Abstract：
Yersinia pestis, the causative agent of plague, is a gram-negative bacterium that can be fatal if not treated properly. Three types of plague are currently known: bubonic, septicemic, and pneumonic plague, among which the fatality rate of septicemic and pneumonic plague is very high. Bubonic plague can be treated, but only if antibiotics are used at the initial stage of the infection. But unfortunately, Y. pestis has also shown resistance to certain antibiotics such as kanamycin, minocycline, tetracycline, streptomycin, sulfonamides, spectinomycin, and chloramphenicol. Despite tremendous progress in vaccine development against Y. pestis, there is no proper FDA-approved vaccine available to protect people from its infections. Therefore, effective broad-spectrum vaccine development against Y. pestis is indispensable. In this study, vaccinomics-assisted immunoinformatics techniques were used to find possible vaccine candidates by utilizing the core proteome prepared from 58 complete genomes of Y. pestis. Human non-homologous, pathogen-essential, virulent, and extracellular and membrane proteins are potential vaccine targets. Two antigenic proteins were prioritized for the prediction of lead epitopes by utilizing reverse vaccinology approaches. Four vaccine designs were formulated using the selected B- and T-cell epitopes coupled with appropriate linkers and adjuvant sequences capable of inducing potent immune responses. The HLA allele population coverage of the T-cell epitopes selected for vaccine construction was also analyzed. The V2 constructs were top-ranked and selected for further analysis on the basis of immunological, physicochemical, and immune-receptor docking interactions and scores. Docking and molecular dynamic simulations confirmed the stability of construct V2 interactions with the host immune receptors. Immune simulation analysis anticipated the strong immune profile of the prioritized construct. In silico restriction cloning ensured the feasible cloning ability of the V2 construct in the expression system of E. coli strain K12. It is anticipated that the designed vaccine construct may be safe, effective, and able to elicit strong immune responses against Y. pestis infections and may, therefore, merit investigation using in vitro and in vivo assays.
摘要：
鼠疫耶尔森氏菌,鼠疫的病原体，是一种革兰氏阴性细菌，如果治疗不当，可能会致命。目前已知三种类型的鼠疫：鼠疫，败血症，和肺鼠疫，其中败血症和肺鼠疫的死亡率很高。鼠疫可以治疗，但前提是在感染的初始阶段使用抗生素。但不幸的是，鼠疫菌还显示出对某些抗生素如卡那霉素的抗性，米诺环素,四环素,链霉素,磺胺类药物,壮观霉素,和氯霉素.尽管在针对鼠疫耶尔森氏菌的疫苗开发方面取得了巨大进展，没有适当的FDA批准的疫苗来保护人们免受其感染。因此,针对鼠疫菌的有效广谱疫苗开发是不可或缺的。在这项研究中,通过利用由58个完整的鼠疫耶尔森氏菌基因组制备的核心蛋白质组，使用疫苗组学辅助的免疫信息学技术来寻找可能的疫苗候选物。人类非同源，病原体必需，剧毒,细胞外和膜蛋白是潜在的疫苗靶标。通过利用反向疫苗学方法，将两种抗原蛋白优先用于预测前导表位。使用与适当的接头和能够诱导有效免疫应答的佐剂序列偶联的选择的B-和T-细胞表位配制四种疫苗设计。还分析了选择用于疫苗构建的T细胞表位的HLA等位基因群体覆盖率。V2构建体排名最高，并根据免疫学进行进一步分析。物理化学,以及免疫-受体对接相互作用和评分。对接和分子动力学模拟证实了构建体V2与宿主免疫受体相互作用的稳定性。免疫模拟分析预测了优先结构的强免疫谱。计算机限制性克隆确保了V2构建体在大肠杆菌菌株K12的表达系统中的可行克隆能力。预计设计的疫苗构建体可能是安全的，有效,并能引起强烈的免疫反应，对抗鼠疫菌感染，因此,值得使用体外和体内试验进行研究。
