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Rabies pathobiology and its RNA virus agent – Lyssavirus

Having a dog as a pet presents myriad of benefits. One of them is having a companion reputed for being charismatic and loyal. Dogs, apparently, render a “cure” when melancholy “strikes“. However, there are repercussions to avoid or deal with when handling a dog. One of the most important concerns when domesticating a dog is preventing dog bites. Getting bitten by a dog is, in fact, how microbes could find their way through the skin.  Dogs, inopportunely, can be agents of medically-important diseases like rabies.

dog rabies
Dog infected with rabies

Rabies transmission

Rabies is a viral disease that is almost always deadly. It can be acquired chiefly through a single bite by an infective dog. One could also get it when a broken skin is exposed to infected saliva. Other potential routes include eyes, mouth, and nose. Nonetheless, not all dogs carry the virus causing the disease. Also, dogs are not the only ones that can transmit rabies virus. Most warm-blooded vertebrates (e.g. monkeys, raccoons, cattle, cats, bats, etc.) can carry the virus and transmit it to a human host. The virus has further adapted, and hence, could grow as well as in cold-blooded vertebrates.[1] However, because of the widespread domestication of dogs in human households dogs have consequently incited most rabies cases in humans.[2]  

Lyssavirus – the viral agent

The virus of rabies disease is a Lyssavirus, a type of RNA virus belonging to the family Rhabdoviridae, order Mononegavirales. It has a bullet shape. It carries a single negative-strand RNA as its genome, enough to code for proteins[3] — namely, nucleoprotein, phosphoprotein, matrix protein, glycoprotein, and RNA polymerase — to establish within the host cell.

Lyssavirus rabies virus
A coloured transmission electron micrograph of Australian bat lyssavirus (finger-like projections and the one that bud off from a host cell). Credit: Electron Microscopy Unit AAHL, CSIRO, CC 3.0 Unported license

In particular, the virus makes its way inside the host cell (e.g. muscle cell or nerve cell) through receptor binding and membrane fusion by way of endosome using its glycoprotein G. The virus transcribes its genome by its polymerase inside the endosome. Then, it fuses to the endosome to release its newly transcribed proteins and RNA into the cytosol.

The matrix protein regulates both transcription and replication of the virus. From transcribing, the polymerase shifts into replicating its genome. The nucleoprotein tightly binds to the newly replicated genome, thus, forming ribonucleoprotein complex. This, in turn, can now form new viruses.[4]

The virus performs transcription and replication processes via a specialized inclusion body referred to as the Negri body. In fact, the presence of Negri bodies in the cytoplasm of the host cell indicates histological proof of Lyssavirus infection.

Rabies – two types

Early symptoms of rabies disease include fever, discomfort, and paraesthesia (burning sensation at the bite site). Eventually, the symptoms progress to behavioral changes when the virus spreads to the central nervous system.

Lyssavirus enters and hijacks muscle cells to replicate. From the muscle tissue, it travels to the nervous system through the neuromuscular junctions.[5] The virus enters the peripheral nervous system directly and then spreads to the central nervous system where it can cause fatal inflammation in the brain and spinal cord.

Depending on the symptoms, the rabies may be described as “furious” or “paralytic“. The furious rabies — the more common form (80% [5]) — is characterized by hyperactivity, confusion, abnormal behavior, paranoia, terror, hallucinations, and hydrophobia (“fear of water“). The paralytic rabies, as the name implies, causes paralysis starting from the site of bite (or entry). Both of these types may lead to coma and eventually to death of the patient. However, patients with the furious type have higher risks, due to the likely cardio-respiratory arrest.[2]  Without an early and a proper medical intervention, death may ensue typically two to ten days after these symptoms manifest.

Rabies – pathobiology

How rabies causes behavioural changes baffles scientists. In 1980s and 1990s, researchers explicated how the virus caused paralysis. Accordingly, the glycoprotein at the cell surface of the Lyssavirus competes against acetylcholine in terms of binding affinities to specific muscle receptors (e.g. nicotinic acetylcholine receptors).[6] Lately, researchers conjectured that the virus could also be doing the same with the similar receptors found in the brain. Furthermore, they presumed that the interaction could have affected how the brain cells normally communicate, and thereby induced changes in the behavior of the host.[6] 

Further research

Recently, researchers from the Ohio State University College of Medicine and The Ohio State University Wexner Medical Center conducted a study aimed at identifying dog breeds and physical traits that pose high risk of biting with severe injury.[7] Their data could provide empirical basis when deciding which dogs to own. Still, further studies on rabies are necessary since the disease is marked as fatal as soon as the clinical symptoms set in.[2]  Although vaccine-preventable, rabies, especially via a dog bite, remains a significant cause of annual deaths in humans, both young and old. Novel treatments and vaccines that are effective and economical could preclude death. At present, the staggering cost of treatment remains a major health-care restraint. Without the proper and early treatment, death from rabies, unfortunately, is almost always certain.

— written by Maria Victoria Gonzaga

References:

1 Campbell, J. B. & Charlton, K.M. (1988). Developments in Veterinary Virology: Rabies. Springer. p. 48. ISBN 978-0-89838-390-4.

2 World Health Organization (WHO). (2019, May 21). Rabies. Retrieved from Who.int website: [Link]

3  Finke, S. & Conzelmann, K. K. (August 2005). “Replication strategies of rabies virus”. Virus Res111 (2): 120–131. doi:10.1016/j.virusres.2005.04.004  

4 Albertini, A. A., Schoehn, G., Weissenhorn, W., & Ruigrok, R. W. (January 2008). “Structural aspects of rabies virus replication”. Cell. Mol. Life Sci65 (2): 282–294. doi:10.1007/s00018-007-7298-1

5 Newman, T. (2017, November 15). Rabies: Symptoms, causes, treatment, and prevention. Retrieved May 23, 2019, from Medical News Today website: https://www.medicalnewstoday.com/articles/181980.php

6 University of Alaska Fairbanks. (2017, October 11). How rabies can induce frenzied behavior: Researchers better understand the disease that kills 59,000 people annually. ScienceDaily. Retrieved from website: [Link]

7 The Ohio State University Wexner Medical Center. (2019, May 22). Study identifies dog breeds, physical traits that pose highest risk of biting children. ScienceDaily. Retrieved from website: [Link]