The Meningococcal Vaccine Candidate Neisserial Surface Protein A (NspA) Binds to Factor H and Enhances Meningococcal Resistance to Complement

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Abstract
Complement forms an important arm of innate immunity against invasive meningococcal infections. Binding of the alternative complement pathway inhibitor factor H (fH) to fH-binding protein (fHbp) is one mechanism meningococci employ to limit complement activation on the bacterial surface. fHbp is a leading vaccine candidate against group B Neisseria meningitidis. Novel mechanisms that meningococci employ to bind fH could undermine the efficacy of fHbp-based vaccines. We observed that fHbp deletion mutants of some meningococcal strains showed residual fH binding suggesting the presence of a second receptor for fH. Ligand overlay immunoblotting using membrane fractions from one such strain showed that fH bound to a ∼17 kD protein, identified by MALDI-TOF analysis as Neisserial surface protein A (NspA), a meningococcal vaccine candidate whose function has not been defined. Deleting nspA, in the background of fHbp deletion mutants, abrogated fH binding and mAbs against NspA blocked fH binding, confirming NspA as a fH binding molecule on intact bacteria. NspA expression levels vary among strains and expression correlated with the level of fH binding; over-expressing NspA enhanced fH binding to bacteria. Progressive truncation of the heptose (Hep) I chain of lipooligosaccharide (LOS), or sialylation of lacto-N-neotetraose LOS both increased fH binding to NspA-expressing meningococci, while expression of capsule reduced fH binding to the strains tested. Similar to fHbp, binding of NspA to fH was human-specific and occurred through fH domains 6–7. Consistent with its ability to bind fH, deleting NspA increased C3 deposition and resulted in increased complement-dependent killing. Collectively, these data identify a key complement evasion mechanism with important implications for ongoing efforts to develop meningococcal vaccines that employ fHbp as one of its components. Neisseria meningitidis is an important cause of bacterial meningitis and sepsis worldwide. The complement system is a family of proteins that is critical for innate immune defenses against this pathogen. In order to successfully colonize humans and cause disease, the meningococcus must escape killing by the complement system. In this study we show that meningococci can use one of its surface proteins called Neisserial surface protein A (NspA) to bind to a host complement inhibitory protein called factor H (fH). NspA is a protein vaccine candidate against group B meningococcal disease. Binding of fH limits complement activation on the bacterial surface and enhances the ability of the meningococcus to resist complement-dependent killing. Capsular polysaccharide expression decreases fH binding to NspA, while truncation of the core glycan chain of lipooligosaccharide increases fH binding to meningococcal NspA. Loss of NspA results in enhanced complement activation on the bacterial surface and increased complement-dependent killing of meningococci. Our findings have disclosed a novel function for NspA and sheds further light on how this pathogen evades killing by the complement system.