Complement and N. meningitidis colonization
The complement system is an ancient first-responder branch of the innate immune system to provide immediate protection of the host against invading microorganisms. It consists of about 30 proteins, comprising soluble zymogens of serine proteases and complement regulatory proteins in the blood plasma and interstitial fluid as well as cell-surface bound receptors. The complement system is activated by three initiating pathways: 1. Classical pathway, triggered by antibody:antigen complexes; 2. MBL pathway, triggered by conserved microbial carbohydrate patterns; 3. Alternative pathway, triggered by a constant low level ‘tickover’ mechanism. Once activated, a cascade of subsequent protein cleavage reactions carried out by serine proteases, each activating a downstream protease. Complement activation exerts three main functions: 1. Opsonization (coating) of non-self particles (bacteria, virus, fungi) with C3b to enhance phagocytic uptake; 2. Direct lysis of invading bacteria through the ‘membrane attack complex’; and 3. Initiation of an inflammatory response through anaphylatoxins C3a and C5a to attract immune cells.
The complement system is the most important innate immune effector protecting us against meningococcal disease. This is underscored by the fact that individuals suffering from functional loss of complement activity are exposed to a several thousand-fold higher likelihood to develop invasive meningococcal disease.
As many pathogens, N. meningitidis have evolved several mechanisms to counteract their host’s complement system. Their most important virulence factor is the polysaccharide capsule, that buries the proteinaceous surface epitopes and distances complement activation away from the bacterial cell wall. In fact, non-capsulated meningococci are considered non-pathogenic, as virtually all disease isolates of N. meningitidis produce capsule.
In addition to the capsule, N. meningitidis sequester complement-regulatory proteins to their surface in order to gain additional protection against complement activity. This includes the binding of the complement regulators factor H (fH) and C4b binding protein (C4BP), two proteins that normally function to protect human cells from being damaged by the complement cascade. Meningococci express factor H binding protein (fHbp) and Neisseria surface protein A (NspA) which recognize human factor H. Furthermore, they employ molecular mimicry by sialylation of their lipooligosaccarides, which as well serves fH-dependent protection against host complement. Besides the fH binding moieties, the major constituent of the meningococcal outer membrane, Por A, attracts human C4BP to reduce classical and MBL pathway activation.
While most research on the topic on complement and N. meningitidis has focused on their role during invasive disease, we aim to unravel the influence of the host’s complement as well as the meningococcal anti-complement strategies on mucosal colonization.