Identification and validation of a linear protective neutralizing epitope in the β-pore domain of alpha toxin.
Identification and validation of a linear protective neutralizing epitope in the β-pore domain of alpha toxin.
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在α毒素的β孔域中鉴定和验证线性保护性中和表位。
DOI：
10.1371/journal.pone.0116882
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Cease KB
中科院分区：
文献类型：
--
作者：
Oscherwitz J;Cease KB
与金黄色葡萄球菌相关的过多的毒力因子使这种细菌成为分子设计的以表位为中心的疫苗的有吸引力的候选者。这种方法需要鉴定中和表位以掺入疫苗构建体中，正在评估常规方法未能引起保护性体液应答的病原体，如HIV-1和疟疾，但也可能对S.金黄色葡萄球菌，其中可能需要激发针对多种毒力因子的体液免疫来开发有效的疫苗。在S.金黄色葡萄球菌、动物模型和流行病学数据表明，α毒素（一种来自炭疽芽孢杆菌的多聚体β-孔形成毒素样保护性抗原）是特别关键的，但迄今为止还没有在α毒素中描绘出候选的中和表位。我们以前已经证明，在B的成孔结构域的2β2-2β3环中的线性决定簇。炭疽保护性抗原是线性中和表位。针对该位点的抗体在体外中和炭疽致死毒素和在体内保护兔免受强毒B的攻击是高度有效的。炭疽病我们假设S.与保护性抗原中β孔序列具有结构和功能同源性的金黄色葡萄球菌α毒素将含有类似的关键中和表位。使用在体内映射策略，采用肽免疫原，优化的体外毒素中和试验，并在体内皮肤坏死模型，我们现在已经证实了这种表位在α毒素，称为孔中和决定簇的存在。对该决定簇特异的抗体在体外中和α毒素，并且在S.金黄色葡萄球菌USA 300皮肤感染。这种线性中和决定簇在α毒素中的描绘可以促进针对S的表位聚焦疫苗的开发。金黄色。
The plethora of virulence factors associated with Staphylococcus aureus make this bacterium an attractive candidate for a molecularly-designed epitope-focused vaccine. This approach, which necessitates the identification of neutralizing epitopes for incorporation into a vaccine construct, is being evaluated for pathogens where conventional approaches have failed to elicit protective humoral responses, like HIV-1 and malaria, but may also hold promise for pathogens like S. aureus, where the elicitation of humoral immunity against multiple virulence factors may be required for development of an effective vaccine. Among the virulence factors employed by S. aureus, animal model and epidemiological data suggest that alpha toxin, a multimeric β-pore forming toxin like protective antigen from Bacillus anthracis, is particularly critical, yet no candidate neutralizing epitopes have been delineated in alpha toxin to date. We have previously shown that a linear determinant in the 2β2-2β3 loop of the pore forming domain of B. anthracis protective antigen is a linear neutralizing epitope. Antibody against this site is highly potent for neutralizing anthrax lethal toxin in vitro and for protection of rabbits in vivo from virulent B. anthracis. We hypothesized that sequences in the β-pore of S. aureus alpha toxin that share structural and functional homology to β-pore sequences in protective antigen would contain a similarly critical neutralizing epitope. Using an in vivo mapping strategy employing peptide immunogens, an optimized in vitro toxin neutralization assay, and an in vivo dermonecrosis model, we have now confirmed the presence of this epitope in alpha toxin, termed the pore neutralizing determinant. Antibody specific for this determinant neutralizes alpha toxin in vitro, and is highly effective for mitigating dermonecrosis and bacterial growth in a mouse model of S. aureus USA300 skin infection. The delineation of this linear neutralizing determinant in alpha toxin could facilitate the development of an epitope-focused vaccine against S. aureus.
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影响因子：
168.9
作者：
DeLeo, Frank R.;Otto, Michael;Kreiswirth, Barry N.;Chambers, Henry F.
通讯作者：
Chambers, Henry F.
影响因子：
5.6
作者：
Folettit, Davide;Strop, Pavel;Shelton, Dave
通讯作者：
Shelton, Dave
影响因子：
1.7
作者：
Hering, D;Thompson, W;Pace-Templeton, J
通讯作者：
Pace-Templeton, J
影响因子：
3.7
作者：
Brady, Rebecca A.;Mocca, Christopher P.;Burns, Drusilla L.
通讯作者：
Burns, Drusilla L.
DOI：
10.2165/00063030-200721030-00002
发表时间：
2007
期刊：
BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy
影响因子：
--
作者：
Gershoni JM;Roitburd-Berman A;Siman-Tov DD;Tarnovitski Freund N;Weiss Y
通讯作者：
Weiss Y