Stoeker Laura, Nordone Shila, Gunderson Sara, Zhang Lin, Kajikawa Akinobu, LaVoy Alora, Miller Michael, Klaenhammer Todd R, Dean Gregg A
Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA.
Clin Vaccine Immunol. 2011 Nov;18(11):1834-44. doi: 10.1128/CVI.05277-11. Epub 2011 Sep 7.
Lactobacillus species are commensal bacteria that have long been recognized as probiotic microbes and are generally regarded as safe (GRAS) for human consumption. We have investigated the use of L. gasseri as a vaccine vector for oral immunization against mucosal pathogens. Recent research has shown that the immune response to different lactobacilli can vary widely depending on the species or subspecies of Lactobacillus being studied. While some lactobacilli seem to induce oral tolerance, others induce an adaptive immune response. This study characterized the systemic and mucosal immune response to wild-type and genetically modified L. gasseri. L. gasseri primarily activates TLR2/6, with additional activation through the TLR2 homodimer. To expand the Toll-like receptor (TLR) activation profile of L. gasseri and the immunogenicity of the vector, a plasmid containing fliC, the gene encoding bacterial flagellin, was introduced which resulted in the strong activation of TLR5. The treatment of human myeloid dendritic cells with recombinant lactobacilli expressing flagellin triggered phenotypic maturation and the release of proinflammatory cytokines. In contrast, bacterial treatment also resulted in a statistically significant increase in IL-10 production. In vivo studies established that treatment with L. gasseri led to a diversification of B-cell populations in the lamina propria of the murine colon. Furthermore, treatment with genetically modified L. gasseri led to a significant decrease in the percentage of FoxP3(+) colonic lymphocytes. Taken together, these data clarify the interaction of L. gasseri with the host immune system and support further investigation of the in vivo immunogenicity of L. gasseri expressing both flagellin and candidate vaccine antigens.
乳酸杆菌属是共生细菌，长期以来一直被认为是益生菌微生物，通常被认为可安全用于人类消费。我们研究了将加氏乳杆菌用作口服免疫以抵抗黏膜病原体的疫苗载体。最近的研究表明，针对不同乳酸杆菌的免疫反应可能因所研究的乳酸杆菌的种类或亚种而有很大差异。虽然一些乳酸杆菌似乎会诱导口服耐受，但其他乳酸杆菌会诱导适应性免疫反应。本研究对野生型和基因改造的加氏乳杆菌的全身和黏膜免疫反应进行了表征。加氏乳杆菌主要激活TLR2/6，并通过TLR2同型二聚体进行额外激活。为了扩大加氏乳杆菌的Toll样受体（TLR）激活谱和载体的免疫原性，引入了一个含有fliC（编码细菌鞭毛蛋白的基因）的质粒，这导致了TLR5的强烈激活。用表达鞭毛蛋白的重组乳酸杆菌处理人髓样树突状细胞会触发表型成熟和促炎细胞因子的释放。相比之下，细菌处理也导致IL-10产生在统计学上显著增加。体内研究表明，用加氏乳杆菌处理会导致小鼠结肠固有层中B细胞群体的多样化。此外，用基因改造的加氏乳杆菌处理会导致FoxP3(+)结肠淋巴细胞百分比显著降低。综上所述，这些数据阐明了加氏乳杆菌与宿主免疫系统的相互作用，并支持进一步研究表达鞭毛蛋白和候选疫苗抗原的加氏乳杆菌的体内免疫原性。
