prions and rabies Flashcards
Prions and transmissible spongiform encephalopathies
Unconventional virus like agents- Prions, originally classified as viruses because they are transmissible, cant be grown in pure culture, and not filterable (heat stable)
NO DNA/RNA ever found, induce no immune response, difficult to inactivate, not really viruses
Animal disease
Scrapie: in sheep, goats and mink, animals scrape against fence posts, brain and lymph tissue is infectious, can be trasmitted to mice and hamsters where incubation period is shorter, serves as a model for study
Bovine spongiform encephalopathy or mad cow disease, use of sheep tissue in food supplements- cows are killed
kuru
(means to shiver), characterized by ataxia and shivering-like tremor, progressing towards complete motor incapacity and death within 1 yr of onset
spread by ritualistic cannabalism women and children
creutzfeldt jakob disease
1 cas/million in US and europe and is the most common human prion disease:
Progessive dementia leading ataxia, paralysis, wasting and death usually by pneumonia within 6 months of onset
origin unknown sporadic,
Variant CJD- contaminated BSE beef, occurs in young people similar but atypical symptoms
familial, inherited form
Transmitteted by growth hormone injection, corneal transplant, electrode implants
Gertsmann-straussler-scheinker disease- a familial form of CJD with Prp mutation- 30s to 40s
fatal familial insomnia
describd in 86, inherited prp mutation causes sleep problems–> ataxia and death
prion structure and function
proteinacious infectious particle
Protein particle without a nucleic acid could be infectious and replicate
Normal protein encoded by cellular gene PrP on chromosome 20 , found on cell surface and expressed by many tissues- including normal brain and very high in CJD- synaptic role
PrP sc abnormal version of prp c- aggregates into a highly insoluble form, accounts for resistance to inactivation
Scrapie infectivity co purifies– rod shaped when pure
infectivity of prion
associated with the conversion of normal alpha helical protein to insoluble B sheet form
PrP sc is infectious but it doesnt replicate- it recruites/convers the normal PrPc to the PrPsc form, the prion aggregates taken up by neurons difficult to degrade and long lasting, spongiform appearance from vacuoules comprimised function
protein only hypothesis
PrPsc and infectivity co purify
levels of PrPsc are proportional to prion titer
PrPsc accumulation always linked to disease
over expression of prpc in mice accelerates prpsc formation and shortens incubation time
Trangenic mice expressing WT and prp sc get disease
Prpsc get disease
Prpsc knockout mice are resistent to infection, no normal protein present to convert
Yeast have similar proteins a good model to study conversion mechanism
Pathogenesis, clinical aspects diagnosis and treatment of spongiform encephalopathies`
Spongiform encephalopathies are all CNS neurodegenerative diseases, eventually fatal
Vacuolization in neurons gives a spongiform appearance in grey matter and neuronal loss, sometimes amyloid plaques (not same as in alzheimers pts) and proliferation and hypertrophy of astrocytes
long incubation period- slow infection– months to decades moths to decades Kuru and CJD disease may take 30 yrs
Clinical disease lasts for week to years- chronic progressive pathology, once symptoms become evident , death is within a year
Absence of immune or inflammatory response of any kind, Diagnosisp a few assays diagnosis clinicallay and histology of brain tissue, treatment- none (tonsil biopsy)
Rabies
latin for madness, has been present in human pops thoughout recorded times and probably predates humans
A common cause of death in developing world but rare in US and developed countries due to effective animal vaccination
post exposure prophylaxis (PEP) for suspected exposures
classification, structure and replication of rabies virus
Classified as a rhabdovirus, (rhabdo or rod) theres 2 genera- lyssavirus (rage– rabies, and vesiculor virus - in animals
Virion morphology- rod or bullet shaped, enveloped with membrane spikes of virial glycoprotein, the nucleocapsid of negative ssRNA and protein that is helifally coidled giving striated look in EM
Replication- is the prototype for negative sense RNA viruses
immunological charachteristics of rabies
there is one viral serotype, but several strains from different animal species, strains can be id’d due to genetic variation- sequence can determine if a human was infeected by a virus from a dog, bat etc, the surface G glycoprotein elicits neutralizing Ab but natural timing of antibody production not protective
Fixing of virrus of rabbit –> vaccine,
pathogenesis of rabies
entry is usually through a wound or skin via abrasion via a bite, and introduction of infected saliva
One report of aerosil infection in cave exploreres, can be transmitted by infected cornea transplants, and more recently from organ transplants
Virus replicates in muscle or CT during incubation period which can be months
Virus enters peripheral nerves at muscle, it caried through axons to the CNS and brain rapidly becomes infected, intervention before spread to CNS is effective
CNS- virus replicates to high levels in brain and then disseminates to numerous distal sites via nerves (eye, salivary glands, and innervated skin, salivary glands are important for animal dissemintion
CLinical aspects of rabies
asymptomatic incubation period, usually 3 to 8 wks, as short as 1 week or up to a year or longer, time depends on dose and location of bite (shorter with bite closer to brain- neck or head, low titer, virus in muscle no antibody present at this time
Prodrome- early after infection of brain, symptoms include nervousness, headache, anxiety, pain at bite site fever, nausea, difficult to diagnose rabies on symptoms if pt does not reveal possibility of exposure upon taking history
Last 2-10 days virus in brain and other sites if at other sites
Acute neurological phase of rabies
High virus titer in brain and elsewhere, antibody present in serum and CNS, death is rapid in undeveloped countries but longer with supportive care, progression to disease can take 2 forms
Furious or fulminant- classic rabies, bizzare behavior, hallucinations, seizures, hydrophobia go crazy after drinking water, fury gives way to paralysis then either coma or sudden fatal cardiac or respiratory arrest, paralytic or dumb rabies- 20 % of cases ascending flaccid paralysis leading to fatal paralysis of respiratory muscles
you cant see much, negri bodies- viral replication
