Rabies, Prion diseases, and Herpes - McNally Flashcards Preview

M2 Neuro/Psych > Rabies, Prion diseases, and Herpes - McNally > Flashcards

Flashcards in Rabies, Prion diseases, and Herpes - McNally Deck (54):

What family does the rabies virus belong to?

What genus?

Family: Rhabdovirus

Genus: Lyssavirus

[I think of a rabid "rhabbit" named Alyssa.]


What shape is the rabies virus?

Rod or bullet shaped (rhabdo means rod)


What are the three main layers of the rabies virus that encapsulate the viral genome?

From external to internal:

Viral envelope with glycoproteins

Membrane with M protein

Nucleocapsid layer


What genome type does the rabies virus have? Be specific.

Antisense, single-stranded RNA


What are the five genes of the rabies genome?

Which part of the virus does each encode for?

G, M, NS, L, and N

  1. G: Glycoproteins of the envelope
  2. M: M protein of the membrane
  3. N: Nucleocapsid protein which coats the RNA
  4. NS & L: Make up the viral (RNA dependent) RNA polymerase


The envelope (G) of the rabies virus can bind host cells via several host receptors. Name three and what cell types they are found on.

Muscle cells: Nicotinic ACh receptor

Neurons: Ganglioside and CD56


Following endocytosis, how does the rabies virus get its genome into the cytosol?

Viral envelope fuses with host endosomal membrane (again mediated by glycoprotein G) at low pH, releasing the viral nucleoprotein.


Once its nucleoprotein is within the cytosol, describe how the rabies virus replicates itself.

  1. First, the viral RNAP produces mRNAs from the (-)RNA.
  2. The host's ribosomes produce viral proteins from the viral mRNA.
  3. Eventually, the viral RNAP switches from making mRNA (for protein) to making full-length (+)RNA.
  4. The (+)RNA is used as a template to produce full-length (-)RNA copies of the viral genome
  5. The proteins and genome then assemble. G protein inserts into the host membrane. The other proteins coalesce to assemble new virions, which bud off the cell and acquire an envelope in the process.


What is unique about the budding of nascent rabies virions from host cells?

Budding of rhabdoviruses typically kill the host cell, but not the rabies virus.


What protein of the rabies virus is immunogenic and allows for vaccine production?

G protein (makes sense - it's on the outside of the virion)

[Note: As you might expect, the natural timeline of antibody production is not protective against the virus, necessitating the vaccine.]


  1. If a patient presents with an animal bite from an animal they did not see (it was dark, they fled without getting a good look at it, etc.), and you detemined they had rabies, how could you determine the type of animal the rabies came from?
  2. How many serotypes of the virus are there?

  1. mAbs or genome sequencing would reveal small genetic variations of the virus that differ between animal host species.
  2. Despite these small genetic differences, there is only one true serotype of the rabies virus


By what means is the rabies virus typically spread?

Saliva of the infected animal, via a wound or skin abrasion.

There has been one case of aerosol infection in cave explorers and rare reports of infection via cornea or even organ transplants.


Describe the incubation period of the rabies virus.

Where is the virus?

How long is the incubation period?

Why is the incubation period important clinically?

Virus replicated in muscle or connective tissue around the site of injury.

The incubation period is typically 3-8 weeks long, but can be as short as one week or as long as a year. The disease is almost always lethal once it reaches the CNS. Thus, intervention during the incubation period is critical!


How does the rabies virus reach the CNS? How quickly can the virus "move"?

The virus enters peripheral nerves at the muscle and is carried through axons to the CNS. The brain is rapidly infected. Movement is 8-20mm/day.


Once the rabies virus has replicated throughout the CNS, what other sites can it disseminate to?

  • Eyes (recall: infection possible via cornea transplants)
  • Salivary glands (duh)
  • Innervated skin (e.g. hair follicles)


What factors influence the length of the rabies virus incubation period?

