School of Biotechnology, KIIT University, Bhubaneswar 751024, Odisha, India.
BMC Microbiol. 2013 Oct 22;13:236. doi: 10.1186/1471-2180-13-236.
Development of Salmonella enterica serovar Typhimurium (S. Typhimurium) live attenuated vaccine carrier strain to prevent enteric infections has been a subject of intensive study. Several mutants of S. Typhimurium have been proposed as an effective live attenuated vaccine strain. Unfortunately, many such mutant strains failed to successfully complete the clinical trials as they were suboptimal in delivering effective safety and immunogenicity. However, it remained unclear, whether the existing live attenuated S. Typhimurium strains can further be attenuated with improved safety and immune efficacy or not.
We deleted a specific non-SPI (Salmonella Pathogenicity Island) encoded virulence factor mig-14 (an antimicrobial peptide resistant protein) in ssaV deficient S. Typhimurium strain. The ssaV is an important SPI-II gene involved in Salmonella replication in macrophages and its mutant strain is considered as a potential live attenuated strain. However, fatal systemic infection was previously reported in immunocompromised mice like Nos2-/- and Il-10-/- when infected with ssaV deficient S. Typhimurium. Here we reported that attenuation of S. Typhimurium ssaV mutant in immunocompromised mice can further be improved by introducing additional deletion of gene mig-14. The ssaV, mig-14 double mutant was as efficient as ssaV mutant, with respect to host colonization and eliciting Salmonella-specific mucosal sIgA and serum IgG response in wild-type C57BL/6 mice. Interestingly, this double mutant did not show any systemic infection in immunocompromised mice.
This study suggests that ssaV, mig-14 double mutant strain can be effectively used as a potential vaccine candidate even in immunocompromised mice. Such attenuated vaccine strain could possibly used for expression of heterologous antigens and thus for development of a polyvalent vaccine strain.
开发用于预防肠道感染的沙门氏菌 Typhimurium（鼠伤寒沙门氏菌）活减毒疫苗载体菌株一直是一个研究热点。已经提出了几种鼠伤寒沙门氏菌突变体作为有效的活减毒疫苗株。不幸的是，由于许多此类突变株在提供有效安全性和免疫原性方面不够理想，因此未能成功完成临床试验。然而，目前尚不清楚现有的活减毒鼠伤寒沙门氏菌菌株是否可以进一步降低安全性和免疫效力。
我们在 ssaV 缺陷的鼠伤寒沙门氏菌菌株中缺失了一个特定的非 SPI（沙门氏菌致病性岛）编码的毒力因子 mig-14（一种抗微生物肽抗性蛋白）。ssaV 是参与沙门氏菌在巨噬细胞中复制的一个重要 SPI-II 基因，其突变株被认为是一种潜在的活减毒菌株。然而，以前有报道称，在免疫功能低下的小鼠（如 Nos2-/- 和 Il-10-/-）感染 ssaV 缺陷的鼠伤寒沙门氏菌时，会发生致命的全身感染。在这里，我们报道了在免疫功能低下的小鼠中，ssaV 突变体的进一步衰减可以通过引入额外的 mig-14 基因缺失来实现。ssaV、mig-14 双突变体与 ssaV 突变体一样，在野生型 C57BL/6 小鼠中具有相同的宿主定植能力，并能诱导沙门氏菌特异性黏膜 sIgA 和血清 IgG 反应。有趣的是，这种双突变体在免疫功能低下的小鼠中没有引起任何全身感染。
这项研究表明，ssaV、mig-14 双突变体菌株即使在免疫功能低下的小鼠中也可以有效地用作潜在的疫苗候选物。这种减毒疫苗株可用于表达异源抗原，从而开发多价疫苗株。
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