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

Won Ho Yang, Douglas M. Heithoff, Peter V. Aziz, Benjamin Haslund-Gourley, Julia S. Westman, Sonoko Narisawa, Anthony B. Pinkerton, José Luis Millán, Victor Nizet, Michael J. Mahan, Jamey D. Marth

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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. Yang et al. develop a comparative protocol to identify mechanisms in the pathogenesis of experimental sepsis. Discrete Gram-negative pathogens elicit a TLR4-dependent host response that disrupts the homeostatic regulation of alkaline phosphatase (AP) isozymes through neuraminidase activation. AP augmentation and neuraminidase inhibition are therapeutic by maintaining the de-toxification of LPS-phosphate.

Original languageEnglish
Pages (from-to)500-513.e5
JournalCell Host and Microbe
Volume24
Issue number4
DOIs
Publication statusPublished - 2018 Oct 10

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All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Virology

Cite this

Yang, W. H., Heithoff, D. M., Aziz, P. V., Haslund-Gourley, B., Westman, J. S., Narisawa, S., Pinkerton, A. B., Millán, J. L., Nizet, V., Mahan, M. J., & Marth, J. D. (2018). Accelerated Aging and Clearance of Host Anti-inflammatory Enzymes by Discrete Pathogens Fuels Sepsis. Cell Host and Microbe, 24(4), 500-513.e5. https://doi.org/10.1016/j.chom.2018.09.011