C4BP-IgM protein as a therapeutic approach to treat Neisseria gonorrhoeae infections.

Abstract

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.

• Authors: Serena Bettoni, Jutamas Shaughnessy, Karolina Maziarz, David Ermert, Sunita Gulati, Bo Zheng, Matthias Mörgelin, Susanne Jacobsson, Kristian Riesbeck, Magnus Unemo, Sanjay Ram, Anna M Blom
• Journal: JCI insight (JCI Insight) Vol. 4 Issue 23 (12 05 2019) ISSN: 2379-3708 [Electronic] United States
• PMID: 31661468 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• C4BPA protein, human
• C4bp protein, mouse
• Complement C4b-Binding Protein
• Histocompatibility Antigens
• Immunoglobulin G
• Immunoglobulin M
• Porins

Topics

• Animals
• Complement C4b-Binding Protein (therapeutic use)
• Disease Models, Animal
• Female
• Gonorrhea (drug therapy, immunology)
• Histocompatibility Antigens (therapeutic use)
• Humans
• Immunoglobulin G
• Immunoglobulin M (therapeutic use)
• Mice, Inbred BALB C
• Mice, Transgenic
• Neisseria gonorrhoeae (drug effects)
• Porins
• Protein Domains