Immature neutrophils promote sepsis in hereditary hemochromatosis hosts infected with hyper-yersiniabactin-producing Yersinia pseudotuberculosis

Hereditary hemochromatosis (HH) increases susceptibility to bacterial infections, often leading to sepsis, but underlying mechanisms are unclear. Here, we show that HH mice infected with a hyper–yersiniabactin-producing Yersinia pseudotuberculosis Δfur mutant (Δfur) rapidly develop sepsis, marked by an influx of immature, pro-inflammatory CD101⁻ neutrophils with impaired bacterial killing and enhanced NETosis, unlike mature CD101⁺ neutrophils in wild-type mice. We further demonstrate that type I interferon (IFN-I) signaling impairs neutrophil bactericidal function, increasing bacterial burden and driving emergency granulopoiesis in HH mice, in turn which results in systemic recruitment of immature CD101⁻ neutrophils. Blocking IFNAR signaling restores neutrophil function, reduces bacterial loads, limits neutrophil recruitment, and promotes a shift toward mature CD101⁺ neutrophils, ultimately reducing sepsis severity and improving survival. These findings reveal a pathogenic role for immature CD101⁻ neutrophils in driving sepsis and identify IFN-I signaling as a key regulator of this dysfunctional immune response in HH.