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.