C4BP-IgM protein as a therapeutic approach to treat Neisseria gonorrhoeae infectionsShow others and affiliations
2019 (English)In: JCI Insight, ISSN 2379-3708, Vol. 4, no 23, article id 131886Article in journal (Refereed) Published
Abstract [en]
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.
Place, publisher, year, edition, pages
American Society for Clinical Investigation (ASCI) , 2019. Vol. 4, no 23, article id 131886
Keywords [en]
Bacterial infections, Complement, Immunotherapy, Infectious disease, Therapeutics
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:oru:diva-78562DOI: 10.1172/jci.insight.131886ISI: 000500946900014PubMedID: 31661468Scopus ID: 2-s2.0-85077586369OAI: oai:DiVA.org:oru-78562DiVA, id: diva2:1378550
Funder
Swedish Research Council Formas, 2018-02392
Note
Funding Agencies:
United States Department of Health & Human Services
National Institutes of Health (NIH) - USA AI119327 AI114790 AI132296 AI147930 AI136007
Söderberg Foundation
Österlund Foundation
Royal Physiographic Society of Lund
Sten K. Johnsons Foundation
2019-12-132019-12-132023-12-08Bibliographically approved