Hemochromatosis drives acute lethal intestinal responses to hyperyersiniabactin-producing <i>Yersinia pseudotuberculosis</i>.

Abstract

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 hyperyersiniabactin (Ybt) producing <i>Yersinia pseudotuberculosis</i> Δ<i>fur</i> mutant (termed Δ<i>fur</i>) results in severe systemic infection and acute mortality to hemochromatotic mice due to rapid disruption of the intestinal barrier. Transcriptome analysis of Δ<i>fur</i>-infected intestine revealed up-regulation in cytokine-cytokine receptor interactions, the complement and coagulation cascade, the NF-κB signaling pathway, and chemokine signaling pathways, and down-regulation in cell-adhesion molecules and Toll-like receptor signaling pathways. Further studies indicate that dysregulated interleukin (IL)-1β signaling triggered in hemachromatotic mice infected with Δ<i>fur</i> 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 Δ<i>fur</i> infection. Moreover, early intervention of IL-1β overproduction can completely rescue hemochromatotic mice from the lethal infection.