What is the pathophysiology of rabies?

Answer

Rabies virus infection is remarkable for the lack of evident pathology in the face of dramatic neurological symptoms. Minimal inflammation and neuronal cytopathy may be observed even postmortem. Similarly, viremia does not occur or play a role in spread to the CNS.

Pathophysiology has been best characterized in canine rabies variants. Canine rabies in humans requires deep-muscle inoculation. Endogenous muscle micro-RNA bind to viral transcripts and limit both replication and viral protein production, such that the virus is able to evade detection by antigen-presenting cells. Once enough virus replicates (or with a high-level inoculum or direct nerve injury), it binds motor neuron junctions at postsynaptic nicotinic acetylcholine receptors, which initiates uptake into the motor endplate. From here, the virus rapidly propagates across motor axons and chemical synapses in retrograde fashion toward the ganglia and nerve roots, at which point the prodromal symptoms of neuralgia and hypoesthesia may begin, in addition to fever and flulike illness.

Once reaching the CNS, it spreads throughout via the more ubiquitous nicotinic acetylcholine receptors of the brain. Of note, anterograde spread of rabies virus may then occur via sensory and autonomic pathways from the CNS to viscera, explaining many of the symptoms of progressive disease. Throughout propagation of the virus along motor pathways, the virus elicits little inflammation, and the motor neurons continue their otherwise normal functions of neurotransmission. Increasing signs of inflammation develop as CNS and visceral spread occurs, although a significant paucity of findings remains, other than mild nonspecific MRI T2 enhancements. Spinal fluid remains largely acellular, even in the presence of detectable rabies virus.

Propagation to the CNS via peripheral sensory or autonomic synapses does not seem to occur with canine variants, and only about 30% of cases result in peripheral sensory neuralgia. However, 70% of cases with bat variants result in neuropathic pain in the region of inoculation, as well as Horner syndrome and other findings; thus, these alternate pathways may occur in bat rabies variants.^{[20, 21]}

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Media Gallery

Hematoxylin and eosin stain of Negri body in a rabies-infected neuron. Courtesy of the US Centers for Disease Control and Prevention.
Distribution of the 5 strains of rabies virus and the associated wildlife in the United States.

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Author

Sandra G Gompf, MD, FACP, FIDSA Associate Professor of Infectious Diseases and International Medicine, University of South Florida College of Medicine; Chief, Infectious Diseases Section, Director, Occupational Health and Infection Control Programs, James A Haley Veterans Hospital

Sandra G Gompf, MD, FACP, FIDSA is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Coauthor(s)

Tri M Pham, MD Consulting Physician, Division of Infectious Diseases, Watson Clinic, Lakeland

Tri M Pham, MD is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Charurut Somboonwit, MD, FACP Associate Professor of Internal Medicine, Division of Infectious Disease and International Medicine, University of South Florida College of Medicine; Clinical Research and Communicable Diseases Director, USF Health and Hillsborough Health Department

Charurut Somboonwit, MD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Albert L Vincent, PhD Associate Professor, Division of Infectious Diseases and International Health, Department of Internal Medicine, University of South Florida College of Medicine; Scientific and Research Advisor to the Division of Epidemiology, Hillsborough County Health Department

Disclosure: Partner received none from none for none.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, Association of Professors of Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Acknowledgements

Leslie L Barton, MD Professor Emerita of Pediatrics, University of Arizona College of Medicine

Leslie L Barton, MD is a member of the following medical societies: American Academy of Pediatrics, Association of Pediatric Program Directors, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society