Hemochromatosis drives acute lethal intestinal responses to hyperyersiniabactin-producing Yersinia pseudotuberculosis

Shreya Das, Mohd Saqib, Ryan C. Meng, Sridar V. Chittur, Ziqiang Guan, Fengyi Wan, Wei Sun

Research output: Contribution to journalArticlepeer-review

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 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 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 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-1β overproduction can completely rescue hemochromatotic mice from the lethal infection.

Original languageEnglish (US)
Article numbere2110166119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number2
DOIs
StatePublished - Jan 11 2022

Keywords

  • Hemochromatosis
  • Hyperinflammation
  • Lethal infection
  • Siderophore
  • Yersinia pseudotuberculosis

ASJC Scopus subject areas

  • General

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