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

Publication ,  Journal Article
Das, S; Saqib, M; Meng, RC; Chittur, SV; Guan, Z; Wan, F; Sun, W
Published in: Proc Natl Acad Sci U S A
January 11, 2022

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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

January 11, 2022

Volume

119

Issue

2

Location

United States

Related Subject Headings

  • Yersinia pseudotuberculosis Infections
  • Yersinia pseudotuberculosis
  • Transcriptome
  • Signal Transduction
  • Siderophores
  • Repressor Proteins
  • NF-kappa B
  • Myosin-Light-Chain Kinase
  • Mice
  • Intestines
 

Citation

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Das, S., Saqib, M., Meng, R. C., Chittur, S. V., Guan, Z., Wan, F., & Sun, W. (2022). Hemochromatosis drives acute lethal intestinal responses to hyperyersiniabactin-producing Yersinia pseudotuberculosis. Proc Natl Acad Sci U S A, 119(2). https://doi.org/10.1073/pnas.2110166119
Das, Shreya, Mohd Saqib, Ryan C. Meng, Sridar V. Chittur, Ziqiang Guan, Fengyi Wan, and Wei Sun. “Hemochromatosis drives acute lethal intestinal responses to hyperyersiniabactin-producing Yersinia pseudotuberculosis.Proc Natl Acad Sci U S A 119, no. 2 (January 11, 2022). https://doi.org/10.1073/pnas.2110166119.
Das S, Saqib M, Meng RC, Chittur SV, Guan Z, Wan F, et al. Hemochromatosis drives acute lethal intestinal responses to hyperyersiniabactin-producing Yersinia pseudotuberculosis. Proc Natl Acad Sci U S A. 2022 Jan 11;119(2).
Das, Shreya, et al. “Hemochromatosis drives acute lethal intestinal responses to hyperyersiniabactin-producing Yersinia pseudotuberculosis.Proc Natl Acad Sci U S A, vol. 119, no. 2, Jan. 2022. Pubmed, doi:10.1073/pnas.2110166119.
Das S, Saqib M, Meng RC, Chittur SV, Guan Z, Wan F, Sun W. Hemochromatosis drives acute lethal intestinal responses to hyperyersiniabactin-producing Yersinia pseudotuberculosis. Proc Natl Acad Sci U S A. 2022 Jan 11;119(2).
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

January 11, 2022

Volume

119

Issue

2

Location

United States

Related Subject Headings

  • Yersinia pseudotuberculosis Infections
  • Yersinia pseudotuberculosis
  • Transcriptome
  • Signal Transduction
  • Siderophores
  • Repressor Proteins
  • NF-kappa B
  • Myosin-Light-Chain Kinase
  • Mice
  • Intestines