When Rabies Virus is Not So Toxic (With Narration!)

When Rabies Virus is Not So Toxic

Rabies is a horrible fatal disease most people got to know when they gave their pets annual vaccines. Although it is relatively rare now in the United States (only one US case in 2015, data from Mayo Clinic), it still causes many deaths especially in tropical Africa and Asia. The major symptoms of this deadly disease include high fever, hyperactivity, fear of water and wind, paralysis, and finally death [1]. Usually, there’s no effective treatment once the viruses have entered the nervous system, but instant vaccination after a bite from a suspicious animal can prevent the infection of rabies virus.

As we can see from those typical symptoms of rabies, this virus may infect and do bad things on people’s nervous system. This is exactly the truth that doctors and scientists have confirmed. After entering a human being’s body, this vicious virus may first enter the neurons that innervate muscle cells, and then travel back from the peripheral to the central nervous system with the help of some of our own proteins inside each neuron. It’s usually when viruses arrive at the brain that the most serious symptoms appear and then death follows [2].

All of this indeed sounds very frightening, but neuroscientists have seen hopes in turning this creepy virus into a useful tool in their study of the brain. With its ability to transport in a retrograde direction (which means from axon terminal to the cell body of a neuron) and spread between synapses, scientists have been working for years to make it into a retrograde tracer [3] to help them understand how different parts of the brain are organized and connected. In 2007, a group from the Salk Institute engineered the rabies virus by replacing the gene of its glycoprotein (which is critical for its infection between synapses) with the gene encoding green fluorescent protein [4] to make it an optimal retrograde tracer to show a neuron’s structure. Then, in the same year, they also made it possible to use this virus to trace back between a synapse (which is called monosynaptic tracing) by further engineering its genome [5]. These creative inventions expanded neuroscientists’ toolbox in the following years. However, there has always been a major problem – the toxicity of rabies virus. Because these engineered rabies viruses can still hijack a neuron’s protein expression system and keep replicating, so they also threaten the infected animal’s nervous system and eventually its health. Even with the most updated version of ΔG (which means the glycoprotein gene is deleted) rabies virus, the longest time window for experiments after infection is only about 17 days [6].

In July 13th’s issue of Cell, a group from the MRC Laboratory of Molecular Biology tried something new with rabies virus’s genome [7]. When we take a loser look of this genome, we’ll find a single strand RNA which encodes the genes of N, P, M, L and G (glycoprotein) [8]. These investigators found that tagging the viral protein N with a peptide called PEST which attracts proteasomes [9] to degrade it can surprisingly stop the rabies virus from replicating. In this way, the viruses become self-inactivating which means in around three weeks all the rabies viruses in the infected neurons would have been shut down. So, this new version of engineered ΔG-rabies virus is named self-inactivating ΔG-rabies (SiR). Actually, if we carefully study the function of each viral protein, there would be no surprise for this new finding because protein N controls the switch from gene expression to virus replication [8].

With this new virus, scientists can do many more things with the brain in an unlimited time window which could be potentially life-long. For example, genes encoding optogenetic channels [10] or calcium indicators [11] can be delivered to certain neural circuit with SiR for manipulation or imaging. Also, circuit specific gene manipulation can be achieved with this virus, too. Of course, this new virus has its own down side – the self-inactivating feature is at the cost of turning off the virus’s gene expression. Therefore, delivery of any genes into the neuron by SiR must be done in combination with the Cre [12] or Flp [13] recombinase systems from other virus or transgenic animals.

Anyway, neuroscientists have brought us so many surprises by turning wastes (or even devils) into treasures. Let’s rub our eyes and wait for the next amazement. Or, maybe you could join this amazing team yourself!


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