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Virology > Prions & Viriods > Flashcards

Prions & Viriods Flashcards

1
Q

What are Prions and viroids?

A

Unconventional infectious agents

Not viruses, bacteria or parasites

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2
Q

What are Prions?

A

Infectious Proteins that cause a groups of diseases of the brain and nerous system called transmissible spongiform encephalopathies (TSEs)

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3
Q

What are Viroids?

A

Small, pathogenic RNAs that cause virus like diseases in plants

Do not code for proteins

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4
Q

What are TSEs?

A

Diseases affecting humans, sheep, goats, mink deer, elk, antelopes, cats
None of the TSEs evoke an immune response.
Prions cause a non-inflammatory process that results in vacuolation or spongiosis in the gray matter of the brain.

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5
Q

What are the “Mad Diseases” Transmissible spongiform encephalopathies (TSEs)

Kuru and bannibalism

A

Kuru—human TSE
“laughing sickness”
Mysterious disease affecting large numbers of the South Fore people of Papua, New Guinea in the 1950s and 1960s
Investigated by Vin Zigas, Shirley Lindenbaum, and Carleton Gadjusek
<10% of females survived past child-bearing age
Males only had 20% chance of dying of the disease

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6
Q

What are the three distinct stages of symptoms of Kuru?

A
  1. _Ambulant stage: _unsteady gait, voice, hands and eyes, tremors and shivering, slurred speech, loss of coordination (“classical advancing Parkinson’s”)
  2. Sendentary Stage: patients could no longer walk without support, increased severity of tremors corrdination, jerky movements, outbursts of laughter, depression, mental slowing
  3. Terminal statge: patients could not sit without support, increased tremors and speech slurring incontinence, difficulty swallowing, deep ulcerations
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7
Q

What is the Fore Tribe practiced endocannibalism?

A

Practice of eating dead relatives
Began during the 1900s

Sign of love and respect as part of funeral rites
Human flesh was regarded as meat.
The body fat of Fore dead resembled pork and was an excellent source of food.
Bodies were infected with Kuru.
Men ate muscle.
Women and children ate morsels of the brain and other internal organs.

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8
Q

What are two theories to expalin to the cause of kuru?

A
  • Kuru is a hereditary disease.
  • Unlikely because disease appeared rather quickly in Fore population
  • Reached epidemic proportions in 1960s
  • Kuru is caused by a biological agent transmitted by endocannibalism.
  • Healthy chimpanzees inoculated with brain suspensions from Kuru patients eventually developed Kuru-like symptoms (18-21 months)
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9
Q

What is the PrP and the “Protein only” hypothesis?

A
  • Prions are infectious proteins that cause Kuru and similar diseases such as Creutzfeldt-Jakob disease (CJD), scrapie, etc.
  • Gajdusek shared the Nobel Prize for Physiology or Medicine in 1976 for research on the origin and dissemination of TSEs.
  • Stanley Prusiner’s team isolated the infectious prion agent that caused Kuru.
  • In 1984 Prusiner’s group showed that the gene encoding the prion was found in all animals tested, including humans.
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10
Q

What are the characteristics of prions?

A
  • PrP stands for “proteinaceous infectious particle.”
  • Prions are highly resistant to routine methods of decontamination.
  • Not inactivated by proteases, organic solvents, alkaline cleaners, ultraviolet radiation, ethanol, formaldehyde
  • Resistant to extremely high temperatures (>100 oC)
  • Sterilization for one hour at 121 oC in an autoclave does not kill prions
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11
Q

What are the typical decontamination Protocol that researchers Use:

A

Tissues, infectious waste, and instruments used in the processing of prion-contaminated samples are decontaminated in:
1 N NaOH or undiluted fresh household bleach followed by autoclaving at 132 oC for 4.5 hours`

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12
Q

What are two distinct conformations of the Prion protein?

A
  • PrPC: normal “cellular” form found throughout the tissues of the body in healthy people and animals
  • PrPC is sensitive to denaturing agents.
  • The ‘protein only’ hypothesis proposes that abnormal, mis-folded proteins causes PrPC to convert to the highly resistant or stable form termed PrPres
  • Over time, PrPres accumulates into clumps that damage or destroy nerve cells in the brain.
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13
Q

What is PRNP gene encodes PrPc?

A

PRNP gene located on chromosome 20 of humans
Codes for a 254 amino acid protein
It is unique- no other proteins of similar homology in the database
PrPC is targeted via a secretory pathway to the cell surface of neurons and other cell types.
A glycosylinositol phospholipid anchors it into the membrane.

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14
Q

What is PrP c function?

