Factor H-IgG Chimeric Proteins as a Therapeutic Approach against the Gram-Positive Bacterial Pathogen Streptococcus pyogenes.
Factor H-IgG Chimeric Proteins as a Therapeutic Approach against the Gram-Positive Bacterial Pathogen Streptococcus pyogenes.
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DOI：
10.4049/jimmunol.1700426
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发表时间：
2017-12-01
期刊：
影响因子：
--
通讯作者：
Ermert D
中科院分区：
文献类型：
--
作者：
Blom AM;Magda M;Kohl L;Shaughnessy J;Lambris JD;Ram S;Ermert D
细菌可引起危及生命的感染，如肺炎、脑膜炎或败血症。抗生素治疗是治疗的主要手段，尽管近年来抗生素耐药性急剧增加。不幸的是，针对大多数病原体的安全有效的疫苗尚未获得批准，因此开发替代治疗方法非常重要。我们分析了FH 6 -7/Fc，一种新的抗革兰氏阳性细菌化脓性链球菌的抗菌免疫蛋白的效率。该蛋白由补体抑制剂人因子H的两个结构域（FH补体控制蛋白模块6和7）组成，其结合S。化脓性链球菌，与IgG的Fc区连接（FH 6 -7/Fc）。此前已证明FH 6 -7/Fc可增强对革兰氏阴性病原体流感嗜血杆菌和脑膜炎奈瑟菌动物模型中的补体依赖性杀伤作用并促进细菌清除。我们推测，细菌表面的FH 6 -7/Fc对补体的激活作用与革兰氏阳性菌如S.化脓菌将使专职吞噬细胞消除病原体。我们发现FH 6 -7/Fc减轻了S.化脓性链球菌在表达人FH的转基因小鼠模型中诱导脓毒症（S.化脓性链球菌以人类特异性方式结合FH）。此外，在离体人全血模型中，与蛋白H和选择M蛋白结合的FH 6 -7/Fc从细菌表面置换FH，增强旁路途径活化并通过调理吞噬作用以C3依赖性方式降低细菌血液负荷。总之，FH-Fc嵌合蛋白可以作为针对多药耐药细菌感染的预防性治疗。
Bacteria can cause life-threatening infections, such as pneumonia, meningitis or sepsis. Antibiotic therapy is a mainstay of treatment, although antimicrobial resistance has drastically increased over the years. Unfortunately, safe and effective vaccines against most pathogens have not yet been approved, thus developing alternative treatments is important. We analyzed the efficiency of FH6-7/Fc, a novel antibacterial immunotherapeutic protein against the gram-positive bacterium Streptococcus pyogenes. This protein is composed of two domains of complement inhibitor human factor H (FH complement control protein modules 6 and 7) that bind to S. pyogenes, linked to the Fc region of IgG (FH6-7/Fc). FH6-7/Fc has previously been shown to enhance complement-dependent killing of and facilitate bacterial clearance in animal models of the gram-negative pathogens, Haemophilus influenzae and Neisseria meningitidis. We hypothesized that activation of complement by FH6-7/Fc on the surface of bacteria gram-positive bacteria such as S. pyogenes will enable professional phagocytes to eliminate the pathogen. We found that FH6-7/Fc alleviated S. pyogenes induced sepsis in a transgenic mouse model expressing human FH (S. pyogenes bind FH in a human-specific manner). Furthermore, FH6-7/Fc, which binds to Protein H and select M proteins, displaced FH from the bacterial surface, enhanced alternative pathway activation and reduced bacterial blood burden by opsonophagocytosis in a C3-dependent manner in an ex vivo human whole-blood model. In conclusion, FH-Fc chimeric proteins could serve as adjunctive treatments against multidrug-resistant bacterial infections.
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影响因子：
4.8
作者：
Berge, A;Kihlberg, BM;Bjorck, L
通讯作者：
Bjorck, L
人C4结合蛋白。 ii。 C3B灭活剂在C4B蛋白水解中的作用。
DOI：
10.1084/jem.148.4.1044
发表时间：
1978-10-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fujita T;Gigli I;Nussenzweig V
通讯作者：
Nussenzweig V
DOI：
10.4049/jimmunol.0804031
发表时间：
2009-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ferreira VP;Herbert AP;Cortés C;McKee KA;Blaum BS;Esswein ST;Uhrín D;Barlow PN;Pangburn MK;Kavanagh D
通讯作者：
Kavanagh D
影响因子：
3.6
作者：
Carlsson, F;Sandin, C;Lindahl, G
通讯作者：
Lindahl, G
影响因子：
6.7
作者：
Gustafsson MC;Lannergård J;Nilsson OR;Kristensen BM;Olsen JE;Harris CL;Ufret-Vincenty RL;Stålhammar-Carlemalm M;Lindahl G
通讯作者：
Lindahl G