  • Shorter with larger viral dose
  • Shorter with bite location that is closer to the brain (head or neck)


Describe the timing and features of the prodrome of rabies infection.

  • Early after infection of brain
  • Lasts 2-10 days.
  • Virus typically already disseminated to other sites (can be detected in skin biopsies or saliva)
  • Pt is usually antibody negative at this point
  • Sxs include nervousness, headache, anxiety, pain at bite site, fever, nausea. Progresses to myoclonus, slurred speech, and "tingling".


Describe the features and timing of the acute neurological phase of rabies infection.

What two forms can the disease progression take? Describe each.

  • High virus titer in brain and elsewhere.
  • Antibody present in serum and CNS.
  • Death is rapid (2-3 days without supportive care, 3-10 days with)


  1. Furious or fulminant rabies (classic): hallucinations, seizures, hydrophobia. Fury gives way to paralysis, then coma or sudden cardiac or respiratory arrest
  2. Paralytic or dumb rabies: ~20% of cases. Ascending flaccid paralysis. Eventual fatal paralysis of respiratory muscles.


Describe what hydrophobia actually presents as in rabies patients.

  • Violent spasms of respiratory muscles triggered by drinking water
  • Can also be triggered by the sight, sound, or even mention of water.


How does the pathology of rabies appear histologically?

Little pathology despite the devastating effects.

Negri bodies (foci of virus production) can be seen in some cases.

Diagnoses currently is via antibody tests.


There were five documented cases of clinical rabies survival prior to the succesful use of the Milwaukee Protocol. Why is the Milwaukee case so important then?

It was the first case of survival where NO immunotherapy intervention was initiated; aka the patient's immune system eradicated the virus on its own. In the other five cases, all the patients were either vaccinated or received post-exposure immunotherapy.


Describe the empirical logic behind the treatment used in the Milwaukee Protocol: inducing a coma.

  • Previous observations of rabies patients after death:
    • No gross pathology
    • Abs are present during the final acute phase
      • Body mounted an immune response - just too late
    • Often little virus remaining, indicating the majority was eradicated by the immune system
  • Thus it was hypothesized that the pathogenesis of rabies was largely metabolic than via destruction of brain tissue. So, if one could protect the brain long enough (via coma - low metabolic activity!) for the immune system to eradicate the virus, the brain would be spared.


How is rabies diagnosed in living humans? In humans post-mortem?

  • Diagnosed via neurologic symptoms in persons with suspected exposure.
    • Diagnosis is difficult if pt does not reveal a possible exposure
  • Virus can be detected in CSF, saliva, or skin via PCR.
  • Antibodies usually not present during the prodrome, but would obviously be confirmatory.
    • By the time antibodies are present, it is too late.
  • Post-mortem: confirmed via PCR of infected tissue, direct fluorescence microscopy (dFA) or IHC.


How can rabies be diagnosed in animals suspected to have the disease?

  • Observation for 10 days. No symptoms = no rabies.
  • Gold standard: Euthanization of animal and dFA of brain tissue.


Name three preventative measures useful in reducing the incidence of rabies in humans.

  1. Immunization of domestic animals (the cornerstone: has helped dramatically)
  2. Immunization of high-risk individuals (field biologists, travelers, vets, etc.)
  3. Immunization of wild animals via oral vaccine contained in bait foods


What two components make up rabies post-exposure prophylaxis (PEP)?

Describe each.

  1. Human or equine rabies immune globulin (HRIG/ERIG)
    • Given at wound area and IM to provide Ab until immunization becomes effective. Keeps the virus local
    • Grants passive immunity
  2. Killed virus vaccine. 4 doses at 0, 3, 7, and 14d post-exposure
    • Grants active immunity


What animals account for the majority of rabies cases in the US?

What about in India?

  • Wild animals account for 92% of cases in US
    • Racoons
    • Bats
    • Skunks
    • Fox
  • Most cases are from dogs in India.