A
  • PrPc may bind copper and is then cycled back into the cell via endocytic vesicles where they may be degraded in lysosomes.
  • Within the lysozymes, the infectious PrPres may interact with PrPC, causing the noninfectious form to be converted to the infectious form.
  • Infectious PrPres are resistant to degradation and accumulate, causing neurotoxicity.
  • PrPC are highly conserved in mammals and expressed predominantly in the brain.
  • Exact function is unknown
  • Possible roles in:
    • Signal transduction
    • Cellular differentiation
    • Cell adhesion
    • Copper transport
    • Resistance to the accumulation of destructive free radicals that can result in neuronal death
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15
Q

What are three ways that TSEs can arise?

A

Infection

  • diet, vCJD
  • Iatrogenic means (e.g., surgery)
  • Growth hormone injections
  • Corneal transplants

Inherited

  • Genetic CJD
  • Gerstmann-Straussler-Scheinker disease (GSS)
  • Fatal familial insomnia (FFI)

Sporadic forms (most frequent human form)

  • CJD
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16
Q

What is the oral transmission?

A

Oral transmission of TSEs is very inefficient compared to intracerebral injections.
Infectious dose through ingestion of prion-contaminated food is unknown.
New research suggests infectious prions enter the brain via the hypoglossal nerve of the tongue.
Food products that contain tongue may be a potential source of prion infection for humans.
2005 study: Low doses via diet may be enough to cause a subclinical disease.

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17
Q

What are other routes of transmission?

Such as Iatrogenic disease?

A

Iatrogenic disease—inadvertently caused by a physician or surgeon by a contaminated medical or surgical instrument or diagnostic procedure

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18
Q

What are the examples of Iatrogenic transmission of CJD?

A

Corneal grafts from donors who developed CJD
Sharing of contaminated deep EEG electrodes implanted into brain
Contaminated neurosurgical instruments
Receipt of human growth hormone from CJD-infected donors
Patients who received dura mater grafts from donors who developed CJD

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19
Q

What is the bloodbornes transmission?

A
  • Bloodborne transmission has been suspected for two reasons:
    1. vCJD can be detected in lymphoid tissues, raising the possibility that it also could be found in circulating lymphocytes present in the blood.
    2. Prions may exist in the blood as it travels from the original site of the gut to the brain.
  • Experimental studies have shown the transmission of BSE to sheep by blood transfusion from asymptomatic infected sheep to healthy sheep.
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20
Q

What is the blood transmission surveillance?

A

At least 48 individuals who received blood components from 15 donors who later developed variant CJD are being monitored as a precautionary step for their at-risk status.

Hemophiliacs in the U.K. have been notified that they are at risk for developing variant CJD.

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21
Q

What are the clinical signs and symptoms of variant CJD?

A

50% of variant CJD patients die before the age of 30
Average age at death is 28

Patients suffering from classic CJD die at an average of 68 years of age.

22
Q

What are the Symptoms of Variant CJD?

A
  • Anxiety
  • Memory loss
  • Mood changes
  • Depression
  • Withdrawal
  • Neurological signs
    • Twitching
    • Spasms (jerky movements)
    • Posture and gait abnormalities (motor difficulties)
23
Q

What are the final symptoms of Variant CJD?

A

Loss of speech
Stupor
Persistent vegetative state (coma)
Death (14 months after symptoms appear)

24
Q

What is the DIagnsosis of Vairant CJD?

A

Most patients referred to a psychiatrist because of behavioral changes
Definitive diagnosis: prion-positive immunostaining of biopsy material from
Tonsil
Spleen
Lymph nodes
EEG—looking for slow or negative brain wave activity
MRI—looking for brain lesions
CSF—looking for elevated levels of neuronal, astrocytic, and glial proteins
Elevated levels are a consequence of damage to the blood– brain barrier (extensive brain tissue damage)
No detectable immune response means no routine test to diagnose asymptomatic individuals

25
Q

What is the Pathogenesis of TSEs?

A

Incubation period of TSEs is long
20 to 56 years
with the exception of vCJD
South Fore tribe members still getting Kuru some 39–56 years after the cessation of cannibalism

26
Q

What is the histological brain changes of TSEs?

A

Infected brains become spongiform (the brain has vacuoles—clear zones, similar to a sponge)

Neuronal loss

Astrocystosis (spread of astrocytes to damaged tissues in the brain)

Amyloid plaques—formation of PrPres threadlike aggregates

27
Q

What are the major regions of the human brain?

A

The different TSEs can affect different regions of the brain
Results in different symptoms

28
Q

What are the brain changes?

