Factor H Facilitates Adherence of Neisseria gonorrhoeae to Complement Receptor 3 on Eukaryotic Cells

Abstract

Neisseria gonorrhoeae can engage human complement receptor 3 (CR3) directly or through surface-bound iC3b. Factor H (fH) that binds to bacteria facilitates conversion of C3b to iC3b. fH also binds directly to CR3 on professional phagocytes. Certain nonprofessional phagocytes, such as primary cervical epithelial cells, also express CR3. We hypothesized that fH could bridge bacteria to CR3 and facilitate gonococcal association with host cells. Specificity of the fH–CR3 interaction was confirmed using human CR3-transfected Chinese hamster ovary (CHO-CR3) cells. Using recombinant proteins that comprised contiguous fH domains (fH contains 20 short consensus repeat [SCR] domains) fused to murine Fc, we observed strong binding through SCRs 18–20, whereas weaker binding occurred through SCRs 6–10. Both regions also bound to unsialylated porin (Por) B.1A-expressing N. gonorrhoeae. Accordingly, fH-related protein 1 (three of its five SCRs are highly homologous to fH SCRs 18–20) bound to CHO-CR3 and to unsialylated PorB.1A gonococci. An alternatively spliced variant of fH called fH-like protein-1 (contains fH SCRs 1–7) bound to gonococci but minimally to CHO-CR3. An fH SCRs 6–20 construct enhanced binding of unsialylated PorB.1A gonococci to CHO-CR3. However, a construct that contained only the apparently relevant SCRs (6, 7, and 18–20) bound to CHO-CR3 and to gonococci separately, but did not enhance bacteria–CR3 interactions, suggesting that the intervening SCRs (8–17) may impart a configurational and spatial requirement for fH to bridge gonococci to CR3. These results indicate adherence between fH-coated gonococci and CR3 and may provide a means for gonococci to gain sanctuary into nonprofessional phagocytes.

Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae

“…Therefore, testing the efficacy of FH/Fc molecules in vivo was restricted to wild-type isolates that express sialylatable LNnT on LOS. Not surprisingly, FHD1119G/Fc showed greater efficacy than FH6,7/Fc against all wild-type isolates whose LOSs become sialylated in vivo , which is consistent with our prior observations of decreased binding upon LOS sialylation of a chimeric protein that comprised FH domains 6–10 fused to Fc (55). Lack of efficacy of FH6,7/Fc relative to FHD1119G/Fc was evident in FH/C4BP Tg mice colonized with strain FA1090 (Fig.…”

Molecular Characterization of the Interaction between Sialylated Neisseria gonorrhoeae and Factor H

“…However, sialylated PorB.1A strain 252 required a higher concentration of HufH18 -20/Fc to kill it and complete killing of this strain by HufH18 -20/Fc was not achieved by concentrations that exceeded by nearly 10-fold those required to kill sialylated PorB.1B strain F62. We have reported that sialylated PorB.1B strain F62 binds HufH via domains 18 -20 exclusively, whereas PorB.1A strain 252 binds HufH via domains 18 -20 and separately, by domain 6 (24,51). A proposed functional structure of fH suggests that monomeric HufH adopts a folded-back conformation (52) where domains, 12-14 contain the site of a bend or hinge (30) that increases proximity of short consensus repeat 6 and 20 domains to binding sites on N. gonorrhoeae.…”

Complement factor H in host defense and immune evasion

“…Therefore, in a sharp contrast to its role as a complement inhibitor, FH might promote the physical contact between neutrophils and certain pathogens, thereby increasing antimicrobial activity. Conversely, it has also been found that the FH-CR3 interaction can facilitate the entry of certain pathogens (i.e., Streptococcus pneumoniae and Neisseria gonorrhoeae ) into host cells [102, 103]. …”