The meningococcal vaccine candidate Neisserial surface protein A (NspA) binds to Factor H and enhances meningococcal resistance to complement

Lisa A Lewis,Jutamas Ngampasutadol,Ruth Wallace,Jane E.A Reid,Ulrich Vogel,Sanjay Ram

doi:10.1016/j.molimm.2010.05.139

Lisa A Lewis, Jutamas Ngampasutadol + Show 4 more

Open Access

https://doi.org/10.1016/j.molimm.2010.05.139

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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.

Highlights

The complement system forms an important arm of innate immune defenses against Neisseria meningitidis
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
Capsular polysaccharide expression decreases factor H (fH) binding to NspA, while truncation of the core glycan chain of lipooligosaccharide increases fH binding to meningococcal NspA

Summary

Introduction

The complement system forms an important arm of innate immune defenses against Neisseria meningitidis. Scavenging host complement inhibitors by meningococcal membrane proteins constitutes an important mechanism of subverting complement attack. The molecule that has received much attention in recent literature is factor H-binding protein (fHbp; known as LP2086 [11] or Genome-derived Neisserial Antigen (GNA) 1870 [12]) that binds to the alternative pathway inhibitor, factor H (fH) [13,14]. Based on its amino acid sequence, fHbp has been classified into 3 variants [12], or into 2 subfamilies [11], or more recently, into seven modular groups [18,19]. FHbp is currently being evaluated as protein vaccine candidate against group B meningococcal disease and has shown promise in Phase III clinical trials [20] The co-crystal structure of variant 1 (subfamily B) fHbp with a fragment of fH revealed an extensive interaction surface of ,2,860 A 2 [14]. fHbp is currently being evaluated as protein vaccine candidate against group B meningococcal disease and has shown promise in Phase III clinical trials [20]

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