Factor H and neisserial pathogenesis

Abstract

Both Neisseria gonorrhoeae and N. meningitidis bind to factor H which enhances their ability to evade complement-dependent killing. While porin is the ligand for human fH on gonococci, meningococci use a lipoprotein called factor H binding protein (fHbp) to bind to factor H and enhance their ability to evade complement-dependent killing. This protein is currently being intensively investigated as a meningococcal vaccine candidate antigen. Consistent with the observation that meningococci cause natural infection only in humans, the organism resists human complement, and are more readily killed by complement from lower animals. This human species-specific complement evasion has important implications for evaluation of vaccine-elicited antibodies using non-human complement sources and development of animal models of disease.

Figure 1

Survival of wild-type meningococci and their fHbp deletion mutants in human blood. Meningococcal strains MC58 and H44/76 (high fHbp expressers) and NZ98/254 and 4243 (low fHbp expressers) and their fHbp deletion mutants were examined for their ability to survive in whole blood derived from two individual donors. Survival of the wild-type strains and their respective fHbp mutants are shown by the solid and broken lines, respectively. Loss of fHbp on only the high expressers, but not the low expressers, compromised bacterial survival. The data are from Ref. [44].

Figure 2

Binding of human C4b to the surface of live encapsulated Neisseria meningitidis cells, as determined by indirect fluorescence flow cytometry. The left column shows results for the group B strain H44/76 (high fHbp expresser), and the right column shows results for the group B strain NZ98/254 (low fHbp expresser). Black areas in histograms indicate bacteria with 5% nonimmune human serum, and white areas indicate bacteria with monoclonal antibodies and 5% nonimmune human serum. Row 1: left, anti-PorA, P1.7, 2 μg/mL; right, anti-PorA, P1.4, 10 μg/mL. Row 2: JAR 3, 10 μg/mL. Row 3: JAR 4, 50 μg/mL. Row 4: JAR 3 plus JAR 4 (1 μg/mL for each). The data are adapted from Ref. [44].