Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
J Immunol. 2012 Apr 1;188(7):3416-25. doi: 10.4049/jimmunol.1102746. Epub 2012 Feb 24.
Gonorrhea, a sexually transmitted disease caused by Neisseria gonorrhoeae, is an important cause of morbidity worldwide. A safe and effective vaccine against gonorrhea is needed because of emerging resistance of gonococci to almost every class of antibiotic. A gonococcal lipooligosaccharide epitope defined by the mAb 2C7 is being evaluated as a candidate for development of an Ab-based vaccine. Immune Abs against N. gonorrhoeae need to overcome several subversive mechanisms whereby gonococcus evades complement, including binding to C4b-binding protein (C4BP; classical pathway inhibitor) and factor H (alternative pathway [AP] inhibitor). The role of AP recruitment and, in particular, properdin in assisting killing of gonococci by specific Abs is the subject of this study. We show that only those gonococcal strains that bind C4BP require properdin for killing by 2C7, whereas strains that do not bind C4BP are efficiently killed by 2C7 even when AP function is blocked. C3 deposition on bacteria mirrored killing. Recruitment of the AP by mAb 2C7, as measured by factor B binding, occurred in a properdin-dependent manner. These findings were confirmed using isogenic mutant strains that differed in their ability to bind to C4BP. Immune human serum that contained bactericidal Abs directed against the 2C7 lipooligosaccharide epitope as well as murine antigonococcal antiserum required functional properdin to kill C4BP-binding strains, but not C4BP-nonbinding strains. Collectively, these data point to an important role for properdin in facilitating immune Ab-mediated complement-dependent killing of gonococcal strains that inhibit the classical pathway by recruiting C4BP.
淋病是由淋病奈瑟菌引起的性传播疾病，是全球发病率的重要原因。由于淋球菌对几乎每一类抗生素的耐药性不断出现，因此需要一种安全有效的淋病疫苗。一种由 mAb 2C7 定义的淋球菌脂寡糖表位正在被评估为开发 Ab 为基础的疫苗的候选物。针对淋病奈瑟氏球菌的免疫 Abs 需要克服几种逃避补体的颠覆性机制，包括与 C4b 结合蛋白（C4BP；经典途径抑制剂）和因子 H（替代途径[AP]抑制剂）结合。AP 募集的作用，特别是补体因子 D 在协助特异性 Abs 杀伤淋球菌中的作用是本研究的主题。我们表明，只有那些结合 C4BP 的淋球菌菌株需要补体因子 D 才能被 2C7 杀伤，而不结合 C4BP 的菌株即使在 AP 功能被阻断的情况下也能被 2C7 有效杀伤。细菌上 C3 的沉积与杀伤情况相符。通过因子 B 结合来测量 mAb 2C7 对 AP 的募集，这是一种依赖于补体因子 D 的方式。使用在结合 C4BP 能力上存在差异的同基因突变株证实了这一发现。含有针对 2C7 脂寡糖表位的杀菌 Abs 的免疫人血清以及抗淋病奈瑟氏球菌的鼠抗血清需要功能性补体因子 D 来杀伤结合 C4BP 的菌株，但不能杀伤不结合 C4BP 的菌株。总的来说，这些数据表明补体因子 D 在促进免疫 Ab 介导的补体依赖性杀伤通过募集 C4BP 抑制经典途径的淋球菌菌株方面发挥着重要作用。
