Rabies: effect, mechanism, and treatment

1. Rabies: effect, mechanism, and treatment By: Avinash Sankar, Julia White, Cameron Ho, and Victoria Trinh PHM142 October 1, 2019 PHM142 Fall 2019 Instructor: Chesa Dojo Soeandy Coordinator: Jeffrey Henderson

2. What is Rabies? • An infection caused by the rabies virus transmitted zoonotically • It is transmitted through direct contact with saliva or CNS tissue from an infected animal • It affects the brain and spinal cord of mammals, including humans • It is nearly always deadly if not treated before symptoms begin

3. Structure of the Rabies Virus Pal, 2017

4. Stages of Rabies Progression • Incubation • Prodrome • Acute neurologic period • Coma • Death

6. Incubation Long duration (~2 months)and high variability (week to years) Dependence on various factors such as location of bite relative to CNS, amount of virus inoculated and innervation of bite site Pain around site General symptoms (fever, headache, numbness and tingling sensations)

7. Prodromal Phase and Symptoms First presence of clinical symptoms Fatigue, malaise, vomiting, diarrhea, nausea, insomnia among others Indicates it is too late for any rabies vaccinations Virus has migrated from the muscles of the injury site to peripheral nerves and toward CNS (spinal cord and brain)

8. Acute Neurological Period CNS Dysfunction “Furious Rabies” - 80% of cases characterized by hyperactivity, aggressive behavior, hypersalivation, hyperventilation, seizure activity “Paralytic Rabies” - starting from bite location, progressive muscle weakness and paralysis is spread over the body Hydrophobia - inability to swallow fluids resulting in fear of drinking Major brain inflammation resulting in irregular breathing and coma Inevitable death by cardiac or respiratory arrest

9. Robertson K, Johnson K, et al. 2012

10. Mechanism: Biochemistry • The virus will replicate locally then move through the neuromuscular junction to the unmyelinated nerve. • The nicotinic acetylcholine receptors (nAChR) play a major role in the uptake of rabies into the nerve. Fisher C., et al. 2018

11. CDC 2019

12. Diagnosis General diagnosis • If there is a history of an animal bite, and signs and symptoms have appeared, then diagnosis is simple • However, rabies’ symptoms are very general and are similar to other infectious and noninfectious disease Laboratory diagnosis • Perform a direct immunofluorescence test on a skip biopsy for evidence of the rabies antigen • Isolate the virus from saliva after inoculation of neuroblastoma cells • Perform a rapid fluorescent focus inhibition test (RFFIT) in the serum of an unvaccinated person

13. Pre-exposure Treatment • Only those who are at high risk of exposure • Laboratory workers • Animal handlers • Veterinarians • Spelunkers (cave explorers) • People travelling to parts of the world where exposure to rabies is likely • 3 doses of the rabies vaccine are given: • 2nd is given 7 days after the first dose • 3rd is given 21-28 days after the first dose

14. Post-exposure Prophylaxis (PEP) Treatment: 2 stages 1: Rabies immune globulin (RabIg) • Immediate, short-term protection against the virus via antibodies • One dose is injected in or around the the wound 2: Rabies vaccine • Long lasting protection, helps the immune system to make antibodies • Four doses are given over 14 days in the shoulder: Day 1, 3, 7, and 14

15. Types of Immunity Passive Immunity • Given the antibodies rather than the body producing its own • Provides rapid protection • Not long lasting Active Immunity • Gained through exposure of the disease which would trigger the immune system response to produce antibodies (natural immunity) • Or through vaccine of weakened form of the disease (vaccine induced immunity) • Long lasting

16. Summary • Rabies is a viral infection that is transmitted zoonotically • Stages: Incubation, Prodromal, Acute Neurological, Coma, and Death • Symptoms: fatigue, malaise, vomiting, diarrhea, nausea, insomnia, and ultimately death • Infection travels from the muscle to the neuromuscular junction into the central nervous system to exert effects • Nicotinic acetylcholine receptor allows for uptake into the neuromuscular junction • 2 stages of post-exposure prophylaxis (PEP) treatment: • 1. Rabies Immune Globulin - immediate, short-term protection • 2. Rabies Vaccine - long-lasting protection