Compare and contrast viruses and prions in terms of:



Immune Response

  • Viruses have a defined morphology whereas prions do not.
  • Prions do not (likely) have nucleic acid
  • Prions cannot be disinfected by methods that work for viruses, including formaldehyde, proteases (!), heat, or radiation
  • Prions do no have a cytopathic effect and do not provoke an immune or inflammatory response, unlike viruses


Name four prion diseases and the animals they typically affect.

  1. Scrapie: sheep and goats
  2. Bovine spongiform encephalopathy (Mad Cow): cattle
  3. Transmissible mink encephalopathy: mink
  4. Chronic Wasting Disease (CWD): deer


What is scrapie?

What model do we use to study scrapie?

  • Prion disease of sheep, goats (and mink).
  • Described over 200 years ago.
  • Neuro problems cause animal to 'scrape' against fence posts, unsteady gait, etc.
  • Brain and lymph tissue is infectious
  • Incubation period is shorter in mice & hamsters: models for study.


What is bovine spongiform encephalopathy?

  • aka Mad Cow Disease. Progressive neurodegenerative disease of cattle.
  • Epidemic causes by use of contaminated sheep tissue in food supplements
  • Disease is transmissible to humans via consumption of contaminated beef: results in variable Creutzfeldt-Jakob disease (vCJD)


Can humans contract Chronic Wasting Disease from contaminated venison?

While there is concern, and hunted meat is often tested for CWD, there is currently no evidence of humans contracting a prion disease from deer.


What is Kuru?

What are its symptoms?

How is the disease contracted?

  • Prion / neurodegenerative disease
  • Name means "to shiver". Ataxia, shiver-like tremors. Progresses to complete motor incapacity and death within a year of onset.
  • Spread by ritualistic cannibalism.
    • Women and children most affected
      • They were the ones more likely to have to eat less "desirable" organs (like the brain), and the ones likely responsible for "preparing" the tissue.


What is the most common human prion disease?

What are three ways it can originate?

Creutzfeldt-Jakob disease (CJD)

  • Sporadic: vast majority of cases. Route unknown; believed to be spontaneous change in a protein to a pathologic form
  • Familial: 5-10% of cases, dominant inheritance. The gene that produces the prion protein has a predisposing mutation
  • Transmission via contaminated GH injection, corneal transplant, or electrode implants


What are the symptoms of Creutzfeldt-Jakob disease (CJD)?

How do patients with CJD typically die?

  • Progressive dementia
  • Ataxia
  • Paralysis
  • Wasting
  • Death is usually via pneumonia, within 6 months of onset


What is the origin of variable Creutzfeldt-Jakob disease (vCJD)?

Consumption of beef contaminated with BSE prions.

Note: Earlier age of onset (makes sense.) If you have a young person with signs of CJD, think of the variant form.


What is Gerstemann-Straussler-Scheinker disease?

What is mutated?

What is the course of the disease?

  • Famillial form of CJD
  • PrP mutation
  • Age of onset 35-45. Disease evolves more slowly than regular CJD (3-5 years).


What is fatal familial insomnia?

What is mutated?

What are the symptoms?

A prion diease, ALSO caused by a PrP mutation.

Causes sleep problems. Leads to ataxia & death.


What are the histological features of spongiform encephalopathies?

  • Vacuolization in neurons yields the spongiform appearance in gray matter
  • Sometimes amyloid plaques/tangles (different from those in Alzheimer's)
  • Proliferation and hypertrophy of astrocytes.


How long is the incubation period for spongiform encephalopathies?

Takes at least months, but usually decades for symptoms to appear.

~30 years for Kuru and CJD.


How are prion diseases diagnosed?

  • No methods exist to directly detect prions. Neither EM nor serology works.
  • Diagnosis made on clinical grounds.
  • Can only be confirmed post-mortem by histological examination of brain tissue


How are prion diseases treated? Controlled?

