C4BP-IgM protein as a therapeutic approach to treat Neisseria gonorrhoeae infections
Department of Medicine, Division of Infectious Diseases and Immunology
Amino Acids, Peptides, and Proteins | Bacteria | Bacterial Infections and Mycoses | Female Urogenital Diseases and Pregnancy Complications | Immunology of Infectious Disease | Immunoprophylaxis and Therapy | Infectious Disease | Male Urogenital Diseases
Gonorrhea is a sexually transmitted infection with 87 million new cases per year globally. Increasing antibiotic resistance has severely limited treatment options. A mechanism that Neisseria gonorrhoeae uses to evade complement attack is binding of the complement inhibitor C4b-binding protein (C4BP). We screened 107 porin B1a (PorB1a) and 83 PorB1b clinical isolates randomly selected from a Swedish strain collection over the last 10 years and noted that 96/107 (89.7%) PorB1a and 16/83 (19.3%) PorB1b bound C4BP; C4BP binding substantially correlated with the ability to evade complement-dependent killing (r = 0.78). We designed 2 chimeric proteins that fused C4BP domains to the backbone of IgG or IgM (C4BP-IgG; C4BP-IgM) with the aim of enhancing complement activation and killing of gonococci. Both proteins bound gonococci (KD C4BP-IgM = 2.4 nM; KD C4BP-IgG 980.7 nM), but only hexameric C4BP-IgM efficiently outcompeted heptameric C4BP from the bacterial surface, resulting in enhanced complement deposition and bacterial killing. Furthermore, C4BP-IgM substantially attenuated the duration and burden of colonization of 2 C4BP-binding gonococcal isolates but not a non-C4BP-binding strain in a mouse vaginal colonization model using human factor H/C4BP-transgenic mice. Our preclinical data present C4BP-IgM as an adjunct to conventional antimicrobials for the treatment of gonorrhea.
Bacterial infections, Complement, Immunotherapy, Infectious disease, Therapeutics
DOI of Published Version
JCI Insight. 2019 Dec 5;4(23). pii: 131886. doi: 10.1172/jci.insight.131886. Link to article on publisher's site
Bettoni S, Shaughnessy J, Maziarz K, Ermert D, Gulati S, Zheng B, Morgelin M, Jacobsson S, Riesbeck K, Unemo M, Ram S, Blom AM. (2019). C4BP-IgM protein as a therapeutic approach to treat Neisseria gonorrhoeae infections. Open Access Publications by UMMS Authors. https://doi.org/10.1172/jci.insight.131886. Retrieved from https://escholarship.umassmed.edu/oapubs/4098