Introduction
Rabies is a highly neurotropic infectious disease caused by rabies virus (RABV). The virus belongs to the Lyssavirus genus within theRhabdoviridae family[1-3]. The genome of RABV is about 12-kb. It encodes five proteins, including nucleoprotein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G) and RNA-dependent RNA polymerase (L), among which glycoprotein (G) is the sole protein on the surface of viral particle. RABV G, which initiates viral infection by binding with target cells, is the most important antigen to induce neutralizing antibodies and plays a key role in protective immunity[4-6].
RABV enters host cells through endocytosis. The process starts with the G protein binding to specific receptors on the surface of host cells. Currently, known cell receptors recognized by G mainly include the nicotinic acetylcholine receptor (nAChR), the neural cell adhesion molecule (NCAM) and the low-affinity neurotrophin receptor p75NTR[7-9]. When RABV invades the neuromuscular junction, the nAChR located in the prominent posterior membrane concentrates the extracellular virus in the synaptic space. The NCAM on the presynaptic membrane of the motor neuron may further concentrate RABV in a certain part of the nerve cell membrane, thus facilitating the binding of viral G protein to other membrane molecules[10, 11]. After the virus enters nerve cells, it may combine with p75NTR to promote the reverse transport of viral particles in the cytoplasm[12].
After the infection by RABV, it will almost inevitably lead to death after the onset of clinical symptoms. However, timely treatment of post-exposure prevention (PEP) can prevent the occurrence of rabies. PEP mainly includes three steps: 1. clean of the wound, 2. injection of rabies immunoglobulin (RIG), and 3. vaccination with rabies vaccine[1, 13]. It is estimated that more than 10 million people worldwide receive PEP every year[14, 15]. At present, RIG is a polyclonal antibody reagent derived from the plasma of vaccinated people or horses. It, which can only be produced in a limited amount, is expensive, not easy to obtain, and has safety risks[16-18]. The necessity of replacing these hyperimmune serum preparations with equivalent but more effective and safer products has been widely recognized. Mouse and human monoclonal antibodies have been shown to protect rodents from lethal RABV attacks[19]. In this study, we reported a human-mouse chimeric monoclonal antibody, 12-2A12, which targeted RABV G. The neutralizing activity of the antibody was determined with multiple street viruses of RABV. In addition, the antigenic epitope of the antibody on RABV G was also delineated via the 12-2A12/G complex structure.