Q000378:metabolism*; D002460:Cell Line; D004777:Environment; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D019779:Salmonella enterica / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity; D014774:Virulence; D015032:Zinc / Q000172:deficiency / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; D027682:Cation Transport Proteins; C464647:ZnuC protein, Salmonella enterica; D015032:Zinc