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Cell Host Microbe. 2018 Oct 10;24(4):500-513.e5. doi: 10.1016/j.chom.2018.09.011.

Accelerated Aging and Clearance of Host Anti-inflammatory Enzymes by Discrete Pathogens Fuels Sepsis.

Author information

1
Center for Nanomedicine, University of California Santa Barbara, Santa Barbara, California 93106, USA; Sanford-Burham-Prebys Medical Discovery Institute, University of California Santa Barbara, Santa Barbara, California 93106, USA.
2
Center for Nanomedicine, University of California Santa Barbara, Santa Barbara, California 93106, USA; Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California 93106, USA.
3
Center for Nanomedicine, University of California Santa Barbara, Santa Barbara, California 93106, USA; Sanford-Burham-Prebys Medical Discovery Institute, University of California Santa Barbara, Santa Barbara, California 93106, USA; Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California 93106, USA.
4
Sanford-Burham-Prebys Medical Discovery Institute, University of California Santa Barbara, Santa Barbara, California 93106, USA.
5
Department of Pediatrics, University of California San Diego, La Jolla, CA 92093; 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, California 93106, USA; Sanford-Burham-Prebys Medical Discovery Institute, University of California Santa Barbara, Santa Barbara, California 93106, USA; Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, California 93106, USA. Electronic address: jmarth@sbpdiscovery.org.

Abstract

Sepsis is a life-threatening inflammatory syndrome accompanying a bloodstream infection. Frequently secondary to pathogenic bacterial infections, sepsis remains difficult to treat as a singular disease mechanism. We compared the pathogenesis of murine sepsis experimentally elicited by five bacterial pathogens and report similarities among host responses to Gram-negative Salmonella and E. coli. We observed that a host protective mechanism involving de-toxification of lipopolysaccharide by circulating alkaline phosphatase (AP) isozymes was incapacitated during sepsis caused by Salmonella or E. coli through activation of host Toll-like receptor 4, which triggered Neu1 and Neu3 neuraminidase induction. Elevated neuraminidase activity accelerated the molecular aging and clearance of AP isozymes, thereby intensifying disease. Mice deficient in the sialyltransferase ST3Gal6 displayed increased disease severity, while deficiency of the endocytic lectin hepatic Ashwell-Morell receptor was protective. AP augmentation or neuraminidase inhibition diminished inflammation and promoted host survival. This study illuminates distinct routes of sepsis pathogenesis, which may inform therapeutic development.

KEYWORDS:

Ashwell-Morell receptor; Toll-like receptor 4; alkaline phosphatase; glycosylation; inflammation; lipopolysaccharide; neuraminidase; sepsis

PMID:
30308156
PMCID:
PMC6223661
[Available on 2019-10-10]
DOI:
10.1016/j.chom.2018.09.011

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