Development of Complement Factor H-Based Immunotherapeutic Molecules in Tobacco Plants Against Multidrug-Resistant Neisseria gonorrhoeae.
Development of Complement Factor H-Based Immunotherapeutic Molecules in Tobacco Plants Against Multidrug-Resistant Neisseria gonorrhoeae.
复制标题
DOI：
10.3389/fimmu.2020.583305
复制
发表时间：
2020
影响因子：
7.3
通讯作者：
Ram S
中科院分区：
文献类型：
--
作者：
Shaughnessy J;Tran Y;Zheng B;DeOliveira RB;Gulati S;Song WC;Maclean JM;Wycoff KL;Ram S
迫切需要针对多重耐药淋球菌的全球威胁的新疗法。淋球菌具有几种逃避人补体杀伤的机制，包括与旁路途径的关键抑制剂H因子（FH）结合。FH包含20个短共有重复（SCR）结构域，其以头对尾方式组织为单链。n.淋病结合FH中的两个区域;结构域6和7以及结构域18至20。我们设计了一种新的抗感染免疫球蛋白分子，其将FH的结构域18 - 20（在结构域19的位置1119处含有D至G突变（称为FH *））与人IgG1 Fc融合。FH */Fc保留与淋球菌的结合，但不裂解人红细胞。FH */Fc在烟草植物中的表达作为替代的经济生产平台进行。FH */Fc在烟草植物中以高产率表达（300 - 600 mg/kg生物量）。植物和CHO细胞产生的FH */Fc对淋球菌的活性在体外和淋病的小鼠阴道定植模型中相似。柔性连接体的添加[例如，（GGGGS）2或（GGGGS）3]使FH */Fc的杀菌效力提高2.7倍。接头还改善了PMN介导的调理吞噬作用约11倍。具有接头的FH */Fc还有效地减少了在小鼠中测试的两种淋球菌菌株的定殖的持续时间和负担。FH */Fc丧失效力：i）C6 −/−小鼠（无末端补体）和ii）当Fc突变以消除补体激活时，表明完整的补体是FH */Fc体内功能所必需的。总之，植物产生的FH */Fc代表了有希望的针对多药耐药淋球菌的预防性或预防性免疫治疗剂。
Novel therapeutics against the global threat of multidrug-resistant Neisseria gonorrhoeae are urgently needed. Gonococci possess several mechanisms to evade killing by human complement, including binding of factor H (FH), a key inhibitor of the alternative pathway. FH comprises 20 short consensus repeat (SCR) domains organized in a head-to-tail manner as a single chain. N. gonorrhoeae binds two regions in FH; domains 6 and 7 and domains 18 through 20. We designed a novel anti-infective immunotherapeutic molecule that fuses domains 18–20 of FH containing a D-to-G mutation in domain 19 at position 1119 (called FH*) with human IgG1 Fc. FH*/Fc retained binding to gonococci but did not lyse human erythrocytes. Expression of FH*/Fc in tobacco plants was undertaken as an alternative, economical production platform. FH*/Fc was expressed in high yields in tobacco plants (300–600 mg/kg biomass). The activities of plant- and CHO-cell produced FH*/Fc against gonococci were similar in vitro and in the mouse vaginal colonization model of gonorrhea. The addition of flexible linkers [e.g., (GGGGS)2 or (GGGGS)3] between FH* and Fc improved the bactericidal efficacy of FH*/Fc 2.7-fold. The linkers also improved PMN-mediated opsonophagocytosis about 11-fold. FH*/Fc with linker also effectively reduced the duration and burden of colonization of two gonococcal strains tested in mice. FH*/Fc lost efficacy: i) in C6−/− mice (no terminal complement) and ii) when Fc was mutated to abrogate complement activation, suggesting that an intact complement was necessary for FH*/Fc function in vivo. In summary, plant-produced FH*/Fc represent promising prophylactic or adjunctive immunotherapeutics against multidrug-resistant gonococci.
登录
查看更多内容
影响因子：
4.4
作者：
Fattahi, Fateme;Grailer, Jamison J.;Ward, Peter A.
通讯作者：
Ward, Peter A.
DOI：
10.4049/jimmunol.1102310
发表时间：
2012-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Banda NK;Hyatt S;Antonioli AH;White JT;Glogowska M;Takahashi K;Merkel TJ;Stahl GL;Mueller-Ortiz S;Wetsel R;Arend WP;Holers VM
通讯作者：
Holers VM
影响因子：
16.1
作者：
Chen, Xiaoying;Zaro, Jennica L.;Shen, Wei-Chiang
通讯作者：
Shen, Wei-Chiang
影响因子：
56.9
作者：
DAWSON, PE;MUIR, TW;KENT, SBH
通讯作者：
KENT, SBH
影响因子：
36.8
作者：
FIGUEROA, JE;DENSEN, P
通讯作者：
DENSEN, P