Utilizing complement evasion strategies to design complement-based antibacterial immunotherapeutics: Lessons from the pathogenic Neisseriae.
Utilizing complement evasion strategies to design complement-based antibacterial immunotherapeutics: Lessons from the pathogenic Neisseriae.
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DOI：
10.1016/j.imbio.2016.05.016
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发表时间：
2016-10
期刊：
影响因子：
2.8
通讯作者：
Rice PA
中科院分区：
文献类型：
--
作者：
Ram S;Shaughnessy J;DeOliveira RB;Lewis LA;Gulati S;Rice PA
迫切需要新的治疗方法来对抗多重耐药病原体的全球威胁。补体形成了抵抗感染的先天防御的重要武器。在生理条件下，补体激活受到可溶性和膜相关补体抑制剂的严格控制，但必须在入侵病原体上选择性激活以促进微生物清除。许多病原体，包括淋病奈瑟菌和N.脑膜炎，表达聚糖，包括N-乙酰神经氨酸（Neu5Ac），模拟宿主结构逃避宿主免疫。Neu5Ac是一种带负电荷的9-碳糖，其抑制补体，部分通过增强补体抑制因子H（FH）通过FH上的C-末端结构域（19和20）的结合。其他微生物也结合FH，在大多数情况下通过FH结构域6和7或18 - 20。在这里，我们描述了两种策略，以目标补体激活奈瑟氏球菌。首先，将FH的微生物结合结构域与IgG Fc融合以产生FH18 - 20/Fc（结合淋球菌）和FH6，7/Fc（结合脑膜炎球菌）。FH结构域19中的点突变消除了由未修饰的FH 18 - 20引起的溶血，但保留了与淋球菌的结合。FH18 - 20/Fc和FH6，7/Fc在体外介导补体依赖性杀伤，并分别在淋病和脑膜炎球菌菌血症的动物模型中显示出有效性。第二种策略利用唾液酸的CMP-壬酮糖酸盐（CMP-NulO）类似物，其掺入LOS中并防止生理性CMP-Neu5Ac的补体抑制，并导致小鼠中的淋球菌感染减弱。虽然需要研究以确定这些药物的安全性，但增强补体对微生物的激活可能是治疗抗微生物药物耐药微生物的一种有前景的策略。
Novel therapies are urgently needed to combat the global threat of multidrug-resistant pathogens. Complement forms an important arm of innate defenses against infections. In physiological conditions, complement activation is tightly controlled by soluble and membrane-associated complement inhibitors, but must be selectively activated on invading pathogens to facilitate microbial clearance. Many pathogens, including Neisseria gonorrhoeae and N. meningitidis, express glycans, including N-acetylneuraminic acid (Neu5Ac), that mimic host structures to evade host immunity. Neu5Ac is a negatively charged 9-cabon sugar that inhibits complement, in part by enhancing binding of the complement inhibitor factor H (FH) through C-terminal domains (19 and 20) on FH. Other microbes also bind FH, in most instances through FH domains 6 and 7 or 18-20. Here we describe two strategies to target complement activation on Neisseriae. First, microbial binding domains of FH were fused to IgG Fc to create FH18-20/Fc (binds gonococci) and FH6,7/Fc (binds meningococci). A point mutation in FH domain 19 eliminated hemolysis caused by unmodified FH18-20, but retained binding to gonococci. FH18-20/Fc and FH6,7/Fc mediated complement-dependent killing in vitro and showed efficacy in animal models of gonorrhea and meningococcal bacteremia, respectively. The second strategy utilized CMP-nonulosonate (CMP-NulO) analogs of sialic acid that were incorporated into LOS and prevented complement inhibition by physiologic CMP-Neu5Ac and resulted in attenuated gonococcal infection in mice. While studies to establish the safety of these agents are needed, enhancing complement activation on microbes may represent a promising strategy to treat antimicrobial resistant organisms.