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Science. 2017 Dec 22;358(6370). pii: eaao5610. doi: 10.1126/science.aao5610.

Recurrent infection progressively disables host protection against intestinal inflammation.

Author information

1
Center for Nanomedicine, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
2
Sanford Burnham Prebys Medical Discovery Institute, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
3
Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93106, USA.
4
Walter-Brendel-Centre for Experimental Medicine, Ludwig-Maximilians-University, Munich, Germany.
5
Department of Pediatrics and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
6
Center for Nanomedicine, University of California, Santa Barbara, Santa Barbara, CA 93106, USA. jmarth@sbpdiscovery.com.

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.

PMID:
29269445
PMCID:
PMC5824721
DOI:
10.1126/science.aao5610
[Indexed for MEDLINE]
Free PMC Article

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