Functional Significance of Factor H Binding toNeisseria meningitidis

Abstract

Neisseria meningitidis is an important cause of septicemia and meningitis. To cause disease, the bacterium must successfully survive in the bloodstream where it has to avoid being killed by host innate immune mechanisms, particularly the complement system. A number of pathogenic microbes bind factor H (fH), the negative regulator of the alternative pathway of complement activation, to promote their survival in vivo. In this study, we show that N. meningitidis binds fH to its surface. Binding to serogroups A, B, and C N. meningitidis strains was detected by FACS and Far Western blot analysis, and occurred in the absence of other serum factors such as C3b. Unlike Neisseria gonorrhoeae, binding of fH to N. meningitidis was independent of sialic acid on the bacterium, either as a component of its LPS or its capsule. Characterization of the major fH binding partner demonstrated that it is a 33-kDa protein; examination of insertion mutants showed that porins A and B, outer membrane porins expressed by N. meningitidis, do not contribute significantly to fH binding. We examined the physiological consequences of fH bound to the bacterial surface. We found that fH retains its activity as a cofactor of factor I when bound to the bacterium and contributes to the ability of N. meningitidis to avoid complement-mediated killing in the presence of human serum. Therefore, the recruitment of fH provides another mechanism by which this important human pathogen evades host innate immunity.

Immunity to adeno-associated virus vectors in animals and humans: a continued challenge

“…28 Since factor H co-immunoprecipitated with both, AAVC3b complexes and with AAV alone, it is likely that iC3b is generated on the viral capsid, a possible mechanism used by AAV to limit the innate response. 27 Many pathogens have evolved mechanisms to evade direct activation of the complement system by mimicking host surfaces, thereby recruiting factor H. 29 Consistent with these findings, AAV vectors fail to activate the alternative pathway of complement. 27 Although avoiding complement activation, pathogens opsonized with iC3b are still subject to immune adherence and phagocytosis through engagement with complement receptors on immune cells.…”

Haemophilus influenzae Interacts with the Human Complement Inhibitor Factor H

“…H. influenzae expresses Ͼ30 OMPs and there are several in the size ranging from 25 to 42 kDa that may be potential candidates for FH binding. P1 (35-50 kDa) P2 (40 kDa), P4 (28 kDa), P5 (27)(28)(29)(30)(31)(32)(33)(34)(35), and protein D (42 kDa) are all OMPs of H. influenzae that has approximately the corresponding size to the ligands found in the Far Western blot and may be suggested as possible FH-binding ligands (62). P2 is the most abundant protein in the outer membrane, it is highly immunogenic, and the variability allows the bacteria to evade protective Abs (63).…”

Host Specificity of Bacterial Pathogens

“…During extracellular growth in the human body, N. meningitidis is exposed to complement. A mechanism that confers complement resistance is the recruitment of a molecule that down-regulates complement activation, complement factor H (fH), to the bacterial surface by factor H-binding protein (fHbp) (Schneider et al 2006;Ngampasutadol et al 2008). N. meningitidis fHbp binds fH from humans, but not fH from primates or mice (Granoff et al 2009).…”