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首页> 外文期刊>Vaccine >Characterization of rationally attenuated Francisella tularensis vaccine strains that harbor deletions in the guaA and guaB genes
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Characterization of rationally attenuated Francisella tularensis vaccine strains that harbor deletions in the guaA and guaB genes

机译：表征在guaA和guaB基因中缺失的合理减毒的土拉弗朗西斯菌疫苗株的特性

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Francisella tularensis, the etiologic agent of tularemia, can cause severe and fatal infection after inhalation of as few as 10 -- 100CFU. F. tularensis is a potential bioterrorism agent and, therefore, a priority for countermeasure development. Vaccination with the live vaccine strain (LVS), developed from a Type B strain, confers partial protection against aerosal exposure to the more virulent Type A strains and provides proof of principle that a live attenuated vaccine strain may be efficacious. However LVS suffers from several notable drawbacks that have prevented its licensure and widespread use. To address the specific deficiencies that render LVS a sub-optimal tularemia vaccine, we engineered F. tularensis LVS strains with targeted deletions in the guaA or guaB genes that encode critical enzymes in the guanine nucleotide biosynthetic pathway. F. tularensis LVSDeltaguaA and LVSDeltaguaB mutants were guanine auxotrophs and were highly attenuated in a mouse model of infection. While the mutants failed to replicate in macrophages, a robust proinflammatory cytokine response, equivalent to that of the parental LVS, was elicited. Mice vaccinated with a single dose of the F. tularensis LVSDeltaguaA or LVSDeltaguaB mutant were fully protected against subsequent lethal challenge with the LVS parental strain. These findings suggest the specific deletion of these target genes could generate a safe and efficacious live attenuated vaccine.
机译：tularemia的病原体Francisella tularensis吸入低至10-100CFU可能引起严重和致命的感染。 Tularensis是一种潜在的生物恐怖分子，因此，是发展对策的优先事项。由B型毒株开发的活疫苗株（LVS）进行疫苗接种，可部分保护其免受暴露于更强毒的A型毒株的暴露，并提供减毒活疫苗株可能有效的原理证明。然而，LVS有几个明显的缺点，这些缺点阻止了其许可和广泛使用。为了解决使LVS成为次优Tularemia疫苗的特定缺陷，我们设计了F. tularensis LVS菌株，在guaA或guaB基因中靶向性缺失，该基因编码鸟嘌呤核苷酸生物合成途径中的关键酶。 F. tularensis LVSDeltaguaA和LVSDeltaguaB突变体是鸟嘌呤营养缺陷型，在小鼠感染模型中高度减毒。虽然突变体未能在巨噬细胞中复制，但引发了与亲本LVS相当的强烈的促炎细胞因子反应。接种了单剂量的F. tularensis LVSDeltaguaA或LVSDeltaguaB突变体的小鼠得到了充分的保护，可以抵抗随后用LVS亲本菌株造成的致命攻击。这些发现表明，这些靶基因的特异性缺失可产生安全有效的减毒活疫苗。

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