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Virology Lec 9: Rabies, Slow Virus Infections and viruses isolated from different geographic

Prion Diseases areas


USTMED 2011 Sec C – Substitution of amino acid position 333 of
Professor: Dr. Boromeo the glycoprotein results in loss of
Created: 01-06-09 virulence producing a virulent mutant
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Rabies Pathogenesis
• A major public health problem (widespread • Rabies usually results from the bite of a rabid
among animal reservoir) animal
• An acute infection of CNS (almost always fatal) • It causes secretion of the virus in its saliva and
• Usually transmitted to humans from the bite of a promotes aggressive behavior (mad dog) that
rabid animal promotes its transmission
• Other routes of infection that have been
Properties of the Virus documented?
• STRUCTURE – Inhalation of aerosolized virus
– Rod or bullet-shaped particles surrounded – Transplantation of infected tissue (e.g.
by a membranous envelope with cornea)
protruding spikes – Inoculation through intact mucous
– Inside the envelope is a ribonucleocapsid membrane
(genome is single-stranded RNA) • Rabies virus multiplies in muscle (striated) or
connective tissue at the site of inoculation à
• CLASSIFICATION enters peripheral nerves at neuromuscular
– Belong to Family Rhabdoviridae and to
junction, CNS à multiplies à progressive
the genus Lyssavirus
encephalitis à spread through peripheral nerves
– Rhaboviruses are widely distributed in
nature but rabies is the only medically to highly innervated areas à of skin of the head
important rhabdovirus and neck, salivary glands, retina, cornea, nasal
mucosa, adrenal medulla, renal prenchyma, and
• REACTIONS TO PHYSICAL AND CHEMICAL pancreatic acinar cells
AGENTS • Submaxillary salivary gland is the organ with the
highest titer of the virus
– Survives storage at 4ºC for weeks and at • Virus has not been isolated from the blood of
-70ºC for years infected persons
– Inactivated by CO2 • Invasion of the virus into the brain and spinal cord
– Rapidly killed by exposure to UV causes an encephalitis and neuronal degeneration
radiation, sunlight, heat (1 hour at 50ºC) • Few gross or histopathologic lesions are seen in
by lipid solvents like ether and 0.1% patients with rabies despite extensive CNS
sodium deoxycholate) by trypsin, involvement
detergents, and extremes of pH • With rare exception, rabies is fatal once clinical
disase is apparent
• ANIMAL SUSCEPTIBILITY
– Rabies has a wide host range Factors affecting susceptibility and incubation
– All warm-blooded animals including period
humans can be infected • Host age
– Virus widely distributed in infected • Genetic background
animals especially in the nervous system, • Immune status
saliva, urine, lymph, milk and blood • Viral strain
– Recovery from infection is rare except in • Amount of inoculum
certain bats, where the virus has become • Severity of lacerations
peculiarly adapted to the salivary glands. • Distance the virus has to travel from its point
(vampire bats may transmit the virus for of entry to the CNS
months without themselves ever showing
any signs of disease)

Animal susceptibility to rabies


Very High Moderate Low
High

Foxes Hamsters Dogs Opossums


Coyot Skunks Sheep
es Raccoons Goat
Jackal Cats Horses
s Bats Nonhuman
Wolve Rabbits primates
s Cattle
Cotton
rats

• GROWTH OF VIRUS
– When freshly isolated in the laboratory,
the strains are referred to as street virus
(this strains show long and variable
incubation period of 21-60 days in dogs
and regularly produce intracytoplasmic
inclusion bodies)
– Serial brain to brain passage in rabbits
yields a “fixed” virus (mutant) that no
longer multiplies in extraneural tissues.
This strain multiplies rapidly (incubation
period is shortened to 4-6 days) and
inclusion bodies are found only with
difficulty) Pathology
• Virus produces a
• ANTIGENIC PROPERTIES specific eosinophilic cytoplasmic inclusion, the Negri
– There is a single serotype of rabies virus body in infected cells
but there are strain differences among
• Presence of Negri encephalitis or unusual behavior, they should be
body is pathognomonic of rabies but is not observed sacrificed and the tissues examined in the
in 20% of cases laboratory

