Prof Susan Lea, University of Oxford
The structure of a protein complex between a bacterial and a human protein solved using data collected at Diamond Light Source (UK) and the ESRF (FRANCE) has revealed the way in which bacteria that cause bacterial meningitis mimic human cells to evade the body’s innate immune system. The study, published in Nature, could lead to the development of new vaccines that give better protection against meningitis B, the strain which accounts for the vast majority of cases of the disease in the UK.
Complement is an essential component of the innate and acquired immune system, and consists of a series of proteolytic cascades that are initiated by the presence of micro-organisms. In health, activation of complement is precisely controlled through membrane-bound and soluble plasma-regulatory proteins including factor H (fH), a 155 kDa protein composed of twenty domains (termed complement control protein repeats, or CCPs). This regulator is found as a soluble plasma protein which acts to regulate inappropriate complement activation on self-surfaces by interacting with self-cell glycosaminoglycans to localise its regulatory activities. Many pathogens have evolved the ability to avoid immune- killing by recruiting host complement regulators and several pathogens have adapted to avoid complementmediated killing by sequestering fH to their surfaces [reviewed in 2].
| Figure 1  | These pathogens lack glycosaminoglycans and so cannot directly use the same interactions as those which localise fH on self-cells. Instead they express proteins which specifically bind fH [e.g. 3] via the same regions as those involved in self-cell interactions so leaving the protein capable of complement regulation once bound [2]. The most surprising thing about these systems is that the proteins used by specific pathogens to bind fH share no sequence or structural homologies and before this structure no atomic explanation existed for how pathogens use proteins to mimic GAGs. Neisseria meningitidis, a cause of bacterial meningitis and of more than a million deaths worldwide annually, is one such pathogen with complement factor H scavenging via a ~30 kDa protein (factor H binding protein or fHbp) being a critical component of disease [1]. Using data from both Diamond and the ESRF we have solved the first structure of a complement regulator in complex with its pathogen surfaceprotein ligand [Fig. 1, Fig 2]. | |
| Figure 1: The complex between fHbp (ribbon coloured with N to C terminus rainbow) and domains 6 and 7 of fH (grey ribbon). | ||
Comparison of this structure to our earlier structure of this region of fH in complex with a small sulphated sugar as a mimic of cell surface GAGs [4] reveals how the important human pathogen Neisseria meningitidis subverts immune responses by mimicking the host, using protein instead of charged-carbohydrate chemistry to recruit the host complement regulator, factor H. The structure also indicates the molecular basis of the host-specificity of the interaction between factor H and the meningococcus by revealing that, although factor H is highly conserved, much of the variation between humans and even the closely related rhesus macaque (in which N.m cannot cause meningitis), map to the fHbp bnding site. fHbp is also a major vaccine candidate and on the basis of the structure a minimally mutated form of the protein, which retains antigenicity but looses the ability to bind factor H has been designed. Such an altered protein may form the basis of an improved vaccine.
References
[1]. Schneider MC, Exley RM, Chan H, Feavers I, Kang YH, Sim RB, Tang CM. J Immunol. Jun 15;176(12):7566-75 (2006).
[2]. Zipfel PF, Hallström T, Hammerschmidt S, Skerka C. Vaccine. Dec 30;26 Suppl 8:I67-74 (2008).
[3]. Cordes FS, Roversi P, Kraiczy P, Simon MM, Brade V, Jahraus O, Wallis R, Skerka C, Zipfel PF, Wallich R, Lea SM. Nat Struct Mol Biol. Mar; 12(3):276-7 (2005). Epub 2005 Feb 13.
[4]. Prosser BE, Johnson S, Roversi P, Herbert AP, Blaum BS, Tyrrell J, Jowitt TA, Clark SJ, Tarelli E, Uhrín D, Barlow PN, Sim RB, Day AJ, Lea SM. J Exp Med. Oct 1; 204(10):2277-83. (2007).
Principal publication and authors
Schneider MC, Prosser BE, Caesar JJ, Kugelberg E, Li S, Zhang Q, Quoraishi S, Lovett JE, Deane JE, Sim RB, Roversi P, Johnson S, Tang CM, Lea SM. Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates. Nature. Apr 16; 458(7240):890-3 (2009).
Funding Acknowledgement
The Wellcome Trust, Medical Research Council in the UK, the Engineering and Physical Sciences Council in the UK and the European Molecular Biology Organisation.
Research carried out at Diamond on I03 and ESRF BM14 and ID29.
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| Figure 2: The foreground shows a representation of two SCR domains from complement factor H (grey surface) in complex with the Neisserial factor H binding protein (cartoon, rainbow colouring). In the background an EM of Neisseria meninigitidis is overlaid on a field of Nesseria meningitidis infecting cells. |
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