A

Depends upon what region of the brain is affected
e.g., memory is affected when the cerebral cortex is infected
Precise mechanism leading to brain damage is unknown
No inflammation or immune defense against prions exists.
Natural proteins (body does not recognize as foreign antigens)
Prion proteins are only harmful when they are converted to PrPres.

29
Q

What is genetic research and the function of PrP c?

A

Knockout mice that do not express PrPC are resistant to scrapie infection.
PRNP gene lacking octarepeat copper binding motif was introduced into knock-out mice.
Mice became susceptible to scrapie infection.
Is copper binding unimportant in pathogenesis?
Other copper binding sites exist outside of the octarepeat region; do these play a more important role in copper metabolism?

30
Q

What are other copper experiments?

A

Free copper radicals are toxic to cells and are usually scavenged
Radioactive copper was added to cells expressing the PRNP gene.
Radioactive copper bound to the PrPC.
PRNP expressing cells were more resistant to copper toxicity and oxidative stress compared to cells that did not express PRNP.
PrPC may play a role in cleaning up free radicals (cellular scavenging mechanisms)
Loss of PrPc function may change copper balance and cause oxidative damage throughout the brain

31
Q

What are human genetics: Codon 129?

A

50 known mutations in the PRNP gene known to result in spontaneous PrPres formation
PRNP codon 129 appears to act as a genetic susceptibility factor
codes for methionine or valine at position 129 of the PrPC
All people suffering from vCJD acquired through consuming prion-contaminated beef products were homozygous methionine at codon 129.
Methionine homozygosity associated with rapidly progressing dementing disease

32
Q

What are the steps toward treatment and vaccination?

A

No drug therapies are available.
Congo red
B sheet breakers
siRNAs
Treatment is supportive.
No vaccine is available.
Anti-PrP antibodies inhibit prion replication in cultures cells
Passive immunization delayed onset of disease in mice
PrPC antibodies injected into the brains of mice cause neurotoxicity (safety concerns)

33
Q

What is the species barrier?

A

Transmissibility among species is easy.
Transmission can occur between different species.
High degree of amino acid sequence homology between species increases efficiency
Origin of BSE is unclear.
Accepted hypothesis is that BSE came from cattle ingesting scrapie-contaminated bone meal derived from sheep offal fed to young calves.
Offal contains brain, spleen, thymus, tonsils, guts

34
Q

What is Scrapie?

A

Scrapie was considered a rare disease of sheep that did not cause disease in humans.
Scrapie has been a disease of sheep and goats in United Kingdom and Western Europe for more than 250 years.
First case in the U.S. was in 1947
Michigan flock of sheep
Sheep of British origin imported through Canada
Australia and New Zealand are still scrapie-free.

35
Q

What is Bovine Spongiform Encephalopathy (BSE) ?

A

First diagnosed in 1985
Dairy farmer in England notices several cows with abnormal behavior
Unsteady gait
Aggressiveness
Kicking during milking
The term raging or mad cow disease was coined.

36
Q

What are other signs of BSE?

A

Difficulty in rising from a lying position
Itching
Heightened sensory perception
Anorexia
Excessive licking
Decreased milk production

Symptoms last for 2–6 months before the animal dies.

37
Q

What are the United Kingom BSE stats?

A

By June 1990
14,324 cases of BSE confirmed out of 10 million cattle

Since 1986, over 200,000 cattle in the U.K. have developed mad cow disease
1–3 million were likely to have been infected with the BSE agent

U.K. implemented control measures that included
culling of sick animals
the banning of all bovine materials from the food fed to cattle
1443 case in 2000 down to 11 cases in 2010

38
Q

What is Variant CJD or vCJD stats?

A

First described in the U.K. in 1996
10 people had died from a new form of CJD
Believed to be caused by the ingestion of BSE-contaminated cattle products
Time frame consistent with incubation period (1984-1996)
As of April 2011, 171 deaths of vCJD patients reported in the U.K.
47% of UK population estimated to have methionine homozygosity (MM)

39
Q

What is Mad cow case in calirfornia?

A
  • The nation’s 4th case of bovine spongiform encephalopathy confirmed in a dairy cow in central California on April 24, 2012
  • Baker Commodities Inc. renders animal byproducts and had randomly selected the animal for testing
  • Initial testing at UC Davis was inconclusive
  • Subsequent testing at USDA was positive for atypical BSE (not from infected feed)
  • Infected cow unlikely to spread disease
  • USDA regulations prohibit high-risk parts of the cow, such as brains and spinal cords, from entering the food chain
  • Disease cannot be transmitted via milk
  • CDC: odds of a person contracting mad cow disease are < 1 in 10 billion
  • 29 cases of BSE were reported worldwide in 2011
  • down 99% since the peak of 37,311 cases in 1992
40
Q

What is Chronic Wasting Disease (CWD)?

