Hemochromatosis drives acute lethal intestinal responses to hyper-yersiniabactin-producing Yersinia pseudotuberculosis

Hemachromatosis (iron-overload) increases host susceptibility to siderophilic bacterial infections that cause serious complications, but the underlying mechanisms remain elusive. The present study demonstrates that oral infection with hyper-yersiniabactin (Ybt) producing Yersinia pseudotuberculosis Δfur mutant (termed Δfur) results in severe systemic infection and acute mortality to hemochromatotic mice due to rapid disruption of the intestinal barrier. Transcriptome analysis of Δfur infected intestine revealed upregulation in cytokine-cytokine receptor interactions, the complement and coagulation cascade, the NF-κB signaling pathway, and chemokine signaling pathways, and downregulation in cell adhesion molecules and TLR signaling pathways. Further studies indicate that dysregulated IL-1b signaling triggered in hemachromatotic mice infected with Δfur damages the intestinal barrier by activation of myosin light chain kinases (MLCK) and excessive neutrophilia. Inhibiting MLCK activity or depleting neutrophil infiltration reduces barrier disruption, largely ameliorates immunopathology, and substantially rescues hemochromatotic mice from lethal Δfur infection. Moreover, early intervention of IL-1b overproduction can completely rescue hemochromatotic mice from the lethal infection. Transcriptome analysis of Yersinia pseudotuberculosis PB1 or Δfur infected intestine tissues at 3 days post infection