文章基本信息

标题：Hemochromatosis drives acute lethal intestinal responses to hyperyersiniabactin-producing Yersinia pseudotuberculosis
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作者：Shreya Das ; Mohd Saqib ; Ryan C. Meng 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：2
DOI：10.1073/pnas.2110166119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Our study highlights that hemochromatotic hosts are susceptible to the siderophilic enteropathogenic Yersinia because of dysregulated interleukn (IL)-1β signaling that causes rapid disruption of the intestinal tight junction, leading to acute systemic infection. This study also poses early intervention of anti–IL-1β therapy as a potentially novel strategy for treating hemochromatotic patients with severe siderophilic bacterial infections. 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 Δ fur mutant (termed Δ fur) results in severe systemic infection and acute mortality to hemochromatotic mice due to rapid disruption of the intestinal barrier. Transcriptome analysis of Δ fur-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 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 Δ fur infection. Moreover, early intervention of IL-1β overproduction can completely rescue hemochromatotic mice from the lethal infection.
关键词：enhemochromatosisYersinia pseudotuberculosissiderophorehyperinflammationlethal infection