There are no treatments.

Careful disinfection of medical instruments is important in cases where prion disease is expected (recall: prions resistance to many disinfection methods that work for bacteria and viruses.)


What proteins are known to be prion precursors?

What genes encode these proteins?

While is it possible that other proteins come to light as infectious agents, currently 

all mammalian prion diseases are caused by the so-called prion protein, PrP.

PrP is produced by the PRNP gene.


What is the normal, non-infectious form of PrP referred to as?

What about the misfolded, infectious form?

What secondary structures differ between the normal and prion forms of PrP?

Normal: PrPc ("cellular")

Prion: PrPsc ("scrapie" - named for the first disease linked to the protein)

PrPc has alpha helices, whereas PrPsc has an abnormal beta sheet structure


How is it that PrPsc is considered "infectious"?

The pathologic form of the protein recruits or converts the normal protein to adopt the PrPsc shape. PrPsc is highly insoluble and aggregates over the years to cause damage.


Describe the genome and major structural components of viruses within the herpes family.

  • linear, dsDNA genome. large (100-250 kbp)
  • envelope with glycoproteins (for cell attachment, entry, immune evasion)
  • lack the matrix protein of most enveloped viruses, but contain a related tegument region
    • contains many of the proteins involved in replication
  • icosahedral capsid


Which herpes viruses are:

  1. alphaherpesviruses?
  2. betaherpesviruses?
  3. gammaherpesviruses?

  1. alpha: HSV-1, HSV-2, & VZV
  2. beta: CMV, HHV-6, & HHV-7
  3. gamma: EBV (Epstein-Barr) and KSHV (Kaposi's sarcoma-associated)


Which compartment of the host cell do herpes viruses replicate within?

Do herpes viruses encode their own DNA polymerase?




What is interesting about the DNA of herpes virus while it lies within the host cell?

Once within the host cell nucleus, the viral DNA genome is converted from linear to circular and maintained as an episome by the host cell.


Very little gene expression occurs during the latent phase of herpes virus infection.

  1. What one transcript is known to be produced at this time?
  2. What is its function?
  3. What triggers reactivation to the lytic state?

  1. LAT (Latency-Associated Transcript)
  2. Unknown function
  3. Reactivation is also poorly understood

[Sorry for the trick questions. Translation: don't worry about knowing those things, because they are not known!]


Describe the recurrent pathogenesis of HSV-1 and -2.

  • Virus casues direct cytopathic effects at various anatomical sites (e.g. cold sores)
  • Viruses then infect innervating neurons (but do not damage them), and travel by retrograde transport to CNV ganglia (oral HSV) or sacral ganglia (genital HSV)
  • Upon reactivation, virion components travel via anterograde transport to arrive at or close to the original infection site, causing lesions to again appear


  1. What are the features of HSV encephalitis?
  2. How does it occur?
  3. How common is it?

  1. Seizures, focal neuro deficits, other typical encephalitis sxs. Typically limited to a single temporal lobe.
  2. Upon reactivation, atpyical retrograde transport to the CNS.
  3. HSV (mostly HSV-1) is the most common cause of viral encephalitis.


What is the drug of choice for HSV infection?

Describe its mechanism of action in detail.

Acyclovir and its derivatives

  • Viral thymidine kinase (TK) phosporylates acyclovir
  • Cellular kinases further phosphorylate to form the triphosphate form, which is a dGTP analog chain terminator
  • Viral DNA pol binds the activated drug during replication, causing termination


What factors explain the low toxicity of acyclovir (ACV) in its use against herpes viruses?

Is acyclovir useful against the lytic, latent, or both forms of herpes viruses?

  • Cellular DNA pol does not bind activated ACV
  • ACV requires viral TK for initial activation, so only virus-infected cells activate it
    • Other drugs in this class do not require the viral TK (come pre-phospohrylated, I assume?)
  • Only useful against lytic infections (mechanism requires active viral proteins)