期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2110166119
关键词
hemochromatosis; Yersinia pseudotuberculosis; siderophore; hyperinflammation; lethal infection
资金
- NIH [R01AI125623, R01AI148366, R21AI137719]
Hemachromatosis increases susceptibility to siderophilic bacterial infections. The study found that infection with Yersinia pseudotuberculosis Delta fur mutant disrupts the intestinal barrier and triggers inflammatory responses in hemochromatotic mice, leading to severe systemic infection and mortality. Inhibiting specific molecule activity or intervening in the inflammatory signaling pathways can partially or completely rescue hemochromatotic mice from lethal infection.
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 Delta fur mutant (termed Delta fur) results in severe systemic infection and acute mortality to hemochromatotic mice due to rapid disruption of the intestinal barrier. Transcriptome analysis of Delta fur-infected intestine revealed up-regulation in cytokine-cytokine receptor interactions, the complement and coagulation cascade, the NF-kappa B 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)-1 beta signaling triggered in hemachromatotic mice infected with Delta fur 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 Delta fur infection. Moreover, early intervention of IL-1 beta overproduction can completely rescue hemochromatotic mice from the lethal infection.
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