Human Factor H Interacts Selectively with Neisseria gonorrhoeae and Results in Species-Specific Complement Evasion

Abstract

Complement forms a key arm of innate immune defenses against gonococcal infection. Sialylation of gonococcal lipo-oligosaccharide, or expression of porin 1A (Por1A) protein, enables Neisseria gonorrhoeae to bind the alternative pathway complement inhibitor, factor H (fH), and evade killing by human complement. Using recombinant fH fragment-murine Fc fusion proteins, we localized two N. gonorrhoeae Por1A-binding regions in fH: one in complement control protein domain 6, the other in complement control proteins 18–20. The latter is similar to that reported previously for sialylated Por1B gonococci. Upon incubation with human serum, Por1A and sialylated Por1B strains bound full-length human fH (HufH) and fH-related protein 1. In addition, Por1A strains bound fH-like protein 1 weakly. Only HufH, but not fH from other primates, bound directly to gonococci. Consistent with direct HufH binding, unsialylated Por1A gonococci resisted killing only by human complement, but not complement from other primates, rodents or lagomorphs; adding HufH to these heterologous sera restored serum resistance. Lipo-oligosaccharide sialylation of N. gonorrhoeae resulted in classical pathway regulation as evidenced by decreased C4 binding in human, chimpanzee, and rhesus serum but was accompanied by serum resistance only in human and chimpanzee serum. Direct-binding specificity of HufH only to gonococci that prevents serum killing is restricted to humans and may in part explain species-specific restriction of natural gonococcal infection. Our findings may help to improve animal models for gonorrhea while also having implications in the choice of complement sources to evaluate neisserial vaccine candidates.

TLR4-Mediated Sensing of Campylobacter jejuni by Dendritic Cells Is Determined by Sialylation

“…In Neisseria meningitidis, sialylation of LOS results in a reduced phagocytosis by DCs, without influencing cytokine secretion (29). Sialylation of LOS may also inhibit complement activation, as was demonstrated for Neisseria gonorrheae (30). Sialylation of LOS helps C. jejuni to invade intestinal epithelial cells (16).…”

Complement and its role in innate and adaptive immune responses

“…They may interact with host regulators, such as binding Factor H, which increases the degradation of C3b and reduces formation of C3 convertase, thereby limiting complement activity [151]. This phenomenon is well characterized in the Nesseria family of pathogens, including N. meningitidis and N. gonorrhoeae, both of which have been shown to bind to Factor H in an attempt to avoid destruction by the host complement system [42,152]. Interestingly, recent structural determinations of the N. meningitidis: Factor H complex have revealed that the pathogen subverts the host complement system through the use of protein mimetics of host carbohydrate motifs, thereby recruiting Factor H to its surface and evading destruction [153].…”

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).…”