Antigen-expressed recombinant Salmonella typhimurium driven by an in vivo-activated promoter is capable of inducing cellular immune response in transgenic mice.

Hong-Wei Wang, Min Zhang, Jie Luan, Wei-Jiang Hu, Ping Zhao, Jun Gao, Zhong-Tian Qi
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Abstract

To explore the approaches and mechanisms for reversing the immune tolerance in transgenic mouse, and the pathogenicity of hepatitis G virus (HGV), the promoter of phoP-activated gene (P(pagC)) of Salmonella typhimurium was used as a transcriptionally regulating element to construct an attenuated S. typhimurium expressing HGV NS3. The recombinant S. typhimurium was orally administered to HGV transgenic mice. As the results, HGV antigen in serum and liver as well as HGV mRNA in liver were decreased significantly, although the serum anti-HGV NS3 remained undetectable as the control transgenic mice. The spleen cell proliferation, in vitro HGV NS3 specific CTL, and IFN-gamma assays with the primed cultured splenocytes indicated the induction of Th1 immune responses in those administered transgenic mice. Adoptive transfer of fractionated primed spleen cells to the transgenic mice showed that T lymphocytes were responsible for, maybe through IFN-gamma, the down-regulation of HGV mRNA transcription. Histological examination found no significant inflammatory changes in liver of the transgenic mice. These findings suggested that the oral inoculation of the HGV NS3-expressed attenuated S. typhimurium driven by an in vivo-activated promoter should be a simple and effective approach for potential treatment of chronic viral infection.

抗原表达重组鼠伤寒沙门菌在体内激活启动子驱动下能够在转基因小鼠中诱导细胞免疫应答。
为了探索逆转转基因小鼠免疫耐受的途径和机制,以及G型肝炎病毒(HGV)的致病性,以鼠伤寒沙门菌phop激活基因启动子(P(pagC))为转录调控元件,构建了表达HGV NS3的减毒鼠伤寒沙门菌。将重组鼠伤寒沙门氏菌口服给药于HGV转基因小鼠。结果表明,转基因小鼠血清和肝脏中HGV抗原以及肝脏中HGV mRNA含量均显著降低,但血清中抗HGV NS3仍未检测到。脾细胞增殖、体外HGV NS3特异性CTL和ifn - γ检测表明,转基因小鼠的脾细胞诱导了Th1免疫应答。将分离的脾细胞过继转移到转基因小鼠体内,表明T淋巴细胞可能通过ifn - γ下调了HGV mRNA的转录。组织学检查未发现转基因小鼠肝脏有明显炎症变化。这些结果表明,口服接种由体内激活启动子驱动的HGV ns3表达的减毒鼠伤寒沙门氏菌可能是一种简单有效的治疗慢性病毒感染的方法。
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