Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates

Abstract

Complement is an essential component of the innate and acquired immune system1, 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)2, a 155 kDa protein composed of twenty domains (termed complement control protein repeats, or CCPs). Many pathogens have evolved the ability to avoid immune- killing by recruiting host complement regulators3 and several pathogens have adapted to avoid complement-mediated killing by sequestering fH to their surface4. Here we present the first structure of a complement regulator in complex with its pathogen surface-protein ligand. This 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, and informs attempts to develop novel therapeutics and vaccines.

The Dual Role of Lipids of the Lipoproteins in Trumenba, a Self-Adjuvanting Vaccine Against Meningococcal Meningitis B Disease

“…The atomic structure of NmB rLP2086-B01 polypeptide by NMR in the solution phase was consistent with the X-ray crystal structures reported for similar NmB lipoproteins (24,25). Both showed that the polypeptides of the lipoproteins fold into mainly two conformational motifs in two sideby-side domains, i.e., the N-terminal and the C-terminal domains.…”

“…Both showed that the polypeptides of the lipoproteins fold into mainly two conformational motifs in two sideby-side domains, i.e., the N-terminal and the C-terminal domains. This domain structure was shown to be important for factor H binding to fHbps (24), which allows meningococcal bacteria to avoid the human innate immune system. The human factor H (hfH) in the crystal structure is shown to simultaneously interact with both the N-terminal and the Cterminal domains.…”

Host Specificity of Bacterial Pathogens

“…N. meningitidis fHbp binds fH from humans, but not fH from primates or mice (Granoff et al 2009). Interestingly, differences between human and primate fH sequences cluster to the precise site of interaction with fHbp (Schneider et al 2009), which likely represents another interaction contributing to the host specificityof N. meningitidis (Everett et al 2011). …”

Complement in age-related macular degeneration: a focus on function

“…11 For example, Neisseria meningitidis specifically survive in human hosts and express proteins that bind to human negative regulators of the complement system such as complement factor H (CFH) in order to protect themselves from complement attack. 12 A selection pressure is therefore exerted on the microbe, which evolves quickly due to its short generation time, to successfully deceive the host immune system. A countervailing selection pressure is also exerted on the host to detect infectious microbes, to change its own proteins to prevent them either being bound to microbes with high affinity or to have a configuration different from any mimicked proteins on the microbe's exterior.…”