Arthropathic properties of gonococcal peptidoglycan fragments: implications for the pathogenesis of disseminated gonococcal disease

Abstract

We examined the arthropathic activity of purified peptidoglycan (PG) fragments derived from (i) lysozymeresistant, extensively 0-acetylated PG from Neisseria gonorrhoeae FA19 (0-PG), and (ii) lysozyme-sensitive, 0-acetyl-deficient PG from N. gonorrhoeae RD5 (non-O-PG). Male Lewis rats were injected intradermally in the tail with 200 ,ug of PG emulsified in mineral oil and water (1:1) or with the oil and water emulsion alone (controls). Quantitation of hind paw size indicated that macromolecular PG of various chemical and physical forms induced paw swelling (P versus controls, less than 0.01) that was evident at about day 14 and that reached a maximum at about day 24. PG-mediated paw swelling was accompanied by intense synovitis with some cartilage and bone involvement. The minimal arthropathic dose of soluble macromolecular PG was 20 ,ug per rat. Of particular interest was that macromolecular O-PGs from strain FA19 caused considerably more extensive swelling than did either their RD5 non-O-PG counterparts or the homologous FA19 PG that had been de-0-acetylated by mild alkali treatment. This suggested that the persistence of hydrolase-resistant highmolecular-weight fragments, afforded by extensive 0-acetylation, may be important for optimal expression of arthropathic activity. However, oligomeric PG was not an absolute requirement, since even low-molecularweight fragments, including the anhydro-muramyl-containing disaccharide peptide monomer released by growing gonococci, were also arthritogenic. Experiments employing purified gonococcal lipopolysaccharide indicated that the arthropathic activity of PG preparations was not due to contaminating lipopolysaccharide. Based on the arthritogenicity of gonococcal PG in this model system, we suggest that PG may play a role in the pathogenesis of gonococcal arthritis, and that such an activity might be potentiated by the persistence of hydrolase-resistant O-PG. 600 on July 31, 2020 by guest http://iai.asm.org/ Downloaded from

Degradation of gonococcal peptidoglycan by granule extract from human neutrophils: demonstration of N-acetylglucosaminidase activity that utilizes peptidoglycan substrates

“…To test this hypothesis, our main objectives have been to identify and purify those PG fragments that might arise in vivo and to test their biological activities in diverse assays that are associated with modulation of inflammation and immunity. In general, we have found that various classes of physiologically realistic PG fragments possess numerous activities consistent with the notion that PG plays a role in gonococcal disease, e.g., toxicity (14), ability to activate complement (15), arthritogenicity (6), and ability to stimulate the release of functional interleukin-1 and prostaglandin E2 (T. J. Fleming and S. L. Myers, Abstr. Annu.…”

Structural variation in the glycan strands of bacterial peptidoglycan

“…However, O-acetylated peptidoglycan might resist the hydrolytic activity of human lysozyme, resulting in the persistence of O-acetylated, high-molecular-weight peptidoglycan fragments in the host organism. Rheumatoid arthritis, an autoimmune disease, is induced in animal models by undigestible high-molecularweight peptidoglycan fragments (Hamerman, 1966;Ginsburg & Sela, 1976;Chedid et al, 1978;Fox et al, 1982;Esser et al, 1985;Koga et al, 1985;Fleming et al, 1986;Stimpson et al, 1986). Indeed, in vivo studies demonstrated that the persistence of peptidoglycan in a host is directly attributable to the high degree of O-acetylation (Blundell et al, 1980;Rosenthal et al, 1982;Swim et al, 1983;Fleming et al, 1986).…”

A variable genetic island specific for Neisseria gonorrhoeae is involved in providing DNA for natural transformation and is found more often in disseminated infection isolates

“…The major PG fragment released by gonococci is the 1,6 anhydro disaccharide tetrapeptide monomer (PG-cytotoxin), a molecule that has multiple biological and immunological activities and is chemically identical to the tracheal cytotoxin (TCT) of Bordetella pertussis (Sinha and Rosenthal, 1980;Cookson et al, 1989). Not only does PG-cytotoxin cause the death and sloughing of ciliated fallopian tube cells, but it also induces arthritis (Fleming et al, 1986), stimulates production of inflammatory cytokines interleukin (IL)-1 and IL-6 (Heiss et al, 1993;Dokter et al, 1994), and induces slow wave sleep (Krueger et al, 1987). Thus, PG-cytotoxin is implicated in the pathogenesis of PID and DGI and may contribute to the inflammatory response in local infections.…”