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Neutralization of meningococcal endotoxin by antibody to core glycolipid
Abstract:
Antibodies to Escherichia coli J5, a uridine 5'-diphosphate-galactose epimerase-less mutant of E. coli 0111, neutralized meningococcal endotoxemia from all three major capsular serogroups. We chose the dermal necrosis of the local Shwartzman phenomenon and the renal cortical necrosis of the general Shwartzman phenomenon as assays because these are the hallmarks of meningococcemia, and because meningococcal lipopolysaccharide (LPS) is a uniquely potent cause of dermal purpura and necrosis. Meningococcal antisera raised against LPS from MGC A, B, and C also provided good protection against endotoxemia from the homologous capsular groups, but it was inconsistent against the heterologous serogroups. The superiority of J5 antibodies (purified IgG as well as antiserum) is probably due to the fact that J5 LPS contains only the endotoxin core. Consequently, immunization with this mutant stimulates production of antibodies to core LPS without interference by the "0" antigenic determinants of the side chains. These observations indicate that the endotoxin core is the toxic moiety of meningococcal LPS, that the core LPS of meningococcus (MGC) is immunologically similar to enteric LPS, and that the antigenically variable "0" side chains of MGC LPS interfere with antibody production against the common core. They also suggest that antibodies prepared against this E. coli mutant could interrupt the devastating course of meningococcal endotoxemia in man, regardless of the capsular serogroup of the infecting strain.
Insights
Antibodies targeting the core of Escherichia coli J5 neutralized severe meningococcal disease. This approach, using E. coli J5 antibodies, offers broad protection against various meningococcal serogroups by targeting the common endotoxin core.
Area of Science:
- Immunology
- Microbiology
- Pathogenesis
Background:
- Meningococcal disease, caused by Neisseria meningitidis, is a significant cause of morbidity and mortality.
- Lipopolysaccharide (LPS) from meningococcal bacteria is a potent endotoxin responsible for severe disease manifestations, including endotoxemia.
- Current treatments lack broad efficacy against all meningococcal serogroups due to variable O-antigenic side chains.
Purpose of the Study:
- To evaluate the efficacy of antibodies against the Escherichia coli J5 mutant in neutralizing meningococcal endotoxemia.
- To determine if targeting the conserved endotoxin core of LPS provides broader protection than serogroup-specific antibodies.
Main Methods:
- Utilized the Shwartzman phenomenon (local dermal necrosis and general renal cortical necrosis) as an in vivo assay for endotoxemia.
- Compared the protective effects of antibodies raised against E. coli J5 LPS with those raised against specific meningococcal serogroup LPS (MGC A, B, and C).
Main Results:
- Antibodies to E. coli J5 demonstrated neutralization of meningococcal endotoxemia across all tested capsular serogroups.
- Antisera against specific meningococcal LPS provided protection against homologous serogroups but were inconsistent against heterologous ones.
- E. coli J5 antibodies showed superior broad-spectrum protection, attributed to targeting the conserved endotoxin core LPS, free from variable O-antigenic side chains.
Conclusions:
- The endotoxin core of meningococcal LPS is a critical toxic component and a conserved immunogenic target.
- Antibodies targeting the conserved endotoxin core, such as those from E. coli J5, offer a promising strategy for broad-spectrum treatment of meningococcal disease.
- The variable O-antigenic side chains of meningococcal LPS can hinder effective antibody responses against the common core.