{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T07:58:49Z","timestamp":1787731129283,"version":"build-2784847793"},"reference-count":88,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T00:00:00Z","timestamp":1661817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI132296, AI147930, AI160247"],"award-info":[{"award-number":["AI132296, AI147930, AI160247"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Novel therapeutics against the global threat of multidrug-resistant <jats:italic>Neisseria gonorrhoeae<\/jats:italic> are urgently needed. Gonococci evade killing by complement by binding factor H (FH), a key inhibitor of the alternative pathway. FH comprises 20 short consensus repeat (SCR) domains organized as a single chain. Gonococci bind FH through domains 6 and 7, and C-terminal domains 18 through 20. Previously, we showed that a chimeric protein comprising (from the N- to C-terminus) FH domains 18-20 (containing a point mutation in domain 19 to prevent lysis of host cells) fused to human IgG1 Fc (called FH*\/Fc1) killed gonococci in a complement-dependent manner and reduced the duration and bacterial burden in the mouse vaginal colonization model of gonorrhea. Considering the <jats:italic>N. gonorrhoeae<\/jats:italic>-binding FH domains 18-20 are C-terminal in native FH, we reasoned that positioning Fc N-terminal to FH* (Fc1\/FH*) would improve binding and bactericidal activity. Although both molecules bound gonococci similarly, Fc1\/FH* displayed a 5-fold lower IC50 (the concentration required for 50% killing in complement-dependent bactericidal assays) than FH*\/Fc1. To further increase complement activation, we replaced human IgG1 Fc in Fc1\/FH* with Fc from human IgG3, the most potent complement-activating IgG subclass, to obtain Fc3\/FH*. Bactericidal activity was further increased ~2.3-fold in Fc3\/FH* compared to Fc1\/FH*. Fc3\/FH* killed (defined by &amp;lt;50% survival) 45\/45 (100%) diverse PorB1B-expessing gonococci, but only 2\/15 PorB1A-expressing isolates, in a complement-dependent manner. Decreased Fc3\/FH* binding accounted for the limited activity against PorB1A strains. Fc3\/FH* was efficacious against all four tested PorB1B gonococcal strains in the mouse vaginal colonization model when administered at a dose of 5 \u00b5g intravaginally, daily. Furthermore, Fc3\/FH* retained bactericidal activity when reconstituted following lyophilization or spray-drying, suggesting feasibility for formulation into intravaginal rings. In conclusion, Fc3\/FH* represents a promising prophylactic immunotherapeutic against multidrug-resistant gonococci.<\/jats:p>","DOI":"10.3389\/fimmu.2022.975676","type":"journal-article","created":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T08:41:53Z","timestamp":1661848913000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["An optimized Factor H-Fc fusion protein against multidrug-resistant Neisseria gonorrhoeae"],"prefix":"10.3389","volume":"13","author":[{"given":"Jutamas","family":"Shaughnessy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleyo","family":"Chabeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Nowak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolynn","family":"Steffens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosane B.","family":"DeOliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunita","family":"Gulati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa A.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Maclean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Moss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith L.","family":"Wycoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Ram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"548","DOI":"10.2471\/BLT.18.228486","article-title":"Chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence and incidence estimates, 2016","volume":"97","author":"Rowley","year":"2019","journal-title":"Bull World Health Organ"},{"key":"B2","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1097\/00002030-199301000-00015","article-title":"Non-ulcerative sexually transmitted diseases as risk factors for HIV- 1 transmission in women: results from a cohort study [see comments]","volume":"7","author":"Laga","year":"1993","journal-title":"Aids"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1086\/314465","article-title":"Effect of human immunodeficiency virus type 1 infection upon acute salpingitis: a laparoscopic study","volume":"178","author":"Cohen","year":"1998","journal-title":"J Infect Dis"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(97)02190-9","article-title":"Reduction of concentration of HIV-1 in semen after treatment of urethritis: implications for prevention of sexual transmission of HIV-1. 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