Characterization of rationally attenuated Francisella tularensis vaccine strains that harbor deletions in the guaA and guaB genes.
Characterization of rationally attenuated Francisella tularensis vaccine strains that harbor deletions in the guaA and guaB genes.
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DOI：
10.1016/j.vaccine.2009.02.073
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发表时间：
2009-04-21
期刊：
影响因子：
5.5
通讯作者：
Barry EM
中科院分区：
文献类型：
--
作者：
Santiago AE;Cole LE;Franco A;Vogel SN;Levine MM;Barry EM
土拉热弗朗西斯菌是土拉菌病的病原体，吸入低至10-100 CFU即可引起严重和致命的感染。F.土拉热是一种潜在的生物恐怖主义制剂，因此是制定对策的优先事项。用从B型菌株开发的活疫苗株（LVS）接种，可提供部分保护，使其免于暴露于毒性更强的A型菌株的空气中，并提供了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，阻碍了其许可和广泛使用。为了解决使LVS成为次优兔热病疫苗的特定缺陷，我们设计了F。在编码鸟嘌呤核苷酸生物合成途径中的关键酶的guaA或guaB基因中具有靶向缺失的土拉热菌LVS菌株。F.土拉热菌LVSΔguaA和LVSΔguaB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，但引起了与亲本LVS相当的强烈的促炎细胞因子应答。用单剂量的F.土拉热菌LVSΔguaA或LVSΔguaB突变体完全免受LVS亲本菌株的后续致死攻击。这些发现表明这些靶基因的特异性缺失可以产生安全有效的减毒活疫苗。
Francisella tularensis, the etiologic agent of tularemia, can cause severe and fatal infection after inhalation of as few as 10-100 CFU. 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 LVSΔguaA and LVSΔguaB 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 LVSΔguaA or LVSΔguaB 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.
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影响因子：
5.5
作者：
Bakshi CS;Malik M;Mahawar M;Kirimanjeswara GS;Hazlett KR;Palmer LE;Furie MB;Singh R;Melendez JA;Sellati TJ;Metzger DW
通讯作者：
Metzger DW
DOI：
10.1073/pnas.0504271103
发表时间：
2006-01-03
影响因子：
11.1
作者：
Gavrilin, MA;Bouakl, IJ;Wewers, MD
通讯作者：
Wewers, MD
影响因子：
3.1
作者：
Golovliov, I;Baranov, V;Sjöstedt, A
通讯作者：
Sjöstedt, A
影响因子：
3.1
作者：
Cole, Leah E.;Shirey, Kari Ann;Vogel, Stefanie N.
通讯作者：
Vogel, Stefanie N.
影响因子：
3.1
作者：
Ericsson, M;Golovliov, I;Sjostedt, A
通讯作者：
Sjostedt, A