Progress toward the Development of a NEAT Protein Vaccine for Anthrax Disease
Progress toward the Development of a NEAT Protein Vaccine for Anthrax Disease
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DOI：
10.1128/iai.00755-16
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发表时间：
2016-12-01
影响因子：
3.1
通讯作者：
Maresso, Anthony W.
中科院分区：
文献类型：
--
作者：
Balderas, Miriam A.;Nguyen, Chinh T. Q.;Maresso, Anthony W.
炭疽芽孢杆菌是一种产生孢子的革兰氏阳性细菌，是炭疽病的病原体，也是生物恐怖主义的潜在武器。美国许可的炭疽疫苗是由未完全表征的非包膜产毒菌株（炭疽疫苗吸收[AVA]）的培养物上清液制成，其主要保护成分被认为是保护性抗原（PA）。 AVA 可有效保护动物并在人体中引发毒素中和抗体，但由于其成分不明确、多次注射方案、推荐的加强剂以及潜在的不良反应，热情受到了抑制。改进下一代炭疽疫苗对于保护公民和军队非常重要。在这里，我们报告说，用革兰氏阳性病原体中常见的保守结构域（近铁转运蛋白 [NEAT]）的重组形式进行疫苗接种，可以在炭疽杆菌感染的小鼠模型中引起保护。弗氏佐剂和明矾佐剂分别通过皮下和肌内注射以及 NEAT 混合复合物观察到了保护作用。保护作用与针对 NEAT 结构域的抗体反应以及主要器官中细菌数量的减少相关。抗 NEAT 抗体促进肺泡巨噬细胞对杆菌的调理吞噬作用。为了指导无活性且安全的 NEAT 抗原的开发，我们还报告了 NEAT 结构域之一 (Hal) 的晶体结构，并鉴定了介导其血红素结合和获取活性的关键残基。这些结果表明我们应该在开发改进的抗炭疽疫苗时考虑 NEAT 蛋白。
Bacillus anthracis is a sporulating Gram-positive bacterium that is the causative agent of anthrax and a potential weapon of bioterrorism. The U. S.-licensed anthrax vaccine is made from an incompletely characterized culture supernatant of a nonencapsulated, toxigenic strain (anthrax vaccine absorbed [AVA]) whose primary protective component is thought to be protective antigen (PA). AVA is effective in protecting animals and elicits toxin-neutralizing antibodies in humans, but enthusiasm is dampened by its undefined composition, multishot regimen, recommended boosters, and potential for adverse reactions. Improving next-generation anthrax vaccines is important to safeguard citizens and the military. Here, we report that vaccination with recombinant forms of a conserved domain (near-iron transporter [NEAT]), common in Gram-positive pathogens, elicits protection in a murine model of B. anthracis infection. Protection was observed with both Freund's and alum adjuvants, given subcutaneously and intramuscularly, respectively, with a mixed composite of NEATs. Protection correlated with an antibody response against the NEAT domains and a decrease in the numbers of bacteria in major organs. Anti-NEAT antibodies promote opsonophagocytosis of bacilli by alveolar macrophages. To guide the development of inactive and safe NEAT antigens, we also report the crystal structure of one of the NEAT domains (Hal) and identify critical residues mediating its heme-binding and acquisition activity. These results indicate that we should consider NEAT proteins in the development of an improved antianthrax vaccine.