Rabies virus is a neurotropic negative-strand RNA rhabdovirus. It is transmitted mostly via bites from diseased animals and causes a fatal infection of the nervous system in both animals and humans. A key step in rabies virus pathogenesis is rapid transfer to the Central Nervous System (CNS) through the Peripheral Nervous System. Due to its extraordinary properties in directed axonal transport and trans-synaptic spread, rabies virus has also been used as a neuro-tracing agent to map neuronal circuitry. Understanding the mechanism of rabies virus neuronal transport is important for both basic and applied fields.
Rabies virus enters the peripheral nervous system and undergoes long-distance transport before arriving at the cell body and subsequently the CNS. Axonal transport is the cellular process of trafficking proteins, organelles, vesicles, RNA and other cellular factors to and from the neuronal cell body. The molecular motor kinesin drives transport from the cell body anterogradely, supplying proteins, lipids and other essential materials to the cell periphery. Dynein/dynactin complexes drive retrograde transport, moving damaged proteins for degradation and critical signaling molecules such as neurotrophins to the cell body. Although rabies virus phosphoprotein P, a component of the viral nucleocapsid of infecting virions, was shown to directly interact with a light chain of the dynein motor complex, axonal RABV transport and CNS infection are independent of that interaction and long distance transport of complete enveloped virions within internalized endosomes is more likely. The cellular and molecular mechanisms involved in rabies virus’ infection and retrograde trafficking are yet to be understood.
A new paper in PLOS Pathogens shows that rabies virus interacts with the p75 neurotrophin receptor (p75NTR) at peripheral neuron tips to enter the axon. Then the virus moves in acidic compartments, mostly with p75NTR. Rabies virus is transported faster than NGF, an endogenous p75NTR ligand. p75NTR-dependent transport of rabies virus is faster and more directed than p75NTR-independent rabies virus transport. Hence, rabies virus not only exploits the neurotrophin transport machinery, but also has a positive influence on transport kinetics, facilitating its own arrival at the CNS. These findings reveal how RABV can spread from the periphery, describe a novel role for the RABV-p75NTR interaction beyond ligand-receptor binding, and define a mechanism that allows proficient long-distance accelerated transport in axons.
Rabies Virus Hijacks and Accelerates the p75NTR Retrograde Axonal Transport Machinery. (2014) PLoS Pathog 10(8): e1004348. doi:10.1371/journal.ppat.1004348
Rabies virus (RABV) is a neurotropic virus that depends on long distance axonal transport in order to reach the central nervous system (CNS). The strategy RABV uses to hijack the cellular transport machinery is still not clear. It is thought that RABV interacts with membrane receptors in order to internalize and exploit the endosomal trafficking pathway, yet this has never been demonstrated directly. The p75 Nerve Growth Factor (NGF) receptor (p75NTR) binds RABV Glycoprotein (RABV- G) with high affinity. However, as p75NTR is not essential for RABV infection, the specific role of this interaction remains in question. Here we used live cell imaging to track RABV entry at nerve terminals and studied its retrograde transport along the axon with and without the p75NTR receptor. First, we found that NGF, an endogenous p75NTR ligand, and RABV, are localized in corresponding domains along nerve tips. RABV and NGF were internalized at similar time frames, suggesting comparable entry machineries. Next, we demonstrated that RABV could internalize together with p75NTR. Characterizing RABV retrograde movement along the axon, we showed the virus is transported in acidic compartments, mostly with p75NTR. Interestingly, RABV is transported faster than NGF, suggesting that RABV not only hijacks the transport machinery but can also manipulate it. Co-transport of RABV and NGF identified two modes of transport, slow and fast, that may represent a differential control of the trafficking machinery by RABV. Finally, we determined that p75NTR-dependent transport of RABV is faster and more directed than p75NTR-independent RABV transport. This fast route to the neuronal cell body is characterized by both an increase in instantaneous velocities and fewer, shorter stops en route. Hence, RABV may employ p75NTR-dependent transport as a fast mechanism to facilitate movement to the CNS.