Conversion of RpoS(-) Attenuated Salmonella enterica Serovar Typhi Vaccine Strains to RpoS(+) Improves Their Resistance to Host Defense Barriers.
Conversion of RpoS(-) Attenuated Salmonella enterica Serovar Typhi Vaccine Strains to RpoS(+) Improves Their Resistance to Host Defense Barriers.
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DOI：
10.1128/msphere.00006-18
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发表时间：
2018-01
期刊：
影响因子：
4.8
通讯作者：
Curtiss R 3rd
中科院分区：
文献类型：
--
作者：
Burda WN;Brenneman KE;Gonzales A;Curtiss R 3rd
重组减毒沙门氏菌疫苗 (RASV) 代表了对抗传染病的独特预防策略，因为它们利用沙门氏菌侵入和定植深层效应淋巴组织的能力，并以最低免疫剂量提供异源和同源衍生抗原。我们最近在人类志愿者中进行的临床试验表明，Ty2 的 RpoS+ 衍生物比其 RpoS− 衍生物更能诱导免疫反应。在这项研究中，我们证明功能性 RpoS 等位基因有利于开发针对伤寒沙门氏菌的有效减毒活疫苗或使用伤寒沙门氏菌作为重组减毒疫苗载体来传递其他保护性抗原。绝大多数伤寒减毒活疫苗是由伤寒沙门氏菌血清型伤寒菌株 Ty2 构建的，由于存在移码突变，该菌株缺乏功能性替代 Sigma 因子 RpoS。 RpoS 是一种特殊的西格玛因子，在包括沙门氏菌在内的许多革兰氏阴性生物体的一般应激反应中发挥着重要作用。先前的研究表明，这种西格玛因子对于暴露于酸、过氧化氢、营养限制条件和饥饿后的生存是必需的。此外，对肠沙门氏菌伤寒血清型和伤寒小鼠模型的研究表明，RpoS 对于受感染的小鼠宿主体内的定植和存活很重要。我们将 4 种临床研究的候选伤寒疫苗株（源自 Ty2 [CVD908-htrA、Ty800 和 χ9639(pYA3493)] 和获得许可的活伤寒疫苗 Ty21a（也源自 Ty2））转化为 RpoS+，并将它们承受宿主内可能遇到的环境压力的能力与 RpoS− 进行比较 亲本菌株。我们的研究结果表明，含有功能性 RpoS 的菌株能够在应激后更好地生存，并且非常适合进一步开发作为预防伤寒沙门氏菌感染的安全、有效的疫苗，或作为旨在预防人类其他传染病病原体的重组减毒沙门氏菌疫苗 (RASV) 的载体。此处构建和描述的伤寒沙门氏菌菌株将根据要求免费提供，用于将 rpoS 突变体转化为 RpoS+ 的自杀载体也将免费提供。重要性 重组减毒沙门氏菌疫苗 (RASV) 代表了一种对抗传染病的独特预防策略，因为它们利用沙门氏菌侵入和定植深层效应淋巴组织的能力，并以最低免疫剂量提供异源和同源衍生抗原。我们最近在人类志愿者中进行的临床试验表明，Ty2 的 RpoS+ 衍生物比其 RpoS− 衍生物更能诱导免疫反应。在这项研究中，我们证明功能性 RpoS 等位基因有利于开发针对伤寒沙门氏菌的有效减毒活疫苗或使用伤寒沙门氏菌作为重组减毒疫苗载体来传递其他保护性抗原。
Recombinant attenuated Salmonella vaccines (RASVs) represent a unique prevention strategy to combating infectious disease because they utilize the ability of Salmonella to invade and colonize deep effector lymphoid tissues and deliver hetero- and homologous derived antigens at the lowest immunizing dose. Our recent clinical trial in human volunteers indicated that an RpoS+ derivative of Ty2 was better at inducing immune responses than its RpoS− counterpart. In this study, we demonstrate that a functional RpoS allele is beneficial for developing effective live attenuated vaccines against S. Typhi or in using S. Typhi as a recombinant attenuated vaccine vector to deliver other protective antigens. The vast majority of live attenuated typhoid vaccines are constructed from the Salmonella enterica serovar Typhi strain Ty2, which is devoid of a functioning alternative sigma factor, RpoS, due to the presence of a frameshift mutation. RpoS is a specialized sigma factor that plays an important role in the general stress response of a number of Gram-negative organisms, including Salmonella. Previous studies have demonstrated that this sigma factor is necessary for survival following exposure to acid, hydrogen peroxide, nutrient-limiting conditions, and starvation. In addition, studies with Salmonella enterica serovar Typhimurium and the mouse model of typhoid fever have shown that RpoS is important in colonization and survival within the infected murine host. We converted 4 clinically studied candidate typhoid vaccine strains derived from Ty2 [CVD908-htrA, Ty800, and χ9639(pYA3493)] and the licensed live typhoid vaccine Ty21a (also derived from Ty2) to RpoS+ and compared their abilities to withstand environmental stresses that may be encountered within the host to those of the RpoS− parent strains. The results of our study indicate that strains that contain a functional RpoS were better able to survive following stress and that they would be ideal for further development as safe, effective vaccines to prevent S. Typhi infections or as vectors in recombinant attenuated Salmonella vaccines (RASVs) designed to protect against other infectious disease agents in humans. The S. Typhi strains constructed and described here will be made freely available upon request, as will the suicide vector used to convert rpoS mutants to RpoS+. IMPORTANCE Recombinant attenuated Salmonella vaccines (RASVs) represent a unique prevention strategy to combating infectious disease because they utilize the ability of Salmonella to invade and colonize deep effector lymphoid tissues and deliver hetero- and homologous derived antigens at the lowest immunizing dose. Our recent clinical trial in human volunteers indicated that an RpoS+ derivative of Ty2 was better at inducing immune responses than its RpoS− counterpart. In this study, we demonstrate that a functional RpoS allele is beneficial for developing effective live attenuated vaccines against S. Typhi or in using S. Typhi as a recombinant attenuated vaccine vector to deliver other protective antigens.