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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.

Hereditary Hemochromatosis Predisposes Mice to Yersinia pseudotuberculosis Infection Even in the Absence of the Type III Secretion System