title: Klebsiella pneumoniae yersiniabactin promotes respiratory tract infection through evasion of lipocalin 2.
abstract: Klebsiella pneumoniae is a pathogen of increasing concern because of multidrug resistance, especially due to K. pneumoniae carbapenemases (KPCs). K. pneumoniae must acquire iron to replicate, and it utilizes iron-scavenging siderophores, such as enterobactin (Ent). The innate immune protein lipocalin 2 (Lcn2) is able to specifically bind Ent and disrupt iron acquisition. To determine whether K. pneumoniae must produce Lcn2-resistant siderophores to cause disease, we examined siderophore production by clinical isolates (n = 129) from respiratory, urine, blood, and stool samples and by defined siderophore mutants through genotyping and liquid chromatography-mass spectrometry. Three categories of K. pneumoniae isolates were identified: enterobactin positive (Ent(+)) (81%), enterobactin and yersiniabactin positive (Ent(+) Ybt(+)) (17%), and enterobactin and salmochelin (glycosylated Ent) positive (Ent(+) gly-Ent(+)) with or without Ybt (2%). Ent(+) Ybt(+) strains were significantly overrepresented among respiratory tract isolates (P = 0.0068) and β-lactam-resistant isolates (P = 0.0019), including the epidemic KPC-producing clone multilocus sequence type 258 (ST258). In ex vivo growth assays, gly-Ent but not Ybt allowed evasion of Lcn2 in human serum, whereas siderophores were dispensable for growth in human urine. In a murine pneumonia model, an Ent(+) strain was an opportunistic pathogen that was completely inhibited by Lcn2 but caused severe, disseminated disease in Lcn2(-/-) mice. In contrast, an Ent(+) Ybt(+) strain was a frank respiratory pathogen, causing pneumonia despite Lcn2. However, Lcn2 retained partial protection against disseminated disease. In summary, Ybt is a virulence factor that is prevalent among KPC-producing K. pneumoniae isolates and promotes respiratory tract infections through evasion of Lcn2.
authors.affiliation: Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Bachman
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Oyler
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Burns
authors.forename: Mélissa
authors.initials: M
authors.lastname: Caza
authors.forename: François
authors.initials: F
authors.lastname: Lépine
authors.forename: Charles M
authors.initials: CM
authors.lastname: Dozois
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Weiser
mesh_terms: D000209:Acute-Phase Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000276:immunology; D000818:Animals; D001769:Blood / Q000382:microbiology; D004269:DNA, Bacterial / Q000235:genetics; D004195:Disease Models, Animal; D005243:Feces / Q000382:microbiology; D006801:Humans; D007155:Immunologic Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D007710:Klebsiella Infections / Q000276:immunology* / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity*; D000071068:Lipocalin-2; D054834:Lipocalins / Q000037:antagonists & inhibitors* / Q000276:immunology; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000276:immunology; D010636:Phenols / Q000032:analysis / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D012137:Respiratory System / Q000382:microbiology; D012141:Respiratory Tract Infections / Q000276:immunology* / Q000382:microbiology; D013844:Thiazoles / Q000032:analysis / Q000378:metabolism*; D014556:Urine / Q000382:microbiology; D014774:Virulence; D037521:Virulence Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D000209:Acute-Phase Proteins; D004269:DNA, Bacterial; D007155:Immunologic Factors; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D010636:Phenols; D011518:Proto-Oncogene Proteins; D013844:Thiazoles; D037521:Virulence Factors; C104398:yersiniabactin; C071332:Lcn2 protein, mouse