Rabies pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Overview

The rabies virus is categorized as a Lyssavirus. The molecular biology of rabies consists of bullet shaped virus with helical symmetry that has a length of approximately 180 nm. Rabies typically has its greatest effect on the brain. Rabies is typically defined by encephalitis and myelitis. Various carnivorous animal species have been identified as the source of rabies virus (RV). In Africa and Asia, domestic dogs are the main reservoirs of rabies virus infection. Whereas, in the United States, racoons, foxes, skunks, coyotes, possums and bats are understood to be responsible for the spread of rabies virus.The neuromuscular junction is the major site of entry into neurons. RV infects peripheral nerves and then reaches the central nervous system (CNS) via retrograde axonal transport. The primary mechanism involved in the neuroinvasion of RV is trans-synaptic neuronal spread. RV infects neurons and leads to the degeneration of the neuronal processes by disrupting cytoskeletal integrity. Histopathologic evidence of rabies encephalomyelitis (inflammation) in brain tissue and meninges includes, mononuclear infiltration, perivascular cuffing of lymphocytes or polymorphonuclear cells, lymphocytic foci, Babes nodules consisting of glial cells and Negri bodies.

Pathophysiology

The organism causing rabies is called rabies virus (RV), a negative-stranded RNA virus of the rhabdovirus family. Rabies is an acute encephalomyelitis that causes disease in the human host via two features associated with the rabies virus (RV):[1][2]

  • Neurotropism
  • Neuroinvasiveness

Transmission

Common route of tranmission

  • Various carnivorous animal species have been identified as the source of rabies virus (RV)[3][4]
The infectious path of rabies virus in a raccoon

Less common routes of transmission

Virology

The rabies virus (RV) belongs to the genus Lyssavirus. This genus of RNA viruses also includes the Aravan virus, Australian bat lyssavirus, Duvenhage virus, European bat lyssavirus 1, European bat lyssavirus 2, Irkut virus, Khujand virus, Lagos bat virus, Mokola virus and West Caucasian bat virus. Lyssaviruses have helical symmetry, so their infectious particles are approximately cylindrical in shape.

  • The virus has a bullet-like shape with a length of about 180 nm and a cross-sectional diameter of about 75 nm[16][17]
  • One end is rounded or conical and the other end is planar or concave[18]
  • The lipoprotein envelope carries knob-like spikes composed of Glycoprotein G. Spikes do not cover the planar end of the virion (virus particle)[19]
  • Beneath the envelope is the membrane or matrix (M) protein layer which may be invaginated at the planar end. The core of the virion consists of helically arranged ribonucleoprotein[20]
  • The genome is unsegmented linear antisense RNA. Also present in the nucleocapsid are RNA dependent RNA transcriptase and some structural proteins

Longitudinal schematic view of rabies virus Cross section of Rabies virus
Longitudinal and cross-sectional schematic view of rabies virus

Pathogenesis

Incubation period and eclipse phase

Neuromuscular junction invasion

Inter-neuronal spread

CNS invasion

Microscopic Pathology

Histologic examination of biopsy or autopsy tissues is occasionally useful in diagnosing unsuspected cases of rabies that have not been tested by routine methods. When brain tissue from rabies virus-infected animals are stained with a histologic stain, such as hematoxylin and eosin, evidence of encephalomyelitis may be recognized. Histopathologic evidence of rabies encephalomyelitis (inflammation) in brain tissue and meninges includes the following:[33][34][35][30]

  1. Mononuclear infiltration
  2. Perivascular cuffing of lymphocytes or polymorphonuclear cells
  3. Lymphocytic foci
  4. Babes nodules consisting of glial cells
  5. Negri bodies

