Rabies- the scariest disease ever?

Rabies is a viral disease that primarily affects the central nervous system (CNS), usually in mammals. Wild animals such as foxes, dogs, and raccoons are frequent carriers of the virus. Transmission occurs through the saliva of an infected animal through a bite or a scratch, allowing the virus to enter the body and travel through the nervous system toward the brain. While rabies can be prevented with a vaccine, once symptoms begin to show, the disease is nearly always fatal once symptoms begin to show. What makes this virus so deadly, and how can it take control of the human body with just five genes in its genome?

Why is the virus so hard to kill?

To arrive at a sensible answer, we must first understand the ‘tropism’ of the virus – the cell type it likes to infect. Rabies virus infects the neurones (neurotropic), which creates a massive problem for the immune system. Macrophages and neutrophils, which are the prominent cells in killing foreign pathogens that kill foreign pathogens, usually deal collateral damage to the body’s own cells to some extent. This must be avoided with neurones, as neurones cannot replenish themselves after cell death. An inflammation of the nerve cells could lead to paralysis and seizures, compromising the CNS.

As a result, the immune system response is significantly lowered around nerve cells to prevent accidental damage, which allows the virus to infect the neural pathway easily.

Transmission of the virus

See Figure 1

The strategy of the immune system is that the neurones can be protected if the pathogens are intercepted before they travel to their destination. However, this strategy ultimately fails when it comes to rabies, because the transmission is through a bite, which can penetrate and cut through many layers of tissue, providing a direct access to nerve cells.

If you were bitten on the leg, then the time it takes for the rabies virus to travel to your brain would be the time it takes for you to travel from Florida, USA to Sweden. This may seem like a long time, but the rabies virus has evolved a technique that is able to hijack the cellular transport system can trick your cells’ transport system to travel quickly through the nerves by binding to a protein called dynein. Dynein is a motor protein that move along the microtubules in cells, converting the chemical energy of ATP into mechanical work. Microtubules are polarized structures, with a plus end (typically towards the axon terminal in neurones) and a minus end (towards the cell body). 

Dynein moves toward the minus end, facilitating retrograde transport, meaning it moves materials from the periphery of the cell, such as the axon terminals, back toward the cell body. Dynein is transports chemicals inside cells via endocytosis and plays a vital role in the movement of eukaryotic flagella.

Rabies has evolved to stick to dynein via the Glycoprotein (G) present on its viral envelope, which allows rabies to travel to the brain much quicker. Dynein may be small, weighing around two megadaltons (3 x 10-18 grams), but it can move at a speed of 800 nanometres per second. At this speed, it takes rabies around 14 days to move up a metre- long neuron. This implies that the closer the animal bites you to the brain, the less time it takes for the symptoms to appear. If you’re bitten on the foot, it could take months for the virus to reach your brain. But if you’re bitten on the neck or face, the virus can get to your brain in just a few days, making it much more dangerous. This explains the broad range in the incubation time which is between 20 to 90 days.

Infection and replication- see Figure 2

As the rabies travels through neuronal tracks, it sets up points of concentrated viral production centres called Negri bodies. These replicate the rabies virus within the neurones and inhibit interferon action, which are chemicals that alert white blood cells to the area of infection. Interferon inhibition along with lowered immune response to neurones make rabies extremely effective. However, neurones can undergo apoptosis—controlled cell death—to limit the spread of the virus and allow macrophages to clear the debris. Research in mice suggests that some strains of rabies may prevent this apoptotic response in cells. Additionally, studies indicate that rabies promotes apoptosis in killer T cells, which are responsible for inducing apoptosis in other cells. This mechanism helps to shield nerve cells from immune system attacks.

Symptoms

Patients with rabies initially experience flu-like symptoms and muscle pain. Once these early symptoms appear, treatment is virtually impossible. As the disease progresses, neurological symptoms develop including hydrophobia due to painful throat spasms when swallowing liquids. About 10 days after these neurological symptoms start, patients enter a coma, often accompanied by prolonged sleep apnoea. As virus attacks the brain throughout this stage, patients develop the urge to bite other organisms to transmit the virus. The virus can reach the salivary glands, allowing for transmission through a bite to occur again. Most patients typically die within three days of reaching this coma stage.

Legends

Rabies may have influenced the development of vampire and zombie myths due to its distinct symptoms. The disease causes aggression and sensitivity to light, which could have inspired some characteristics of vampires, such as their aversion to light and erratic movements. Additionally, rabies leads to excessive salivation and a tendency to bite, traits that align with vampire lore. Similarly, the delirium and motor dysfunction seen in rabies may have contributed to the depiction of zombies as shuffling, incoherent beings.

Conclusion

Rabies is a uniquely deadly virus due to its mechanism of hijacking the nervous system. After entering the body, the virus binds to dynein, using it to travel along neuronal pathways toward the brain. It replicates rapidly, forming Negri bodies disrupting neurone function. The virus effectively suppresses immune responses, making it nearly impossible to treat once symptoms appear, leading to almost 100% fatality. Beyond its biological impact, rabies has influenced cultural stories like those of vampires and zombies, with its symptoms—such as aggression, fear of water, and neurological decay—providing eerie parallels to these myths. Despite modern medical advances, rabies remains one of the most feared infectious diseases due to its fatal nature.

Written by Baraytuk Aydin

Related articles: Rare zoonotic diseases / rAAV gene therapy

REFERENCES

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Hendricks, A.G. et al. (2012) Dynein tethers and stabilizes dynamic microtubule plus ends, Current biology : CB. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347920/ (Accessed: 13 September 2024).

Lahaye, X. et al. (2009) Functional Characterization of Negri Bodies (NBS) in rabies virus-infected cells: Evidence that NBS are sites of viral transcription and replication, Journal of virology. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715764/ (Accessed: 13 September 2024).

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