Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates

A mimic in meningitis The human pathogen Neisseria meningitidis , a leading cause of bacterial meningitis and septic shock, possesses a surface protein, factor H binding protein or fHbp, that binds to host complement regulator factor H, thereby interfering with the immune response. Now the structure of the complex between human complement regulator factor H and fHbp has been determined. It reveals that the bacterial protein binds factor H by mimicking the glycosaminoglycans that occur naturally on host endothelial cells where they recruit factor H to prevent complement-mediated damage of the vascular tree. This work has important implications for the development of vaccines and therapeutics to counter meningococcal disease. Neisseria meningitidis possesses a surface protein called fHbp that binds to the complement regulator factor H, thereby interfering with the host immune response. Now the structure of N. meningitidis fHbp bound to factor H is presented, revealing the molecular interactions between these two molecules. The complement system is an essential component of the innate and acquired immune system 1 , and consists of a series of proteolytic cascades that are initiated by the presence of microorganisms. In health, activation of complement is precisely controlled through membrane-bound and soluble plasma-regulatory proteins including complement factor H (fH; ref. 2 ), a 155 kDa protein composed of 20 domains (termed complement control protein repeats). Many pathogens have evolved the ability to avoid immune-killing by recruiting host complement regulators 3 and several pathogens have adapted to avoid complement-mediated killing by sequestering fH to their surface 4 . Here we present the 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, fH. The structure also indicates the molecular basis of the host-specificity of the interaction between fH and the meningococcus, and informs attempts to develop novel therapeutics and vaccines.