17. Works Cited BC Centre for Disease Control. Rabies Health Info [Internet]. Provincial Health Services Authority; c2019 [cited Sep 29]. Available from: http://www.bccdc.ca/health-info/diseases-conditions/rabies Brouhard R., Symptoms of Rabies [Internet]. Sep 2019 [cited 2019 Sep 29]. Available from: https://www.verywellhealth.com/rabies-symptoms-1298793 Centers for Disease Control and Prevention. Immunity Types [Internet]. 2019 [cited 2019 Sep 29]. Available from: https://www.cdc.gov/vaccines/vac-gen/immunity-types.htm Centers for Disease Control and Prevention. What is rabies [Internet]. 2019 [cited 2019 Sep 29]. Available from:https://www.cdc.gov/rabies/about.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Frabies%2Ftransmission%2Fvirus.html Children’s Hospital of Philadelphia. A Look at Each Vaccine: Rabies Vaccine [Internet]. [cited ..]. Available from: https://www.chop.edu/centers-programs/vaccine-education-center/vaccine-details/rabies-vaccine Christine R., et Al. The Spread and evolution of rabies virus: conquering new frontiers. Nature Reviews Microbiology 16 [Internet]. 2018 Feb [cited 2019 Sep]. Available from: https://www.nature.com/articles/nrmicro.2018.11

18. El-Sayed A. Advances in rabies prophylaxis and treatment with emphasis on immunoresponse mechanisms. Int J Vet Sci Med [Internet]. 2018 Jun [Cited Sep 29]; 6(1): 8-15. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149183/ Greenlee J. Rabies. Merck Manual Consumer Version [Internet]. Merck Sharp & Dohme Corp, Kenilworth, NJ, USA; c2019 [cited 2019 Sep 29]. Available from: https://www.merckmanuals.com/en-ca/home/brain,-spinal-cord,-and-nerve-disorders/brain-infections/rabies HealthLink BC. Rabies Immune Globulin and Vaccine [Internet]. 2018 Sept [cited 2019 Sep 29]. Available from https://www.healthlinkbc.ca/healthlinkbc-files/rabies-immune-globulin-and-vaccine HealthLink BC. Rabies [Internet]. 2019 Jan [cited 2019 Sep 29]. Available from: https://www.healthlinkbc.ca/health-topics/hw181108#targetText=Rabies%20is%20an%20infection%20caused,saliva%20or%20through%20brain%20tissue. Mcgettigan J. Experimental Rabies Vaccines for Humans. Expert Rev Vaccines [Internet]. 2010 Oct [cited sept 29]; 9(10): 1177-1186. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072237/ Medlifeweb. Rabies Virus [Internet]. [cited 2019 Sep 29]. Available from: https://www.medlifeweb.com/rabies-virus-symptoms-treatment/

19. Mehadevan A., Suja M. S., Mani R., Shankar S., Perspectives in Diagnosis and Treatment of Rabies Viral Encephalitis: Insights from Pathogenesis. Neurotherapeutics [Internet]. 2016 Jul [cited 2019 Sep 29]; 13(3): 477–492, Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965414/ PLOS. From bite site to brain: How rabies virus hijacks and speeds up transport in nerve cells. ScienceDaily [Internet]. 2014 Aug [cited 2019 Sep 29]. Available from: https://www.sciencedaily.com/releases/2014/08/140828142736.htm Pal M. Rabies Virus Figure [Internet]. 2017 [cited 2019 Sep 29]. Available from: https://www.researchgate.net/figure/Figure1-Rabies-virus-shape-and-its-structures-Source-h-t-t-p-s-d-o-k-u-w-i-k-i_fig2_313247700 Robertson K., et al. Rabies Transmission. Netter’s Infectious Diseases [Internet]. 2012 [cited 2019 Sep 29]. Available from: https://www.sciencedirect.com/topics/immunology-and-microbiology/rabies-transmission Rupprecht C. Medical Microbiology 4th Edition [Internet]. Galveston, Texas: University of Texas Medical Branch at Galveston; 1996 [cited 2019 Sep 29]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK8618/