Recurrent infection progressively disables host protection against intestinal inflammation

Won Ho Yang, Douglas M. Heithoff, Peter V. Aziz, Markus Sperandio, Victor Nizet, Michael J. Mahan, Jamey D. Marth

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

Intestinal inflammation is the central pathological feature of colitis and the inflammatory bowel diseases. These syndromes arise from unidentified environmental factors. We found that recurrent nonlethal gastric infections of Gram-negative Salmonella enterica Typhimurium (ST), a major source of human food poisoning, caused inflammation of murine intestinal tissue, predominantly the colon, which persisted after pathogen clearance and irreversibly escalated in severity with repeated infections. ST progressively disabled a host mechanism of protection by inducing endogenous neuraminidase activity, which accelerated the molecular aging and clearance of intestinal alkaline phosphatase (IAP). Disease was linked to a Toll-like receptor 4 (TLR4)–dependent mechanism of IAP desialylation with accumulation of the IAP substrate and TLR4 ligand, lipopolysaccharide-phosphate. The administration of IAP or the antiviral neuraminidase inhibitor zanamivir was therapeutic by maintaining IAP abundance and function.

Original languageEnglish
Article numbereaao5610
JournalScience
Volume358
Issue number6370
DOIs
Publication statusPublished - 2017 Dec 22

Bibliographical note

Funding Information:
This research was funded by NIH grants HL125352 (J.D.M. and V.N.) and HL131474 (J.D.M., M.J.M., and V.N.). Additional support was provided by the Wille Family Foundation (J.D.M.) and by SFB914 from the German Research Foundation (M.S.). The data presented in this study are in the main text and in the Supplementary Materials. W.H.Y., D.M.H., P.V.A., M.J.M., and J.D.M. designed the experimental strategies. J.D.M. and M.J.M. supervised the project. W.H.Y., D.M.H., and P.V.A. performed the experiments and acquired data. All authors contributed to data analysis and manuscript preparation. The authors declare that they have no competing interests.

All Science Journal Classification (ASJC) codes

  • General

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