Everything You Always Wanted to Know About Rabies Virus (But Were Afraid to Ask)

Abstract

The cultural impact of rabies, the fatal neurological disease caused by infection with rabies virus, registers throughout recorded history. Although rabies has been the subject of large-scale public health interventions, chiefly through vaccination efforts, the disease continues to take the lives of about 40,000-70,000 people per year, roughly 40% of whom are children. Most of these deaths occur in resource-poor countries, where lack of infrastructure prevents timely reporting and postexposure prophylaxis and the ubiquity of domestic and wild animal hosts makes eradication unlikely. Moreover, although the disease is rarer than other human infections such as influenza, the prognosis following a bite from a rabid animal is poor: There is currently no effective treatment that will save the life of a symptomatic rabies patient. This review focuses on the major unanswered research questions related to rabies virus pathogenesis, especially those connecting the disease progression of rabies with the complex dysfunction caused by the virus in infected cells. The recent applications of cutting-edge research strategies to this question are described in detail.

Keywords: lyssaviruses; neuroinvasive virus; neurotropic virus; rabies virus; viral transport.

Figure 1:

The RABV transcription and replication strategy. The negative-sense genomic RNA (in orange) is the template for the L-P polymerase complex. A) During transcription, Five 5′-end capped (C) and polyadenylated (A) mRNAs (in green) encode the viral proteins. The polymerase complex disassociates from the template at each termination signal (STOP). The polymerase does not always re-engage successfully, leading to a negative transcription gradient from 3′ to 5′. B) During replication, the negative-sense genome is transcribed into a positive-sense antigenomic RNA intermediate (in green) by a more processive form of the viral polymerase. The anti-genome is then transcribed back into a negative-sense RNA to complete replication.

Figure 2:

The path of RABV infection through the host. Most natural RABV infections start with exposure of muscle tissue to RABV particles by an animal bite or scratch. The infection spreads to the peripheral nervous system through neuromuscular junctions (bottom insert). Virus particles travel as an enveloped vesicle using dynein-mediate retrograde axonal transport pathways (top insert), spreading trans-synaptically from post-synaptic to pre-synaptic neurons until widespread infection of the central nervous system is achieved.

Figure 3:

The RABV neuroinvasive strategy. Two possible mechanisms are depicted, both of which have been observed experimentally. A) RABV-G interacts with the nicotinic acetylcholine receptor (nAcHR; in green), mediating entry into muscle cells. This leads to local replication of the virus before budding into the synaptic cleft of the neuromuscular junction. B) Alternatively, RABV-G interacts with one of several cellular receptors on the neuron, such as NCAM or p75NTR (shown in purple or blue). This leads to direct entry into the neuron without prior local replication in muscle.