title: The pathogen-associated iroA gene cluster mediates bacterial evasion of lipocalin 2.
abstract: Numerous bacteria cope with the scarcity of iron in their microenvironment by synthesizing small iron-scavenging molecules known as siderophores. Mammals have evolved countermeasures to block siderophore-mediated iron acquisition as part of their innate immune response. Secreted lipocalin 2 (Lcn2) sequesters the Escherichia coli siderophore enterobactin (Ent), preventing E. coli from acquiring iron and protecting mammals from infection by E. coli. Here, we show that the iroA gene cluster, found in many pathogenic strains of Gram-negative enteric bacteria, including E. coli, Salmonella spp., and Klebsiella pneumoniae, allows bacteria to evade sequestration of Ent by Lcn2. We demonstrate that C-glucosylated derivatives of Ent produced by iroA-encoded enzymes do not bind purified Lcn2, and an iroA-harboring strain of E. coli is insensitive to the growth inhibitory effects of Lcn2 in vitro. Furthermore, we show that mice rapidly succumb to infection by an iroA-harboring strain of E. coli but not its wild-type counterpart, and that this increased virulence depends on evasion of host Lcn2. Our findings indicate that the iroA gene cluster allows bacteria to evade this component of the innate immune system, rejuvenating their Ent-mediated iron-acquisition pathway and playing an important role in their virulence.
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fischbach
authors.forename: Hening
authors.initials: H
authors.lastname: Lin
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Abergel
authors.forename: David R
authors.initials: DR
authors.lastname: Liu
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Raymond
authors.forename: Barry L
authors.initials: BL
authors.lastname: Wanner
authors.forename: Roland K
authors.initials: RK
authors.lastname: Strong
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Walsh
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
authors.forename: Kelly D
authors.initials: KD
authors.lastname: Smith
mesh_terms: D000209:Acute-Phase Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D004758:Enterobactin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics* / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000235:genetics / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D000071068:Lipocalin-2; D054834:Lipocalins; D008561:Membrane Fusion; D051379:Mice; D018345:Mice, Knockout; D005810:Multigene Family / Q000235:genetics*; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D000209:Acute-Phase Proteins; D001425:Bacterial Outer Membrane Proteins; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; C083821:iroA protein, bacteria; C071332:Lcn2 protein, mouse; D004758:Enterobactin