Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; Research Centre for Advanced Oral Science, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Vaccine. 2019 Jan 3;37(1):160-168. doi: 10.1016/j.vaccine.2018.11.015. Epub 2018 Nov 13.
Vaccination is an effective strategy to prevent pneumococcal diseases. Currently, licensed vaccines include the pneumococcal polysaccharide vaccine (PPSV) and the pneumococcal conjugate vaccine (PCV), which target some of the most common of the 94 serotypes of S. pneumoniae based on their capsular composition. However, it has been reported that PPSV is not effective in children aged less than 2 years old and PCV induces serotype replacement, which means that the pneumococcal population has changed following widespread introduction of these vaccines, and the non-vaccine serotypes have increased in being the cause of invasive pneumococcal disease. Therefore, it is important that there is development of novel pneumococcal vaccines to either replace or complement current polysaccharide-based vaccines. Our previous study suggested that S. pneumoniae releases elongation factor Tu (EF-Tu) through autolysis followed by the induction of proinflammatory cytokines in macrophages via toll-like receptor 4, that may contribute to the development of pneumococcal diseases. In this study, we investigated the expression of EF-Tu in various S. pneumoniae strains and whether EF-Tu could be an antigen candidate for serotype-independent vaccine against pneumococcal infection. Western blotting and flow cytometry analysis revealed that EF-Tu is a common factor expressed on the surface of all pneumococcal strains tested, as well as intracellularly. In addition, we demonstrate that immunization with recombinant (r) EF-Tu induced the production of inflammatory cytokines and the IgG1 and IgG2a antibodies in mice, and increased the CD4 T-cells proportion in splenocytes. We also reveal that anti-EF-Tu serum increased the phagocytic activity of mouse peritoneal macrophages against S. pneumoniae infection, independent of their serotypes. Finally, our results indicate that mice immunized with rEF-Tu were significantly and non-specifically protected against lethal challenges with S. pneumoniae serotypes (2 and 15A). Therefore, pneumococcal EF-Tu could be an antigen candidate for the serotype-independent vaccine against pneumococcal infection.
疫苗接种是预防肺炎球菌疾病的有效策略。目前，已获得许可的疫苗包括肺炎球菌多糖疫苗（PPSV）和肺炎球菌结合疫苗（PCV），它们基于荚膜组成针对肺炎链球菌 94 种血清型中的一些最常见血清型。然而，据报道，PPSV 在 2 岁以下儿童中效果不佳，PCV 会引起血清型替代，这意味着这些疫苗广泛应用后，肺炎球菌人群发生了变化，非疫苗血清型成为侵袭性肺炎球菌病的病因。因此，开发新型肺炎球菌疫苗来替代或补充当前基于多糖的疫苗非常重要。我们之前的研究表明，肺炎链球菌通过自溶释放延伸因子 Tu（EF-Tu），然后通过 Toll 样受体 4 诱导巨噬细胞中的促炎细胞因子，这可能有助于肺炎球菌病的发展。在这项研究中，我们研究了各种肺炎链球菌菌株中 EF-Tu 的表达情况，以及 EF-Tu 是否可以成为针对肺炎球菌感染的血清型非依赖疫苗的抗原候选物。Western blot 和流式细胞术分析表明，EF-Tu 是所有测试的肺炎链球菌菌株表面以及细胞内的共同因子。此外，我们证明用重组（r）EF-Tu 免疫可诱导小鼠产生炎症细胞因子和 IgG1 和 IgG2a 抗体，并增加脾细胞中 CD4 T 细胞的比例。我们还揭示了抗 EF-Tu 血清可增加小鼠腹腔巨噬细胞对肺炎球菌感染的吞噬活性，而与它们的血清型无关。最后，我们的结果表明，用 rEF-Tu 免疫的小鼠可显著且非特异性地抵抗肺炎球菌血清型（2 和 15A）的致死性挑战。因此，肺炎球菌 EF-Tu 可能是针对肺炎球菌感染的血清型非依赖疫苗的抗原候选物。