Clinical Findings Treatment


• Rabies is an acute, fulminant, fatal encephalitis • 99% of infections in humans who develop
• Incubation period in humans is typically 1-2 symptoms end fatally because treatment is of no
months but may be as short as 1 week or as long benefit after the onset of clinical disease
as many years (up to 19 years), usually shorter in • It is therefore essential that individuals at high
children than in adults risk receive preventive immunization, that the
nature and risk of any exposure be evaluated and
Clinical spectrum is divided into 3 phases that individuals be given post exposure
• Prodromal phase (short) prophylaxis if their exposure is believed to have
• Acute neurologic phase been dangerous
• Coma
High risk persons requiring pre-exposure
Prodromal phase (last 2-10 days) prophylaxis
• Malaise • Veterinarians and vet med students
• Anorexia • Animals handlers
• Headache • Animal control and wildlife workers
• Photophobia • Community health workers
• Nausea • Research and laboratory workers
• Vomiting
• Sore throat Post-exposure Rabies Prophylaxis
• Fever • Immediate cleansing of all wounds with soap and
• Abnormal sensation around the wound site (pain water
or paresthesia) • Vaccinations
• Active – human diploid cell vaccine, duck
Acute neurologic phase (last 2-7 days) embryo vaccine, purified chick embryo
A. Nervous system dysfunction • Passive – immune globulin (human, or
– Nervousness equine)
– Apprehension
– Hallucinations Factors affecting the decision to administer rabies
– Bizarre behavior vaccination whether active or passive or both
• Nature of biting animals and its vaccination status
B. General symphatetic overactivity • Availability of the animal for laboratory
– Lacrimation examination
– Pupillary dilatation • Existence of rabies in the area
– Increased salivation and perspiration • Manner of attack (provoked or unprovoked)
– Hydrophobia (most characteristic • Severity of the bite and contamination by saliva of
symptom occuring in 20-50% of patients) the animal

C. Convulsion, coma and death Human Slow Virus and Prion Diseases
• Subacute Sclerosing Panencephalitis
Laboratory Diagnosis • Progressive multifocal leukoencephalopathy
• Rabies antigen or Nucleic Acids Detection • Creutzfeldt-Jakob disease
• Viral isolation • Kuru
• Serology
• Animal observation Subacute Sclerosing Panencephalitis
• Caused by persistent measles virus infections
Rabies Antigen or Nucleic Acids Detection with slowly progressive demyelination in the CNS
• Immunofluorescence or immunoperoxidase ending in death
staining using antirabies monoclonal antibodies • Measles infection below 18 months of age
on infected tissues (biopsy specimen taken from increases risk
skin of the neck at the hairline or impression • Manifest as progressive behavioral and
preparation of brain or corneal tissue intellectual deterioration with seizures, most often
• Negri bodies in the brain and spinal cord. They myoclonic jerks, motor incoordination, visual and
contain rabies virus antigen and can be speech impairment
demonstrated by immunofluorescence • High titers of measles antibody in serum and CSF
• PCR testing to amplify rabies virus genome from
fixed or unfixed tissue Progressive Multifocal Leukoencephalopathy
• Caused by JC virus (Family Polyomaviridae)
Viral Isolation • Occurs in some immunosuppressed individuals
• Intracerebral inoculation of suckling mice of • Causes demyelination in the CNS
infected tissue resulting to encephalitis and death
à examination of CNS of inoculated animal for Kuru
Negri bodies and rabies antigen • Occurred in Eastern highbands of New Guinea
• Isolated virus is identified by fluorescent antibody • Spread by customs surrounding ritual cannibalism
test with specific antiserum of dead relatives

Serology CJD
• Rabies antibodies can be detected by • Develops gradually
immunofluorescence or Nt test • Progressive dementia
• In infected animals or humans, these antibodies • Ataxia
develop slowly during progression of the disease • Myoclonus
but promptly after vaccination with cell-derived • Death in 5 – 12 months
vaccines
• Antibodies in CSF are produced in infected Iatrogenic CJD
individuals but not after vaccination • Transmitted accidentally by contaminated growth
hormone preparation
Animal Observation • By corneal transplant
• All animals considered rabid or suspected rabid • By contaminated surgical instrument
should be sacrificed immediately for laboratory • By cadaveric human dura matter graft for surgical
examination of neural tissues repair of head injury
• Other animals should be held for observation for
10 days. If the observed animal develop
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Medical Student/Biologist
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