References

  1. Mrak RE, Young L (1994). "Rabies encephalitis in humans: pathology, pathogenesis and pathophysiology". J. Neuropathol. Exp. Neurol. 53 (1): 1–10. PMID 8301314.
  2. Lafon M (2004). "Subversive neuroinvasive strategy of rabies virus". Arch. Virol. Suppl. (18): 149–59. PMID 15119770.
  3. Swanepoel R, Barnard BJ, Meredith CD, Bishop GC, Brückner GK, Foggin CM, Hübschle OJ (1993). "Rabies in southern Africa". Onderstepoort J. Vet. Res. 60 (4): 325–46. PMID 7777317.
  4. Bingham J, Foggin CM, Wandeler AI, Hill FW (1999). "The epidemiology of rabies in Zimbabwe. 2. Rabies in jackals (Canis adustus and Canis mesomelas)". Onderstepoort J. Vet. Res. 66 (1): 11–23. PMID 10396757.
  5. "www.who.int" (PDF).
  6. "CDC - Rabies Surveillance in the U.S.: Wild Animals - Rabies".
  7. Constantine DG, Woodall DF. Related Articles, Links Transmission experiments with bat rabies isolates: reactions of certain Carnivora, possum, rodents, and bats to rabies virus of red bat origin when exposed by bat bite or by intrasmuscular inoculation. Am J Vet Res. 1966 Jan;27(116):24-32. No abstract available. PMID: 5913032 [PubMed - indexed for MEDLINE]
  8. Constantine DG 1967 Rabies transmission by air in bat caves. US Pub Health Serv, Publ. 1617
  9. 1: Am J Vet Res. 1960 May;21:507-10.Links Resistance of the opossum to rabies virus.BEAMER PD, MOHR CO, BARR TR. PMID: 13797881 [PubMed - indexed for MEDLINE]
  10. Ettinger, Stephen J.;Feldman, Edward C. (1995). Textbook of Veterinary Internal Medicine (4th ed. ed.). W.B. Saunders Company. ISBN 0-7216-6795-3.
  11. The Merck manual of Medical Information. Second Home Edition, (2003), p. 484.
  12. "Rabies | Clinical Infectious Diseases | Oxford Academic".
  13. "www.microbiologyresearch.org" (PDF).
  14. "CDC - Transmission - Rabies".
  15. "www.microbiologyresearch.org" (PDF).
  16. "Rhabdoviruses: Rabies Virus - Medical Microbiology - NCBI Bookshelf".
  17. Iseni F, Barge A, Baudin F, Blondel D, Ruigrok RW (1998). "Characterization of rabies virus nucleocapsids and recombinant nucleocapsid-like structures". J. Gen. Virol. 79 ( Pt 12): 2909–19. doi:10.1099/0022-1317-79-12-2909. PMID 9880004.
  18. Hummeler K, Koprowski H, Wiktor TJ (1967). "Structure and development of rabies virus in tissue culture". J. Virol. 1 (1): 152–70. PMC 375516. PMID 4918232.
  19. Gaudin Y, Ruigrok RW, Tuffereau C, Knossow M, Flamand A (1992). "Rabies virus glycoprotein is a trimer". Virology. 187 (2): 627–32. PMID 1546457.
  20. Mebatsion T, Weiland F, Conzelmann KK (1999). "Matrix protein of rabies virus is responsible for the assembly and budding of bullet-shaped particles and interacts with the transmembrane spike glycoprotein G". J. Virol. 73 (1): 242–50. PMC 103828. PMID 9847327.
  21. Charlton KM, Nadin-Davis S, Casey GA, Wandeler AI (1997). "The long incubation period in rabies: delayed progression of infection in muscle at the site of exposure". Acta Neuropathol. 94 (1): 73–7. PMID 9224533.
  22. "Rabies | Clinical Infectious Diseases | Oxford Academic".
  23. "CDC - Doctors: Transmission - Rabies".
  24. Israsena N, Mahavihakanont A, Hemachudha T (2011). "Rabies virus infection and microRNAs". Adv. Virus Res. 79: 329–44. doi:10.1016/B978-0-12-387040-7.00015-9. PMID 21601053.
  25. Burrage TG, Tignor GH, Smith AL (1985). "Rabies virus binding at neuromuscular junctions". Virus Res. 2 (3): 273–89. PMID 3890406.
  26. Thoulouze MI, Lafage M, Schachner M, Hartmann U, Cremer H, Lafon M (1998). "The neural cell adhesion molecule is a receptor for rabies virus". J. Virol. 72 (9): 7181–90. PMC 109940. PMID 9696812.
  27. Finke S, Conzelmann KK (2005). "Replication strategies of rabies virus". Virus Res. 111 (2): 120–31. doi:10.1016/j.virusres.2005.04.004. PMID 15885837.
  28. Dietzschold B, Schnell M, Koprowski H (2005). "Pathogenesis of rabies". Curr. Top. Microbiol. Immunol. 292: 45–56. PMID 15981467.
  29. "Rabies Virus P Protein Interacts with STAT1 and Inhibits Interferon Signal Transduction Pathways".
  30. 30.0 30.1 Lahaye X, Vidy A, Pomier C, Obiang L, Harper F, Gaudin Y, Blondel D (2009). "Functional characterization of Negri bodies (NBs) in rabies virus-infected cells: Evidence that NBs are sites of viral transcription and replication". J. Virol. 83 (16): 7948–58. doi:10.1128/JVI.00554-09. PMC 2715764. PMID 19494013.
  31. Li XQ, Sarmento L, Fu ZF (2005). "Degeneration of neuronal processes after infection with pathogenic, but not attenuated, rabies viruses". J. Virol. 79 (15): 10063–8. doi:10.1128/JVI.79.15.10063-10068.2005. PMC 1181611. PMID 16014967.
  32. Pleasure SJ, Fischbein NJ (2000). "Correlation of clinical and neuroimaging findings in a case of rabies encephalitis". Arch. Neurol. 57 (12): 1765–9. PMID 11115243.
  33. Théodoridès J (1981). "[Histological research on rabies in the 19th century]". Clio Med (in French). 16 (2–3): 83–92. PMID 6176396.
  34. Kristensson K, Dastur DK, Manghani DK, Tsiang H, Bentivoglio M (1996). "Rabies: interactions between neurons and viruses. A review of the history of Negri inclusion bodies". Neuropathol. Appl. Neurobiol. 22 (3): 179–87. PMID 8804019.
  35. Burton EC, Burns DK, Opatowsky MJ, El-Feky WH, Fischbach B, Melton L, Sanchez E, Randall H, Watkins DL, Chang J, Klintmalm G (2005). "Rabies encephalomyelitis: clinical, neuroradiological, and pathological findings in 4 transplant recipients". Arch. Neurol. 62 (6): 873–82. doi:10.1001/archneur.62.6.873. PMID 15956158.



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