Expansion of CD101⁻ neutrophils drives susceptibility to hyperyersiniabactin-producing Yersinia infection in hereditary hemochromatotic hosts

Hereditary hemochromatosis (HH) increases susceptibility to bacterial infections. In our previous study, an oral Yersinia pseudotuberculosis Δ fur mutant (Δ fur ) infection led to intestinal barrier disruption and acute mortality in HH ( Hfe −/− ) mice. However, the systemic features of this fulminant infection are incompletely characterized. Here, HH mice infected with a hyperyersiniabactin-producing Δ fur rapidly develop sepsis symptoms, marked by an influx of immature CD101 − neutrophils with impaired bactericidal capacity and heightened inflammation, whereas infected wild-type mice harbor functional mature CD101 + neutrophils. This phenotype is partially recapitulated by the hyperyersiniabactin-producing clinical isolate, Y. enterocolitica WA strain. We further show that type I interferon (IFN-I) signaling impairs neutrophil bactericidal capacity, increasing bacterial burden, disrupting barrier disruption, and promoting emergency granulopoiesis, resulting in massive recruitment of CD101 − neutrophils in Δ fur -infected HH mice. Blocking IFN-I signaling restores neutrophil function, reduces bacterial loads, limits neutrophil recruitment, promotes a shift toward CD101 + neutrophils, preserves barrier integrity, mitigates hyperinflammation, and improves survival. These findings reveal that in HH mice infected with high-yersiniabactin producing Yersinia species, immature CD101 − neutrophils act as key mediators of sepsis, with IFN-I signaling as an essential regulator of this pathogenic response.