Host Defense Evasion Mechanisms of Rabies Virus
Rabies Virus
Rabies virus (RABV) is a prototypical neurotropic virus and is often counted as one of the most deadly zoonotic diseases. Both wild and domestic animals can be afflicted with the disease and it is most commonly spread to humans via the saliva of an infected animal entering a bite wound or scratch. In Asia, most rabies infections are caused by rabid dogs. However in the Americas, and recently Australia and Western Europe, bat rabies has become a public health threat. Rabies is present on all continents except Antarctica, but the majority of rabies related deaths occur in Asia and Africa (WHO fact sheet 99).
RABV infections occur mainly in remote, rural communities where measures such as vaccinating dogs to prevent animal to human transmission have not occurred. Due to lack of resources and preventative measures, 95% of rabies related human deaths occur in Africa and Asia. Most at risk populations generally do not have the ability to access nor the money for the rabies vaccine or post-exposure prophylaxis, turning a rabies infection into a death sentence (WHO fact sheet 99). Most patients only survive for seven days after the onset of symptoms (Schnell et al 2009).
There are two main phylogroups of RABV which cause two distinct types of symptoms. Classical rabies, also known as furious rabies, causes 70% of animal and human infections while non-classical or paralytic rabies causes the remaining 30% of cases. Classical rabies is the more well-known strain and is characterized by symptoms such as hydrophobia, hallucinations, excited behavior, hyperactivity, and occasionally aerophobia. Paralytic rabies is less dramatic, as the patient’s muscles slowly become paralyzed with the paralysis radiating from the infection site. The patient eventually falls into a coma and dies. This non-classical form of rabies is often misdiagnosed, leading to an underrepresentation of the incidences of rabies (WHO and Schnell et al 2009). Both forms of rabies cause death through cardiorespiratory arrest (WHO fact sheet 99).
Great progress has been made in developing new rabies vaccines and preventative measures, but much of the molecular mechanisms of rabies virus remain a mystery. Improved genetic manipulation techniques that allow for direct manipulation of the rabies viral genome have given researchers a more detailed picture of rabies pathogenesis and a greater insight into virus-host cell interactions (Schnell et al 2009). Understanding viral-host cell interactions are key to understanding how rabies virus is able to evade the host’s immune response and make its way from the site of infection to the central nervous system and the brain. A better understanding of these mechanisms could help improve neuronal labeling and nuerotracer studies and treatments for other central nervous system diseases (Schnell et al 2009).
Topic 1
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Topic 2
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Topic 3
While some neurotropic viruses such as West Nile virus or polio virus effectively kill motor neurons, RABV actively seeks to prevent neuronal degradation. RABV enters the NS through a neuromuscular junction or by passing through a synapse and utilizes the central nervous system as a transport system to the brain. Neuronal cell bodies, and possibly dendrites, are used for viral propagation and the virions travel in a retrograde direction towards the brain. Due to its dependence on neurons and the neuronal network, it would suggest that the virulence of RABV correlates to the survival of neurons (Lafon 2011). In fact, motor neurons of non-human primates infected with RABV showed no signs of degradation four days post infection (cited in Lafon 2011).
This prevention of apoptosis and axonal degradation is caused by the cytoplasmic form of the glycoprotein (G). In vitro RABV induced neuronal death is rare, however many laboratory created, attenuated strains induce neuronal apoptosis (Lafon 2011). The survival of the neuron and continued axonal growth depend on signaling cascades within the cell. PDZ domains are used in signal transferring and assemble and or regulate certain protein networks (Prehaud et al 2010, Lafon et al 2011). The RAVB G protein contains a PDZ-binding cite (PDZ-BS) in its C terminus. The only difference between two laboratory RABV strains, VIR and ATT, is in their G protein sequence. However, VIR is more virulent strain causing fatal encephalitis in mice and ATT is an attenuated strain. It has been suggested that the Gln to Glu mutation in the C terminus PDZ-BS in the ATT G protein is what causes the attenuated phenotype by inducing neuronal apoptosis. In vitro, VIR was able to prevent nueronal apoptosis and maintain axon and dendritic growth while ATT was not (Fig 4). Instead, ATT actually triggered apoptosis in infected cells (Fig4) (Prehaud et al 2010).
The different phenotypes stem from the different binding specificities of the two PDZ-BS. The G protein of the virulent strain only interacts with microtubule associated serine-threonine kinase 1 and 2 (MAST1 and MAST2 respectively) while the mutated G protein interacts with three unrelated PDZ binding partners, the most interesting of which is non-receptor protein tyrosine phosphate 4 (PTPN4). PTPN4 silencing has been suggested to trigger apoptosis, and it has been demonstrated that ATT G protein silences PTPN4. However, un-mutated G protein binding to MAST2 causes nuerite outgrowth (Prehaud et al 2010). The specificity of the G protein suggests that RABV walks a fine line de-activating some signaling cascades while leaving others intact.
Conclusion
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References
Edited by Alexandra Gonzales, student of Joan Slonczewski for BIOL 375 Microbiology, 2014, Kenyon College.
