An optimized HMGB1 expressed by recombinant rabies virus enhances immunogenicity through activation of dendritic cells in mice

// Zhao Wang 1, 2 , Qian Liang 1, 2 , Yajing Zhang 1, 2 , Jie Yang 1, 2 , Mingming Li 1, 2 , Kunlun Wang 1, 2 , Min Cui 1, 2, 3 , Huanchun Chen 1, 2, 3 , Zhen F. Fu 1, 2, 3, 4 , Ling Zhao 1, 2, 3 and Ming Zhou 1, 2, 3 1 State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, China 2 College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, China 3 Key Laboratory of Preventive Veterinary Medicine of Hubei Province, Huazhong Agricultural University, Wuhan, China 4 Department of Pathology, University of Georgia, Athens, GA, USA Correspondence to: Ming Zhou, email: mikchail@163.com Ling Zhao, email: lingzhao@mail.hzau.edu.cn Keywords: rabies virus, HMGB1, dendritic cells, T follicular helper cells, germinal center B cells Received: April 07, 2017     Accepted: May 02, 2017     Published: June 05, 2017 ABSTRACT 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 wt ) and an optimized HMGB1 (HMGB1 mut ) were individually inserted into the genome of the rRABV strain LBNSE (designated as LBNSE-HMGB1 wt and LBNSE-HMGB1 mut , respectively), and the effect of over-expression of HMGB1 on the immunogenicity of RABV was investigated. The results demonstrated that LBNSE-HMGB1 mut 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 wt or parent virus LBNSE. Further investigations suggested that mice vaccinated with LBNSE-HMGB1 mut produced significantly higher level of RABV-neutralizing antibodies and offered a better protection than those vaccinated with LBNSE or LBNSE-HMGB1 wt . 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.