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 journalArticle

13 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

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Alkaline Phosphatase
Inflammation
Infection
Toll-Like Receptor 4
Salmonella enterica
Neuraminidase
Salmonella typhimurium
Zanamivir
Foodborne Diseases
Colitis
Inflammatory Bowel Diseases
Antiviral Agents
Lipopolysaccharides
Stomach
Colon
Phosphates
Ligands
Therapeutics

All Science Journal Classification (ASJC) codes

  • General

Cite this

Yang, W. H., Heithoff, D. M., Aziz, P. V., Sperandio, M., Nizet, V., Mahan, M. J., & Marth, J. D. (2017). Recurrent infection progressively disables host protection against intestinal inflammation. Science, 358(6370), [eaao5610]. https://doi.org/10.1126/science.aao5610
Yang, Won Ho ; Heithoff, Douglas M. ; Aziz, Peter V. ; Sperandio, Markus ; Nizet, Victor ; Mahan, Michael J. ; Marth, Jamey D. / Recurrent infection progressively disables host protection against intestinal inflammation. In: Science. 2017 ; Vol. 358, No. 6370.
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Yang, WH, Heithoff, DM, Aziz, PV, Sperandio, M, Nizet, V, Mahan, MJ & Marth, JD 2017, 'Recurrent infection progressively disables host protection against intestinal inflammation', Science, vol. 358, no. 6370, eaao5610. https://doi.org/10.1126/science.aao5610

Recurrent infection progressively disables host protection against intestinal inflammation. / Yang, Won Ho; Heithoff, Douglas M.; Aziz, Peter V.; Sperandio, Markus; Nizet, Victor; Mahan, Michael J.; Marth, Jamey D.

In: Science, Vol. 358, No. 6370, eaao5610, 22.12.2017.

Research output: Contribution to journalArticle

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Yang WH, Heithoff DM, Aziz PV, Sperandio M, Nizet V, Mahan MJ et al. Recurrent infection progressively disables host protection against intestinal inflammation. Science. 2017 Dec 22;358(6370). eaao5610. https://doi.org/10.1126/science.aao5610