Department of Translational Medicine, Lund University, Malmö, Sweden.
Department of Medicine, Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
JCI Insight. 2019 Dec 5;4(23):131886. doi: 10.1172/jci.insight.131886.
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.
淋病是一种性传播感染，全球每年有 8700 万例新发病例。抗生素耐药性的增加严重限制了治疗选择。淋病奈瑟菌逃避补体攻击的一种机制是结合补体抑制剂 C4 结合蛋白（C4BP）。我们从过去 10 年瑞典菌株库中随机筛选了 107 个 Porin B1a（PorB1a）和 83 个 PorB1b 临床分离株，注意到 96/107（89.7%）PorB1a 和 16/83（19.3%）PorB1b 结合 C4BP；C4BP 结合与逃避补体依赖性杀伤的能力密切相关（r = 0.78）。我们设计了 2 种嵌合蛋白，将 C4BP 结构域融合到 IgG 或 IgM 的骨架上（C4BP-IgG；C4BP-IgM），旨在增强补体激活和杀伤淋球菌的能力。这两种蛋白都结合淋球菌（KD C4BP-IgM = 2.4 nM；KD C4BP-IgG 980.7 nM），但只有六聚体 C4BP-IgM 能有效地从细菌表面竞争出七聚体 C4BP，从而增强补体沉积和细菌杀伤。此外，C4BP-IgM 显著减弱了 2 种 C4BP 结合淋球菌分离株的定植持续时间和负担，但对非 C4BP 结合株没有影响，在使用人因子 H/C4BP 转基因小鼠的小鼠阴道定植模型中。我们的临床前数据表明，C4BP-IgM 可作为传统抗菌药物治疗淋病的辅助药物。
