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Neisserial lipooligosaccharide is a target for complement component C4b. Inner core phosphoethanolamine residues
Sanjay Ram1, Andrew D Cox, J Claire Wright
1Section of Infectious Diseases, Evans Biomedical Research Center, Boston University Medical Center, Boston, Massachusetts 02118, USA. sram@bu.edu
The Journal of Biological Chemistry
|October 4, 2003
Summary
Neisseria meningitidis lipooligosaccharide (LOS) binds complement component C4b via phosphoethanolamine (PEA) residues. The position of PEA on LOS influences C4b binding and bacterial susceptibility to complement-mediated killing, impacting Neisseria meningitidis survival.
Area of Science:
- Immunology
- Microbiology
- Biochemistry
Background:
- Neisseria meningitidis utilizes lipooligosaccharide (LOS) for immune evasion.
- The complement system, particularly component C4b, plays a crucial role in bacterial clearance.
- Understanding the molecular interactions between LOS and complement is vital for developing therapeutic strategies.
Purpose of the Study:
- To identify the specific sites on Neisseria meningitidis LOS that bind complement component C4b.
- To investigate how variations in LOS structure, specifically phosphoethanolamine (PEA) residues, affect C4b binding and complement-mediated killing.
- To elucidate the mechanisms by which C4b interacts with different LOS glycoforms.
Main Methods:
- Analysis of Neisseria meningitidis lipooligosaccharide (LOS) structure.
- Biochemical assays to detect and quantify complement component C4b binding to LOS.
- Serum bactericidal assays to assess bacterial susceptibility to complement-mediated killing.
- Genetic manipulation of LOS structure to study the role of PEA residues.
Main Results:
- Phosphoethanolamine (PEA) residues on the second heptose (HepII) of LOS act as C4b acceptors, forming amide linkages.
- The 6-position PEA (6-PEA) on HepII demonstrates higher efficiency in C4b binding compared to the 3-position PEA (3-PEA).
- Strains with 6-PEA exhibit increased C4b binding and enhanced susceptibility to complement-mediated killing.
- Glycose chain extensions on the first heptose (HepI) influence the linkage type (ester vs. amide) between C4b and LOS, with 6-PEA mediating binding even with extended chains.
Conclusions:
- The interaction between Neisseria meningitidis LOS and complement C4b is primarily mediated by PEA residues on HepII.
- The position of PEA (6-PEA vs. 3-PEA) significantly impacts C4b binding affinity and subsequent bacterial killing.
- Structural variations in LOS, influenced by glyco-chain extensions, modulate C4b binding mechanisms.
- The findings may explain the prevalence of 3-PEA meningococci in clinical isolates, as 6-PEA enhances clearance via the classical complement pathway.