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

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


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase / genetics
  • Alkaline Phosphatase / metabolism*
  • Animals
  • Disease Models, Animal
  • Escherichia coli / pathogenicity
  • Escherichia coli Infections / blood
  • Escherichia coli Infections / enzymology
  • Escherichia coli Infections / microbiology*
  • Escherichia coli Infections / pathology
  • Host-Pathogen Interactions*
  • Humans
  • Inflammation / blood
  • Inflammation / enzymology
  • Inflammation / microbiology
  • Inflammation / pathology
  • Lipopolysaccharides / metabolism*
  • Mice
  • Mice, Knockout
  • Neuraminidase / genetics
  • Neuraminidase / metabolism*
  • Salmonella Infections / blood
  • Salmonella Infections / enzymology
  • Salmonella Infections / microbiology*
  • Salmonella Infections / pathology
  • Salmonella typhimurium / pathogenicity
  • Sepsis / blood
  • Sepsis / enzymology
  • Sepsis / microbiology*
  • Sepsis / pathology
  • Toll-Like Receptor 4 / drug effects


  • Lipopolysaccharides
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Alkaline Phosphatase
  • Neu1 protein, mouse
  • Neu3 protein, mouse
  • Neuraminidase