title: Hereditary Hemochromatosis Predisposes Mice to Yersinia pseudotuberculosis Infection Even in the Absence of the Type III Secretion System.
abstract: The iron overload disorder hereditary hemochromatosis (HH) predisposes humans to serious disseminated infection with pathogenic Yersinia as well as several other pathogens. Recently, we showed that the iron-sulfur cluster coordinating transcription factor IscR is required for type III secretion in Y. pseudotuberculosis by direct control of the T3SS master regulator LcrF. In E. coli and Yersinia, IscR levels are predicted to be regulated by iron bioavailability, oxygen tension, and oxidative stress, such that iron depletion should lead to increased IscR levels. To investigate how host iron overload influences Y. pseudotuberculosis virulence and the requirement for the Ysc type III secretion system (T3SS), we utilized two distinct murine models of HH: hemojuvelin knockout mice that mimic severe, early-onset HH as well as mice with the Hfe (C282Y∕C282Y) mutation carried by 10% of people of Northern European descent, associated with adult-onset HH. Hjv (-∕-) and Hfe (C282Y∕C282Y) transgenic mice displayed enhanced colonization of deep tissues by Y. pseudotuberculosis following oral inoculation, recapitulating enhanced susceptibility of humans with HH to disseminated infection with enteropathogenic Yersinia. Importantly, HH mice orally infected with Y. pseudotuberculosis lacking the T3SS-encoding virulence plasmid, pYV, displayed increased deep tissue colonization relative to wildtype mice. Consistent with previous reports using monocytes from HH vs. healthy donors, macrophages isolated from Hfe (C282Y∕C282Y) mice were defective in Yersinia uptake compared to wildtype macrophages, indicating that the anti-phagocytic property of the Yersinia T3SS plays a less important role in HH animals. These data suggest that Yersinia may rely on distinct virulence factors to cause disease in healthy vs. HH hosts.
authors.affiliation: Department of Microbiology and Environmental Toxicology, University of California Santa Cruz Santa Cruz, CA, USA.
authors.forename: Halie K
authors.initials: HK
authors.lastname: Miller
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California Santa Cruz Santa Cruz, CA, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Schwiesow
authors.affiliation: Department of Microbiology and Environmental Toxicology, University of California Santa Cruz Santa Cruz, CA, USA.
authors.forename: Winnie
authors.initials: W
authors.lastname: Au-Yeung
authors.affiliation: Department of Microbiology and Environmental Toxicology, University of California Santa Cruz Santa Cruz, CA, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Auerbuch
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D058851:GPI-Linked Proteins; D030342:Genetic Diseases, Inborn / Q000150:complications*; D020022:Genetic Predisposition to Disease; D006432:Hemochromatosis / Q000150:complications*; D000071020:Hemochromatosis Protein / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008565:Membrane Proteins / Q000172:deficiency; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics; D000069296:Type III Secretion Systems / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*; D015011:Yersinia pseudotuberculosis / Q000472:pathogenicity; D015012:Yersinia pseudotuberculosis Infections / Q000235:genetics*
chemical_list: D058851:GPI-Linked Proteins; C103673:HFE protein, human; C504414:HJV protein, mouse; D000071020:Hemochromatosis Protein; D008565:Membrane Proteins; D050505:Mutant Proteins; D000069296:Type III Secretion Systems; D037521:Virulence Factors
keywords: HFE; IscR; Yersinia pseudotuberculosis; hemochromatosis; hemojuvelin; type III secretion system