A
  • Prion disease of deer, elk, and moose (rare)
  • Symptoms:
    • Chronic weight loss (ribs showing)
    • Blank facial expression
    • Excessive drooling and thirst
    • Frequent urination
    • Teeth grinding
    • Holding head in lower position
    • Nervousness
    • Sluggish behavior
    • Isolation from the herd
    • Poor hair coats
    • Animals appear emaciated, starving, or “wasting away.”
    • Some animals die from aspiration pneumonia
41
Q

What is the history of CWD?

A

1978: researchers classified CWD as a TSE
First cases in free-range elk and deer in northern Colorado, adjacent parts of southern Wyoming
Spread to South Dakota, Wisconsin, etc.
2010: spread to 16 U.S. states, and Alberta, Saskatchewan, Canada
Imported cases in South Korea

42
Q

What is CWD animal to animal transmission?

A

CWD incidence

  • 15% in free-ranging deer
  • 90% in captive deer
  • Incubation period ~5 years

Transmission

  • Direct animal-to-animal contact
  • Indirect transmission (contaminated water or feed)
    • Saliva
    • Feces
    • Blood
    • Decomposing tissues
    • Urine
43
Q

What is CWD proions in the environment?

A

CWD more likely to occur where deer or elk congregate at artificial feeding, watering, and birthing areas
PrPCWD remain infectious in the soil for at least two years
Makes them difficult if not impossible to eliminate from the environment

44
Q

What is CWD Diagnosis and Management?

A

Diagnosis: immunocytochemistry on tissues from obex portion of the animal’s brain
No certified testing for live animals
Management has become a major concern
Deer hunting
Game farmers

45
Q

What are the deer hunter’s precautions?

A
  • Wear latex/rubber gloves when field dressing carcasses
  • Carefully bone out the meat of the entire carcass
  • Catchphrase: “no skull, no backbone.”
  • Prions concentrated in nervous tissue
  • Evidence that antler velvet from CWD-infected elk contain prions
46
Q

What are potential transmission to humans?

A

Cluster of patients investigated
Three young patients diagnosed with CJD between January 1997 and May 2000
All ate venison but none of the patients had eaten deer or elk in CWD endemic areas; CDC ruled out zoonotic transmission

Laboratory results have been variable.
Injecting ferrets intracerebrally with PrPCWD, 100% were susceptible
Feeding the ferrets with PrPCWD, none were susceptible

47
Q

What is CWD and Nonhuman Primate Research?

A

Early work by Richard F. Marsh
Two squirrel monkeys injected with infected intracerebrally with mule deer brain homogenate developed a TSE-like disease.
Research by Race et al.
Squirrel monkeys injected or fed CWD-positive homegenates developed TSE (11 out of 13).
Cynomolgus macaques did not (8+ yrs)
these monkeys are evolutionarily more similar to humans
Raises the question that CWD might not be infectious to humans

48
Q

What are Plant Viriods?

A

Viroids are small RNA molecules that infect plants in the same manner as conventional plant viruses
+ssRNA, covalently, closed circular pathogenic molecules
Internal base-pairing
Discovered in Theodor Diener 1971
Viroids do not code for any proteins.
Viroids depend upon the plant host enzymes for their replication and other functions.

49
Q

What are Two families of Viroids?

A

Avsunviroidae
Branched, ‘quasi’ rod-like structure
Accumulate and replicate in chloroplasts

Pospiviroidae
True rod-like secondary structure
Nuclear localization

Viroids contain 5 structural or functional domains
Central ( C )
Pathogenicity (P)
Variable (V)
Two terminal domains (T1 and T2)

50
Q

What is the Additional viriod characteristics?

A

Viroids do not replicate in the cytoplasm like conventional plant RNA viruses.
Viroids traffic within the cell through the nuclear pores using a host nuclear localization protein that binds to viroid RNA.
Viroids replicate in either the nucleus or chloroplast of the plant.
The cell’s DNA-dependent RNA polymerase III synthesizes viroid RNA in the nucleus.

51
Q

What is the Rolling circle model of viroid RNA replication?

A

Cellular RNA polymerase makes copies of viroid
Longer (+) strand RNA than synthesized
Enzymatic self-cleavage cuts long strand into multiunit +ssRNAs (ribozyme)
Host RNA ligase causes circularization

52
Q
A

Virology (23 decks)

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