Expression of paragloboside-like lipooligosaccharides may be a necessary component of gonococcal pathogenesis in men.

Abstract

Summal~To learn how lipooligosaccharide (LOS) phase variations affect pathogenesis, we studied two male volunteers who were challenged intraurethrally with Neisseria gonorrhoeae that make a single LOS of 3,600 daltons and sequentially followed LOS expression by gonococci as urethritis developed. LOS variation occurred in vivo. Signs and symptoms of gonorrhea began with the appearance of variants making 4,700-dalton LOS that are immunochemically similar to glycosphingolipids of human hematopoietic cells (Man&ell, R. E., J. M. Griffiss, and B. A. Macher. 1989. J. Exp. Med. 168:107) and that have acceptors for sialic acid. A variant that appeared at the onset of leukorrhoea was shed by 34/36 men with naturally acquired gonorrhea at the time they sought medical attention; the other two shed the variant associated with dysuria. None shed the challenge variant. These data show that in vivo phase shifts to higher molecular mass LOS that mimic human cell membrane glycolipids are associated with the development of gonococcal leukorrhea. Outer membrane glycolipids of Gram-negative bacteria that cause disease along the respiratory or genital mucosae are relatively small (<7,000-dalton) lipooligosaccharides (LOS) 1 whose multiantennary oligosaccharide structures mimic those of human cell membrane glycosphingolipids (GSL) (1-4). During a study of the effect of piliation on infectivity, human volunteers developed gonorrhea after intraurethral challenge with a piliated Ndsseria gonorrhoeae strfm (5) that made a single LOS of 3,600 daltons. We made serial analyses of the LOS made by the organisms infecting two of the volunteers to learn whether LOS phase variations occurred during infection. We then confirmed the results by studying men with naturally acquired gonorrhea.

Role of N-Acetylglucosamine within Core Lipopolysaccharide of Several Species of Gram-Negative Bacteria in Targeting the DC-SIGN (CD209)

“…For example, GC uses a frame-shifting mechanism at the genetic level, to express different LOS molecules at the phenotypic level. Several of these phenotypes mimic human cell surface structures such as gangliosides (23,55,56). Furthermore, GC LOS interacts with complement receptor 3 (CR3) from female human cervical epithelia (57,58), and the asialoglycoprotein receptor on human sperm (59).…”

“…GC with LOS b (lacto-N-neotetraose, variant C or wild type) and lgtF phenotypes were used (23)(24)(25). MS-lgtF is an isogenic derivative of wild-type GC strain MS11.…”

Variation of gonococcal lipooligosaccharide structure is due to alterations in poly-G tracts in lgt genes encoding glycosyl transferases.

“…Over the course of the infection, an increasing proportion of GC isolated from the volunteers were variants that produced a higher molecular weight LOS. T w o variants, B and C, predominated (16). Nuclear magnetic resonance and immunochemical analysis showed that the o~ chain of variant A was a lactosyl group, whereas variant C produced a complete pentasaccharide 0e chain.…”

A novel factor H-FC chimeric immunotherapeutic molecule against Neisseria gonorrhoeae

“…Compelling evidence for the importance of sialylation of LOS in vivo was provided by Schneider and colleagues who inoculated two human male volunteers intraurethrally with a phase variant of strain MS11 that in vitro (before inoculation) expressed only lactose from HepI, which itself does not sialylate. Bacteria recovered from these subjects at the onset of leukorrhoea all reverted to expressing the extended LNT LOS structure (63). In the same study, N. gonorrhoeae recovered from 100% of 36 men at the time they sought medical attention expressed the LNT LOS (63).…”

“…Bacteria recovered from these subjects at the onset of leukorrhoea all reverted to expressing the extended LNT LOS structure (63). In the same study, N. gonorrhoeae recovered from 100% of 36 men at the time they sought medical attention expressed the LNT LOS (63). An ongoing analysis of over 60 minimally passaged gonococcal strains recovered recently from subjects attending an STD clinic in Nanjing, China (10 randomly selected isolates were used in this study), has shown that every isolate expresses the LNT LOS, as defined by binding to mAb 3F11 (64).…”