Department of Medicine, Division of Infectious Diseases and Immunology
Bacterial Infections and Mycoses | Immunity | Immunology of Infectious Disease | Immunoprophylaxis and Therapy | Immunotherapy | Infectious Disease | Microbiology
Neisseria gonorrhoeae, the causative agent of gonorrhea, has evolved several mechanisms to subvert complement, including binding of the complement inhibitor factor H (FH). We previously reported FH binding to N. gonorrhoeae independently of lipooligosaccharide (LOS) sialylation. Here we report that factor H-like protein 1 (FHL-1), which contains FH domains 1 through 7 and possesses complement-inhibitory activity, also binds to N. gonorrhoeae The ligand for both FH and FHL-1 was identified as neisserial surface protein A (NspA), which has previously been identified as a ligand for these molecules on Neisseria meningitidis As with N. meningitidis NspA (Nm-NspA), N. gonorrhoeae NspA (Ng-NspA) bound FH/FHL-1 through FH domains 6 and 7. Binding of FH/FHL-1 to NspA was human specific; the histidine (H) at position 337 of domain 6 contributed to human-specific FH binding to both Ng- and Nm-NspA. FH/FHL-1 bound Nm-NspA better than Ng-NspA; introducing Q at position 73 (loop 2, present in Ng-NspA) or replacing V and D at positions 112 and 113 in Nm-NspA loop 3 with A and H (Ng-NspA), respectively, reduced FH/FHL-1 binding. The converse Ng-NspA to Nm-NspA mutations increased FH/FHL-1 binding. Binding of FH/FHL-1 through domains 6 and 7 to N. gonorrhoeae increased with truncation of the heptose I (HepI) chain of LOS and decreased with LOS sialylation. Loss of NspA significantly decreased serum resistance of N. gonorrhoeae with either wild-type or truncated LOS. This report highlights the role for NspA in enabling N. gonorrhoeae to subvert complement despite LOS phase variation. Knowledge of FH-NspA interactions will inform the design of vaccines and immunotherapies against the global threat of multidrug-resistant gonorrhea.
factor H, Neisseria, NspA, complement
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Copyright © 2019, American Society for Microbiology. Publisher PDF posted with 6 month embargo as allowed by the publisher's author rights policy at https://journals.asm.org/content/statement-author-rights.
DOI of Published Version
Lewis LA, Rice PA, Ram S. Role of Gonococcal Neisserial Surface Protein A (NspA) in Serum Resistance and Comparison of Its Factor H Binding Properties with Those of Its Meningococcal Counterpart. Infect Immun. 2019 Jan 24;87(2):e00658-18. doi: 10.1128/IAI.00658-18. PMID: 30510105; PMCID: PMC6346132. Link to article on publisher's site
Infection and immunity
Lewis LA, Rice PA, Ram S. (2019). Role of Gonococcal Neisserial Surface Protein A (NspA) in Serum Resistance and Comparison of Its Factor H Binding Properties with Those of Its Meningococcal Counterpart. Infectious Diseases and Immunology Publications. https://doi.org/10.1128/IAI.00658-18. Retrieved from https://escholarship.umassmed.edu/infdis_pp/418
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