Rabies, how it works and how it kills

One of my largest interests as a prospective pharmacy student will be diseases and microbes and how they affect the body. However, the largest mystery for me is an individual's behavior under the effects of rabies lyssavirus, or just rabies for short. Although rabies is very treatable and preventable via vaccines and vaccination of domesticated dogs which make up approximately 99% of cases transmitted to humans via bites or scratch marks (WHO, 2024). It is nearly always fatal when the first symptoms appear, with only a record of 20 individuals surviving after being diagnosed with rabies (Stephenson. C, 2016). At this point, mostly everyone knows the symptoms of rabies via depictions from mainstream media, which typically depict un-ordinarily aggressive behavior, hypersalivation, as well as hydrophobia. But what is largely unknown about the virus is what it is like to live through a rabies diagnosis past the treatment window, such as what it is like to experience the symptoms to explain the loss of rational and terrifying demeanor that is seen sometimes in our beloved pets. The first known survivor of rabies without receiving treatment is Jeanna Giese-Frasseto, who at 15 was first exposed to the viral infection when she was initially bitten on her index finger by a bat she had rescued. A cocktail of experimental drugs now known as the Milwaukee Protocol had placed Jeanna in a medicated comatose state to slow down the viral infection from reaching the brain and eventually death (Stephenson. C, 2016). Even if the Milwaukee Protocol had left her unable to speak, stand, or walk, she was eventually able to relearn these behaviors and as of 2024 has successfully become a mother of twins, due to its success, the Milwaukee Protocol has been used to save 10 other infected patients that had begun showing symptoms (). But how does rabies work? Rabies as many know is transmitted from saliva into an open wound (this explains the hypersalivation and aggressive behavior of the infected individuals due to bite marks or scratches will allow a point of entry for the excess saliva, allowing further propagation within a newly infected individual), the virus then undergoes an incubation period of typically 1-3 months where the virus propagates within affected cells' cytoplasm and uncoats its viral RNA, allowing for virion-associated RNA-dependent RNA polymerase that is translated into 5 viral proteins that lead to the degradation of affected cells (Rupprecht. C, et al. 1996). After multiplication, the virus tends to migrate toward the peripheral nervous system causing irreversible damage (CDC. 2024). The produced protein then attaches to ACh receptors (which we had learned within the class are typically used in the process of memory formation)  within both neurons and immune cells, and when affecting some areas of the brain, the neurological symptoms of rabies can be observed such as the serotoninergic-related motor alterations due to the disruption of cholinergic signaling (Bastos, V, et al. 2023). This gives us insight into how the Milwaukee Protocol works in that it does nothing to prevent the viral protein from binding but rather stalls the virus from affecting critical neurological sites within the brain which gives time for the host's immune system to detect and fend off the virus from doing further damage to the body.

Although this post is not a "deep-dive" into rabies such as the biochemistry of how the viral proteins bind or interact with the ACh inhibitors, I highly encourage readers to look into random pathogens to further their understanding of how medications work and possibly alleviate any sorry of fear of the unknown.

Citations

Bastos V, V., & Pacheco, V. (2023, October 26). Neuroimmunology of rabies: New insights into an ancient disease. Journal of medical virology. https://pubmed.ncbi.nlm.nih.gov/37885152/

Centers for Disease Control and Prevention. (2024, May 17). Rabies symptoms and specimen collection. Centers for Disease Control and Prevention. https://www.cdc.gov/rabies/hcp/suspected-human-rabies/index.html

From the brink of death to motherhood: First person to ever survive rabies reflects on becoming a mom. Children’s Wisconsin. (2016, May 7). https://childrenswi.org/at-every-turn/stories/jeanna-giese-rabies#:~:text=Jeanna%20Giese%2DFrassetto%2C%20the%20first,did%20not%20seek%20medical%20attention.

Rupprecht, C. E. (1996, January 1). Rhabdoviruses: Rabies virus. Medical Microbiology. 4th edition. https://www.ncbi.nlm.nih.gov/books/NBK8618/

Stephenson, C. (2016, March 29). Motherhood is latest milestone for woman who survived rabies. Journal Sentinel. https://www.jsonline.com/story/news/health/2016/03/29/motherhood-is-latest-milestone-for-woman-who-survived-rabies/84941662/

World Health Organization. (2024, April). Rabies. World Health Organization. https://www.who.int/news-room/fact-sheets/detail/rabies