Capsular
polysaccharides (CPS) are a major
virulence factor in
meningococcal infections and form the basis for serogroup designation and protective
vaccines. Our work has identified meningococcal CPS as a pro-inflammatory
ligand that functions through TLR2 and TLR4-MD2-dependent activation. We hypothesized that human
cationic host defense peptides interact with CPS and influence its
biologic activity. Accordingly, the interaction of meningococcal CPS with the human-derived cationic
peptide LL-37, which is expressed by phagocytic and epithelial cells that interface with meningococci during
infection, was investigated. LL-37 neutralized the pro-inflammatory activity of
endotoxin-free CPS as assessed by TLR2 and TLR4-MD-2-dependent release of TNFα,
IL-6 and
IL-8 from human and murine macrophages. The cationic and hydrophobic properties of LL-37 were crucial for this inhibition, which was due to binding of LL-37 to CPS. LL-37 also inhibited the ability of meningococcal CPS to induce
nitric oxide release, as well as TNFα and CXCL10 (IP-10) release from TLR4-sufficient and TLR4-deficient murine macrophages. Truncated LL-37 analogs, especially those that retained the antibacterial domain, inhibited
vaccine grade CPS and meningococcal CPS prepared from the major serogroups (A, B C, Y and W135). Thus, LL-37 interaction with CPS was independent of specific
glucan structure. We conclude that the capacity of meningococcal CPS to activate macrophages via TLR2 and TLR4-MD-2 can be inhibited by the human cationic
host defense peptide LL-37 and propose that this impacts CPS-based
vaccine responses.