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

Abstract

SUMMARY 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.

Plasma Proteome Signature of Sepsis: a Functionally Connected Protein Network

“…Based on these results, the ST sepsis model may represent a valuable sepsis mouse model to study immune‐suppression. Future targeted proteomics and biochemical studies will help corroborate these pathogen‐specific results in connection with: 1) the well‐documented TLR4‐driven immune activation and interleukin‐mediated immune‐suppression; 2) a recent report by our group showing that the alkaline phosphatases IAP and TNAP decrease during sepsis in the ST and EC models (Gram‐negative), but not in the MRSA and SPN (Gramm‐negative) . Due to their low abundance in plasma these two proteins were not identified in our datasets.…”

“…Five pathogenic bacteria were used to infect mice and induce sepsis well characterized by our group . Salmonella enterica Typhimurium strain 14028 (referred to as ST in the text) is Gram‐negative and exhibits a repeating cycle of cellular internalization and shedding .…”

Macrophage galactose lectin is critical for Kupffer cells to clear aged platelets

“…AMR has the capacity to rapidly clear glycoproteins from blood circulation that have exposed galactose linkages ( Ashwell and Morell, 1974 ; Tozawa et al, 2001 ; Grewal, 2010 ; Rice et al, 2003 ; Yang et al, 2015 ). These so-called asialoglycoprotein ligands of the AMR are formed following desialylation of the nascent proteins during aging ( Yang et al, 2015 , 2018 ). Streptococcus pneumoniae and other respiratory pathogens express sialidases (neuraminidases) as virulence factors that desialylate vWF and platelets to induce an early moderate thrombocytopenia dependent upon the AMR ( Grewal et al, 2008 , 2013 ).…”

Role of the Complement Pathway in Inflammatory Skin Diseases: A Focus on Hidradenitis Suppurativa

“…Contextual pathogenicity depends on a series of host and microbial factors that may manifest as disease (Chen et al, 2018). Atopic dermatitis, inflammatory bowel disease, and sepsis are examples of this concept (Biedermann and Rogler, 2015;Kobayashi et al, 2015;Maekawa et al, 2014;Singh et al, 2016;Yang et al, 2018). A combination of factors may contribute to dysbiosis, including immune dysregulation, hormonal change, and microbiota imbalance.…”