The role of C-reactive protein in immune responses to Neisseria meningitidis.

Abstract

Immunity to Neisseria meningitidis (N. meningitidis) involves both innate and antibody-mediated mechanisms. The acute-phase serum protein C-reactive protein (CRP) helps to protect the host from several bacterial pathogens, often by binding to surface phosphorylcholine (PC). Pathogenic Neisseria species can exhibit phase-variable PC modification on type 4 pili of class 1 and 2. This investigation demonstrates that CRP can bind to piliated meningococci in a calcium-dependent manner that is concentration dependent, of low affinity and specific for PC. Separate experiments confirmed that CRP can bind to both live and paraformaldehyde-fixed meningococci, suggesting that CRP has a role in the immune response to meningococci. CRP binding to PC on commensal species of Neisseria is known to increase serum bactericidal activity by initiating the classical complement cascade. In these investigations, CRP-opsonisation did not increase serum killing of N. meningitidis. CRP binding did, however, significantly increase phagocytic uptake of fixed meningococci by macrophages and neutrophils (and increased uptake by dendritic cells was also indicated). This CRP-mediated uptake was attributed to recruitment of the cellular receptor for CRP, FcyR, as blocking of these receptors with human IgG abrogated the increased uptake by macrophages in a concentration-dependent manner. In contrast, macrophage uptake of live meningococci was not increased by CRP-opsonisation and preliminary investigations detected no increase in intracellular killing of CRP-opsonised meningococci, indicating that live meningococci may evade CRP-mediated phagocyte detection. The absence of a direct killing effect of CRP led to the hypothesis that CRP provides an indirect advantage to the host by modulation of inflammation and antigen presentation by phagocytes. CRP-opsonised N. meningitidis induced greater macrophage HLA-DR expression, IL-10 and IL-1beta secretion compared to non-opsonised N. meningitidis in the majority of human donors. These studies indicate that CRP may increase antigen presentation and therefore accelerate the development of acquired immunity to meningococcal infection, whilst limiting the inflammatory damage to the host via increased IL-10 production