Wang Zhao, Liang Qian, Zhang Yajing, Yang Jie, Li Mingming, Wang Kunlun, Cui Min, Chen Huanchun, Fu Zhen F, Zhao Ling, Zhou Ming
State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China.
College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China.
Oncotarget. 2017 Jun 5;8(48):83539-83554. doi: 10.18632/oncotarget.18368. eCollection 2017 Oct 13.
Rabies remains an important public health threat, killing approximately 59,000 people worldwide annually, most of which are from the developing countries of Africa and Asia where dog rabies are endemic. Therefore, developing an affordable and efficacious vaccine for dog-mediated rabies control is needful in these countries. Our previous studies indicated that over-expression of granulocyte-macrophage colony stimulating factor (GM-CSF) or macrophage inflammatory protein-1 (MIP-1α or CCL3) by recombinant rabies virus (rRABV) could enhance the immunogenicity by activating dendritic cells (DCs). In this study, to further characterize the role of activating DCs in RABV immunogenicity, High mobility group box 1 (HMGB1), a highly conserved and non-histone chromosomal protein that can promote DCs maturation and activation, were investigated. The wild-type HMGB1 (HMGB1) and an optimized HMGB1 (HMGB1) were individually inserted into the genome of the rRABV strain LBNSE (designated as LBNSE-HMGB1 and LBNSE-HMGB1, respectively), and the effect of over-expression of HMGB1 on the immunogenicity of RABV was investigated. The results demonstrated that LBNSE-HMGB1 could promote significantly more DCs activation, and the recruitment of follicular helper T, germinal center B and plasma cells in vaccinated mice than those immunized with LBNSE-HMGB1 or parent virus LBNSE. Further investigations suggested that mice vaccinated with LBNSE-HMGB1 produced significantly higher level of RABV-neutralizing antibodies and offered a better protection than those vaccinated with LBNSE or LBNSE-HMGB1. Taken together, these data provides a better understanding of the mechanism for HMGB1 as a potential adjuvant in enhancing the immunogenicity of RABV, which would contribute to developing more-efficacious rabies vaccines.
狂犬病仍然是一个重要的公共卫生威胁，全球每年约有59000人死于狂犬病，其中大多数来自非洲和亚洲的发展中国家，这些国家犬类狂犬病流行。因此，在这些国家开发一种经济有效的犬介导狂犬病控制疫苗是必要的。我们之前的研究表明，重组狂犬病病毒（rRABV）过表达粒细胞-巨噬细胞集落刺激因子（GM-CSF）或巨噬细胞炎性蛋白-1（MIP-1α或CCL3）可通过激活树突状细胞（DCs）增强免疫原性。在本研究中，为了进一步阐明激活DCs在狂犬病病毒免疫原性中的作用，我们研究了高迁移率族蛋白B1（HMGB1），一种高度保守的非组蛋白染色体蛋白，它可以促进DCs的成熟和激活。将野生型HMGB1（HMGB1）和优化后的HMGB1（HMGB1）分别插入rRABV株LBNSE的基因组中（分别命名为LBNSE-HMGB1和LBNSE-HMGB1），并研究HMGB1过表达对狂犬病病毒免疫原性的影响。结果表明，与接种LBNSE-HMGB1或亲本病毒LBNSE的小鼠相比，LBNSE-HMGB1能显著促进更多DCs的激活，以及滤泡辅助性T细胞、生发中心B细胞和浆细胞在接种小鼠中的募集。进一步研究表明，接种LBNSE-HMGB1的小鼠产生的狂犬病病毒中和抗体水平显著更高，并且比接种LBNSE或LBNSE-HMGB1的小鼠提供了更好的保护。综上所述，这些数据有助于更好地理解HMGB1作为增强狂犬病病毒免疫原性的潜在佐剂的机制，这将有助于开发更有效的狂犬病疫苗。
