Structurally designed attenuated subunit vaccines for S. aureus LukS-PV and LukF-PV confer protection in a mouse bacteremia model.
Structurally designed attenuated subunit vaccines for S. aureus LukS-PV and LukF-PV confer protection in a mouse bacteremia model.
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DOI：
10.1371/journal.pone.0065384
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Aman MJ
中科院分区：
文献类型：
--
作者：
Karauzum H;Adhikari RP;Sarwar J;Devi VS;Abaandou L;Haudenschild C;Mahmoudieh M;Boroun AR;Vu H;Nguyen T;Warfield KL;Shulenin S;Aman MJ
以前的努力S。金黄色葡萄球菌疫苗的开发主要集中在细胞表面抗原上，以诱导调理吞噬细胞杀伤，目的是提供无菌免疫，这一概念成功地应用于其他革兰氏阳性病原体，如肺炎链球菌。然而，这些方法在很大程度上失败了，可能部分是由于葡萄球菌毒力因子的显著多样性，如分泌的免疫抑制和组织破坏性毒素。S.金黄色葡萄球菌产生几种成孔毒素，包括单亚基α溶血素以及双组分白细胞毒素如Panton-Valentine杀白细胞素（PVL）、γ溶血素（Hlg）和LukED。在这里，我们报告的高度减毒突变体的PVL亚基LukS-PV和LukF-PV的合理设计，基于毒素的八聚体结构模型，是缺乏寡聚化的一代。减毒亚单位疫苗具有高度免疫原性，在小鼠S.金黄色葡萄球菌USA 300脓毒症。通过被动转移针对LukS-PV产生的兔免疫球蛋白也证明了针对脓毒症的保护。LukS-PV抗体抑制LukS-PV与LukF-PV的同源寡聚化以及与HlgB的异源寡聚化。重要的是，来自接种LukS突变体的小鼠的免疫血清不仅抑制了由PVL阳性USA 300产生的PMN裂解活性，而且还阻断了由PVL阴性菌株的上清液诱导的PMN裂解，这表明对其他双组分毒素具有广泛的保护活性。这些发现有力地支持了一种旨在预防临床S.金黄色葡萄球菌侵袭性疾病，而不是实现无菌免疫。这样的多价疫苗可以包括减毒的白细胞毒素、α溶血素和超抗原。
Previous efforts towards S. aureus vaccine development have largely focused on cell surface antigens to induce opsonophagocytic killing aimed at providing sterile immunity, a concept successfully applied to other Gram-positive pathogens such as Streptococcus pneumoniae. However, these approaches have largely failed, possibly in part due to the remarkable diversity of the staphylococcal virulence factors such as secreted immunosuppressive and tissue destructive toxins. S. aureus produces several pore-forming toxins including the single subunit alpha hemolysin as well as bicomponent leukotoxins such as Panton-Valentine leukocidin (PVL), gamma hemolysins (Hlg), and LukED. Here we report the generation of highly attenuated mutants of PVL subunits LukS-PV and LukF-PV that were rationally designed, based on an octameric structural model of the toxin, to be deficient in oligomerization. The attenuated subunit vaccines were highly immunogenic and showed significant protection in a mouse model of S. aureus USA300 sepsis. Protection against sepsis was also demonstrated by passive transfer of rabbit immunoglobulin raised against LukS-PV. Antibodies to LukS-PV inhibited the homologous oligomerization of LukS-PV with LukF-PV as well heterologous oligomerization with HlgB. Importantly, immune sera from mice vaccinated with the LukS mutant not only inhibited the PMN lytic activity produced by the PVL-positive USA300 but also blocked PMN lysis induced by supernatants of PVL-negative strains suggesting a broad protective activity towards other bicomponent toxins. These findings strongly support the novel concept of an anti-virulence, toxin-based vaccine intended for prevention of clinical S. aureus invasive disease, rather than achieving sterile immunity. Such a multivalent vaccine may include attenuated leukotoxins, alpha hemolysin, and superantigens.
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影响因子：
3.1
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通讯作者：
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作者：
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