Institute for Translational Vaccinology (InTraVacc), Antonie van Leeuwenhoeklaan 9, 3720 AL Bilthoven, The Netherlands; Department of Infectious Diseases and Immunology, Utrecht University, 3584 CL Utrecht, The Netherlands.
Vaccine. 2013 Nov 12;31(47):5585-93. doi: 10.1016/j.vaccine.2013.07.069. Epub 2013 Aug 6.
Outer membrane vesicles (OMVs) have been extensively investigated as meningococcal vaccine candidates. Among their major components are the opacity (Opa) proteins, a family of surface-exposed outer membrane proteins important for bacterial adherence and entry into host cells. Many Opa-dependent interactions are mediated through the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family of receptors. Importantly, binding of Opa to CEACAM1 has been reported to suppress human CD4 T cell proliferation in vitro in response to OMV preparations. This raises the question whether OMV vaccines should contain Opa proteins at all. Until now it has been difficult to answer this question, as the proposed immunosuppressive effect was only demonstrated with human cells in vitro, while immunization experiments in mice are not informative because the Opa interaction is specific for human CEACAM1. In the present study we have used Opa+ and Opa- OMVs for immunization experiments in a human CEACAM1 transgenic mouse model. OMVs were prepared from a meningococcal strain H44/76 variant expressing the CEACAM1-binding OpaJ protein, and from an isogenic variant in which all opa genes have been inactivated. Both the CEACAM1 expressing transgenic mice and their congenic littermates lacking it were immunized twice with the OMV preparations, and the sera were analyzed for bactericidal activity and ELISA antibody titres. Total IgG antibodies against the OMVs were similar in both mouse strains. Yet the titres for IgG antibodies specific for purified OpaJ protein were significantly lower in the mice expressing human CEACAM1 than in the nontransgenic mice. No significant differences were found in bactericidal titres among the four groups. Overall, these data indicate that expression of human CEACAM1 confers a reduced Opa-specific antibody response in vivo without affecting the overall immune response against other OMV antigens.
外膜囊泡（OMV）已被广泛研究作为脑膜炎球菌疫苗候选物。其主要成分之一是 opacity（Opa）蛋白，这是一组表面暴露的外膜蛋白，对于细菌黏附和进入宿主细胞非常重要。许多 Opa 依赖性相互作用是通过癌胚抗原相关细胞粘附分子（CEACAM）家族的受体介导的。重要的是，据报道 Opa 与 CEACAM1 的结合可抑制 OMV 制剂体外人 CD4 T 细胞增殖。这就提出了一个问题，即 OMV 疫苗是否应该包含 Opa 蛋白。到目前为止，这个问题还难以回答，因为所提出的免疫抑制作用仅在体外用人细胞进行了证明，而在小鼠中的免疫实验则没有提供信息，因为 Opa 相互作用是针对人类 CEACAM1 的特异性的。在本研究中，我们使用 Opa+和 Opa-OMV 进行了在人类 CEACAM1 转基因小鼠模型中的免疫实验。OMV 是从表达与人 CEACAM1 结合的 OpaJ 蛋白的脑膜炎球菌菌株 H44/76 变体和所有 opa 基因均失活的同源变体中制备的。用 OMV 制剂对表达 CEACAM1 的转基因小鼠及其缺乏同源物的同基因同窝仔鼠进行了两次免疫，分析了血清的杀菌活性和 ELISA 抗体滴度。两种小鼠品系的总 IgG 抗体对 OMV 的反应相似。然而，在表达人类 CEACAM1 的小鼠中针对纯化的 OpaJ 蛋白的 IgG 抗体的滴度明显低于非转基因小鼠。在四组之间未发现杀菌滴度的显著差异。总体而言，这些数据表明，在体内表达人类 CEACAM1 可降低 Opa 特异性抗体反应，而不影响针对其他 OMV 抗原的总体免疫反应。
