Bettoni, SerenaShaughnessy, JutamasMaziarz, KarolinaErmert, DavidGulati, SunitaZheng, BoMorgelin, MatthiasJacobsson, SusanneRiesbeck, KristianUnemo, MagnusRam, SanjayBlom, Anna M.2022-08-232022-08-232019-12-052020-01-13<p>JCI Insight. 2019 Dec 5;4(23). pii: 131886. doi: 10.1172/jci.insight.131886. <a href="https://doi.org/10.1172/jci.insight.131886">Link to article on publisher's site</a></p>2379-3708 (Linking)10.1172/jci.insight.13188631661468https://hdl.handle.net/20.500.14038/41312Gonorrhea 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.en-USBacterial infectionsComplementImmunotherapyInfectious diseaseTherapeuticsAmino Acids, Peptides, and ProteinsBacteriaBacterial Infections and MycosesFemale Urogenital Diseases and Pregnancy ComplicationsImmunology of Infectious DiseaseImmunoprophylaxis and TherapyInfectious DiseaseMale Urogenital DiseasesJournal Articlehttps://escholarship.umassmed.edu/oapubs/409816192410oapubs/4098