Meningococcal group W-135 and Y capsular polysaccharides paradoxically enhance activation of the alternative pathway of complement.
Although capsular polysaccharide (CPS) is critical for meningococcal virulence, the molecular basis of alternative complement pathway (AP) regulation by meningococcal CPSs remains unclear. Using serum with only the AP active, the ability of strains to generate C3a (a measure of C3 activation) and subsequently deposit C3 fragments on bacteria was studied in encapsulated group A, B, C, W-135, and Y strains and their isogenic unencapsulated mutants. To eliminate confounding AP regulation by membrane-bound factor H (fH; AP inhibitor) and lipooligosaccharide sialic acid, the meningococcal fH ligands (fHbp and NspA) and lipooligosaccharide sialylation were deleted in all strains. Group A CPS expression did not affect C3a generation or C3 deposition. C3a generated by encapsulated and unencapsulated group B and C strains was similar, but CPS expression was associated with reduced C3 deposition, suggesting that these CPSs blocked C3 deposition on membrane targets. Paradoxically, encapsulated W-135 and Y strains (including the wild-type parent strains) enhanced C3 activation and showed marked C3 deposition as early as 10 min; at this time point C3 was barely activated by the unencapsulated mutants. W-135 and Y CPSs themselves served as a site for C3 deposition; this observation was confirmed using immobilized purified CPSs. Purified CPSs bound to unencapsulated meningococci, simulated findings with naturally encapsulated strains. These data highlight the heterogeneity of AP activation on the various meningococcal serogroups that may contribute to differences in their pathogenic mechanisms.
From the Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605. Electronic address: sanjay.ram@umassmed.edu.
Sanjay
S
Ram
From the Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Lisa A
LA
Lewis
From the Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Sarika
S
Agarwal
D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism*; D016667:Bacterial Capsules / Q000276:immunology / Q000378:metabolism*; D001425:Bacterial Outer Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D015926:Complement C3a / Q000276:immunology / Q000378:metabolism*; D003170:Complement Pathway, Alternative; D006801:Humans; D038582:Neisseria meningitidis, Serogroup W-135 / Q000276:immunology / Q000378:metabolism*
D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; C105506:NspA protein, Neisseria; D015926:Complement C3a
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