Lyssavirus Research Paper

Rabies
Rabies is a viral disease that affects the central nervous system (CNS). The genus Lyssavirus contains more than 80 viruses. Classic rabies, the focus of this article, is the prototypical human Lyssavirus pathogen.
There are 10 viruses in the rabies serogroup, most of which only rarely cause human disease. The genus Lyssavirus, rabies serogroup, includes the classic rabies virus, Mokola virus, Duvenhage virus, Obodhiang virus, Kotonkan virus, Rochambeau virus, European bat Lyssavirus types 1 and 2, and Australian bat Lyssavirus. Five antigenic variants of rabies strains are recognized in the United States.
The fatal madness of rabies has been described throughout recorded history, and its association with rabid canines is well known.
For centuries, dog bites were treated prophylactically with cautery, with predictable and unfortunate results. In the 19th century, Pasteur developed a vaccine that successfully prevented rabies after inoculation and launched a new era of hope in the management of this uniformly fatal disease.

Etiology:
Rabies is a highly neurotropic virus that evades immune surveillance by its sequestration in the nervous system.
Upon inoculation, it enters the peripheral nerves. A prolonged incubation follows, the length of which depends on the size of the inoculum and its proximity to the CNS. Amplification occurs until bare nucleocapsids spill into the myoneural junction and enter motor and sensory axons. At this point, prophylactic therapy becomes futile, and rabies can be expected to follow its fatal course, with a mortality rate of
100%.
The rabies virus travels along these axons at a rate of 12-24 mm/d to enter the spinal ganglion.
Its multiplication in the ganglion is heralded by the onset of pain or paresthesia at the site of the inoculum, which is the first clinical symptom and a hallmark finding. From here, the rabies virus spreads quickly, at a rate of 200-400 mm/d, into the CNS, and spread is marked by rapidly progressive encephalitis. Thereafter, the virus spreads to the periphery and salivary glands.
From the standpoint of diagnosis and therapeutic opportunities, it is important to understand that rabies does not cause cytotoxicity. Neuronal morphology and lifespan is normal throughout the course of the disease. Death occurs from global neurologic and organ dysfunction. The virion acts in the synaptic space, where homology in amino acid sequences between neurotransmitter receptors for acetylcholine, GABA, and glycine may afford a mechanism for viral binding of these receptors. Thus, its action is neurotoxic, rather than direct damage.
Further, as disease progresses, virus may no longer be viable or replicating in tissue, although Negri bodies are present. If the virus could be contained or the binding action reversed, a cure might indeed be
possible.

Epidemiology:
United States
Rabies is recognized as a zoonosis worldwide. The prevalence of rabies varies by location depending on animal-control effectiveness and immunization programs (see the image below). The largest number of human deaths annually was recorded during the first half of the 20th century, with an average of 50 documented cases per year. Most were related to rabid-dog exposure. After 1940, when canine rabies vaccination programs began, the average number of documented cases declined to 2 per year. From 2001-2005, 15 cases of human rabies were reported in the United States.
International
Rabies is more prevalent in the developing world than in industrialized countries. The World Health Organization (WHO) estimates that rabies is responsible for 35,000-50,000 deaths annually worldwide and that gross underreporting is likely. An estimated 10 million people receive postexposure prophylaxis each year after being exposed to animals with suspected rabies. Unvaccinated dogs are the major reservoir for rabies.
Global reservoirs of rabies virus are as follows : * Europe - Foxes, bats * Middle East - Wolves, dogs * Asia - Dogs * Africa - Dogs, mongooses, antelopes * North America - Foxes, skunks, raccoons, insectivorous bats * South America - Dogs, vampire bats
Sex-related demographics
Encounters with rabid animal vectors may be increased in males, who may have greater contact in certain geographic areas. Evidence to support this is found in data on dog bites, which are observed more frequently in males than in females.

Prognosis:
Morbidity and mortality
The prognosis of rabies is excellent if postexposure prophylaxis is administered exactly as recommended and in a timely fashion. Without prophylaxis before the onset of prodromal symptoms, death is almost certain. Coordination with local health authorities is crucial. The paralysis may ascend (similar to Guillain-Barré syndrome), and coma of rabies encephalitis may last for hours to months with active intensive care support. Ultimately, however, autonomic dysfunction and myocarditis lead to cardiac arrhythmia and arrest.
While rabies is still considered a uniformly fatal disease, 3 cases of survival were reported in the 1970s. These cases involved patients who were given duck embryo vaccine or suckling mouse brain vaccine before the onset of clinical symptoms. Three additional cases of survival, which were not clearly documented, were reported in the 1940s, 1950s, and 1960s.
The 2009 investigational (now “open-source”) regimen of ribavirin, amantadine, and a ketamine-midazolam–induced coma has offered limited promise. The original protocol and subsequent variants have been used in the United States and elsewhere since; however, assessing whether this therapy was genuinely efficacious, whether other factors may have been involved, or whether these results are in fact reproducible is difficult. Rabies remains uniformly fatal for all practical purposes.