Virus Infections of the Nervous System Flashcards
Modes of entry to CNS
- neural
- olfactory
- hematogenous
Modes of entry to CNS-neural
2 transport pathways
- retrograde transport along lower motor neurons in spinal cord and brain stem (HSV, rabies, polio)
- anterograde transport via sensory axons to periphery (HSV)
Modes of entry to CNS-olfactory
- spread intranasally acquired virus via exposed dendrites of olfactory neurons
- subsequent spread to brain along the olfactory pathways
- HSV, arboviruses
Modes of entry to CNS-Hematogenous
- penetration of capillary endothelium and blood brain barrier by blood borne virus
- HSV, polio, HIV, arbo, unconventional agents
Cell Targets of Neurotropic Viruses
Most critical targets
-neurons (neurotropic viruses-preference for neurons)-polio, rabies, encephalitic arbo
-oligodendrocytes (myelin-producing)-progressive multifocal leukoencephalopathy (PML)
Other Targets
-astrocytes, microglia
Viruses in Neurological Diseases
-acute viral infections of the CNS (poliomyelitis, rabies, west nile)
-chronic virus infections of the CNS “slow virus diseases”
-conventional virus diseases of animals
-conventional virus diseases of humans
unconventional virus diseases (Kuru and Creutzfeldt-Jakob disease-humans, scrapie (sheep) and Bovine encephalopathy (cattle) in animals)
Acute Viral infections of the CNS-Poliomyelitis
-1% of all polio infections
-invasion of CNS probably via hematogenous route
-target: neurons in anterior horn of spinal cord
vaccines-salk (killed)
-sabin (attenuated, oral vaccine)-largely effective but reversion is a risk
Poliomyelitis Pathogenesis
ingested via food and water small intestine-invasion and replication mesenteric lymph nodes replication blood-viruses in the blood (primary viremia) muscle is preferred site of replication initial antibody appearance CNS (invasion, rep, intraneural spread) high levels of serum antibodies, paralysis
Insect borne encephalitic diseases
- St.louis encephalitis, west nile encephalitis, japanese encephalitis
- virus spread from the subcutaneous site of inoculation via Langerhans cells (skin DCs) to lymph nodes
- viremia and rep in extraneural tissues (spleen, liver, kidneys)
Insect borne Viruses may enter CNS by various mechanisms
- infection or transport through the endothelium or choroid plexus epithelial cells
- infection of olfactory neurons and spread to olfactory bulb
- virus infected immune cells trafficking to CNS
- direct axonal retrograde transport from infected peripheral neurons
West Nile Virus
- spread of old world flavivirus to new world
- until 1973 restricted to Uganda
- 1999-appeared in NY, with subsequent spread
- 2002 epidemic
- flu like symptoms in 20% infected humans
- meningitis, encephalitis, poliomyelitis like symptoms in 1:150 cases
West Nile Virus-Transmission Cycle
- birds to mosquitoes to humans
- humans to humans via organ donation, blood transfusion
- mosquitoes to birds
Disease diversity of flaviviruses
3 major disease types
- hemorrhagic, encephalitic, hepatotropic (liver)
- large differences in disease caused by small differences in genome
Conventional Slow Virus diseases-visna (6)
- disease affecting sheep
- slowly progressive inflammatory destruction of CNS, “wasting” disease
- causative agent is retrovirus (lentivirus) related to HIV
- high rate of antigenic drift in env gene
- by late stage of disease, most cells appear to harbour virus as latent provirus
- damage to CNS due to virus infection and cell destruction, immune mediated (macs and lymphocytes)
Conventional Slow Virus diseases-subactute sclerosing panencephalitis (SSPE) (6)
- children and young adults
- intellectual defects followed by loss of cortical functions
- caused by measles
- inclusion bodies (measles virus nucleocapsids) detected in neurons and oligodendrocytes
- evidence for abortive infection: once measles gets into neurons + oligodendrocytes undergoes a few steps of rep, decreased expression of matrix (M), fusion (F) or hemagluttinin (H) proteins
- damage to CNS due to virus infection and cell destruction, immune mediated
Conventional Slow Virus diseases-Progressive Multifocal Leukoencephalopathy (PML) (8)
- disease of white matter of brain (attacks myelin producing cells)
- requires immunodeficient individual
- deterioration of intellect, vision, speech, muscular coordination
- demyelination
- intranuclear inclusions in oligodendrocytes
- no inflammation
- caused by polyomavirus, related to SV40, infects oligodendrocytes
- damage to CNS due to virus infection and cell destruction
Unconventional slow virus diseases
- unconventional agents involved in “subacute spongiform encephalopathies”-brain tissue shows sponge like appearance due to vacuoles
- amyloid plaques in brain-distinctive protein deposits in brain composed of prion protein
- asymptomatic incubation periods lasting months/years
Nature of Scrapie Agent
- copurification of scrapie infectivity w/ 27-30 kDa protein termed prion protein (PrP)
- PrP cross-reactive amyloid deposits found in Scrapie and CJ brain tissue
Isoforms of PrP
- normal cell isoform is PrPc-membrane bound, prominent in neurons, proteinase K sensitive
- -hallmark of scrapie infection is presence of proteinase K-resistant form of Prp-Prpsc
- Prpsc differs from Prp by folding
Causes of prion disease
- Genetic
- hereditary CJ disease usually linked to specific aa PrP mutations
- non contagious - Infectious
- ingestion: scrapie from sheep to other animals, BSE from cattle to humans (as vCJD), Kuru among humans
- surgical-neurosurgical procedures, growth hormone injections (pituitary gland extract) - spontaneous
- arises from spontaneous misfolding
Model for entry and conversion of prion disease agents
- harmful isoform is ingested or forms in the brain
- seeks out normal isoform, binds and cause misfolding (in gut lumen then to neurons)
- infectious agent able to replicate w/o the presence of DNA or RNA
Normal function of PrP in mammals
Prp knockout mice differ from wild type counterparts in many functions
- circadian rhythms
- neuroprotection
- synaptic function
- lymphocyte activation
- cell adhesion
- stem cell renewal and proliferation
- olfaction
- Prp knockout mice are resistant to scrapie
Analogies between human alzheimer’s and Prion Disease
- amyloid deposits in Alzheimer’s diseased brains contain beta- amyloid protein derived from beta protein precursor
- amyloids also assoc. w/ Huntington’s disease and Parkinson’s
Prions as functional states of normal genes
- protein polymerization as signalling mechanism
- viral RNA binds w/ RIG-I
- produce a tetramer
- complexes w/ other proteins inside the cell (Ub)
- causes aggregation of MAVS prion
- Tc of NF-kappaB and IRF3 is induced
- interferons are produced, which inhibit virus
