TSEs

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Transmissible spongiform encephalopathies

In humans

Sporadic CJD

Occurs worldwide at an incidence of 1 /1000000

Familial disease

Familial CJG

Gerstmann-Straussler-Scheinker syndrome 1/10000000

Fatal familial insomnia

Atypical prion disease

Acquired disease

Kuru

Iatrogenic

vCJD

In Animals

Scrapie

Transmissible mink encephalopathy

Extinct

BSE origin

Chronic wasting disease (CWD) -US

Bovine spongiform encephalopathy (BSE)

Feline spongiform encephalopathy (FSE)

BSE origin

Other spongiform encephalopathies

Scrapie

Disease of sheep and goats

Characterised by

Ataxia

Tremors

Rubbing/scratching

Loss of condition

Death in 1-3 months

Endemic in UK

Incubation period of 2-5 yrs

Varied transmission

Adult animals can transmit it to other animals

Lamb exposed to prions in birth tissue shortly after birth.

Can also spread this way to other ewes

Inoculation

Agent can remain in environment (up to 50yrs)- don't know how

Progression to disease is under strong genetic control

Up to 15 genetic types of PrP gene with varied susceptibility scrapie

Genetic breeding programme

Varied strains

Bovine Spongiformform encephalopathy

Disease of cattle

Characterised by

Ataxia

Nervous or Aggressive behaviour

Loss of condition

Death in 1-6 months

Highly infectious

Can be spread to many other animals

Humans

Sheep

Goats

Cats

Epidemic in UK from 1985

Caused by contaminated feed

Incubation period of 5 years or more

Oral transmission (MBM) only

No transmission form cow to cow/ cow to calf

Little evidence of host genetic effect

Occurs as 2 different strains

MBM= meat and bonemeal

Chronic wasting disease (CWD)

First identified in captive deer in 1967 but then spread to wild deer

Found in

Free-ranging mule deer

White tailed deer

Rocky Mountain elk

Spread widely in North America + into Canada

Europe spread?

Found in Norway

Incubation period 16 months

Only TSE of wild populations

Only naturally spreading TSE

Limited genetic control os susceptibility

Unknown zoonotic potential

Hunting - dear to people??

variant Creutzfeldt-Jakob Disease

1996 UK government announced that vCJD had been detected in 10 people over 14 months

Clinical signs

Psychiatric

Depression

Anxiety

Delusions

Hallucinations

Neurological

Ataxia

Chorea

Myoclonus

Dementia

Pathology: Spongiform change and PrP-containind 'florid plaques' throughout the brain. In human prion diseases, plaques of this type are unique to vCJD

Mean duration of illness 14 months

Young age of onset: mean = 28 yrs (Range 12-74)

Prevalence of infection: 1 in 3000 (spleens)

Genetic control: All non-surgical human cases so far MM not MV or VV

Kuru

Background

Described in 1957 but may have started 1920

Shiver, trembling or laughing disease

Restricted to the Foré linguistic group in the highlands of New Guinea

Natural transmission

Foré ate their dead

Women and children ate internal organs and brains , men ate muscle

Cannibalism stopeed in 1957 encouraged by the governing Australian administration

Incidence of the disease declined from the 1960s, especially in cases of young children

Characteristics of TSE diseases

Long incubation period

Progressive and invariably fatal

Holes in brain give spongiform texture

No signs of fever

No signs of inflammation

No antibody response

No signs of a pathogen with a genome

No sign of infection

Causes

Partial purification of brain tissue of scrapie infected hamsters revealed that a certain protein was essential for infectivity

Procedures that destroy nucleic acid don't alter infectivity, unlike those that denature protein

Stanley prisoner suggested that infectious agents are proteinaceous: devoid of nucleic acid but capable of replication. He called them prions (proteinaceous infectious particles)

The prion protein is a host protein, encoded by the PrP (Protease-resistant protein) gene. It occurs in at least two form PrP^c is normal, PrP^Sc is infectious and associated with disease

PrP^c and PrP^Sc have an identical amino acid sequence but the differ in conformation

Prisoner suggested that PrP^Sc converts PrP^c to itself

PrP^Sc is partially resistant to digestion. In a normal cell PrP^c is constantly made and digested; PrP^Sc is not digested PrP^Sc is not digested and sos accumulates leading to disease

Can take years/decades

NB this is a hypothesis!

c=cellular

Sc=Scrapie

Uniqueness of prion diseases

Some prion diseases originate sporadically by mutation and are then transmissible

Pathogenesis

Oral route infection of sheep

Entry to body through the ileal Peyers patch

Dissemination through the lymphatic/vascular system to tissues of lymphoreticular system (LRS) including tonsil, spleen, reterophryngeal and mesenteric lymph nodes

Presence of PrP^Sc is detectable in the LRS weeks/months after infection, primarily within follicular dendritic cells (FDCs) of primary and secondary B cell follicles

Infection spreads from LRS through the ANS to the CNS

PrP^Sc accumulates primarily in glial cells and neurons. Within brain there is astrocytic gliosis, the accumulation of deposits of PrP^Sc, vacuolation and the characteristics of spongiform degeneration

Neuropathology

NB Astrocytic gliosis =aggregation of astrocytes

Diagnostics

Cant use PCR to detect nucleic acid or serology to detect antibody

Can use

Clinical disease

Histopathological detection of vacuolation , gliosis etc

Bioassay: especially in mice or hamsters

Expensive and time consuming

Molecular detection of PrP^Sc after treatment with proteinase K (PrPSc usually resists proteases)

No PK treatment PrP (c or Sc) deleted

PK treatment, no PrP detected = infer PrPc

PK treatment, PrP detected = infer PrPSc

Cyclic amplification of PrP^Sc from PrP^c

TSE strains

Specific scrapie isolates have characteristic effects which are consistently reproducible

Incubation period

Severity

Distribution

Brain pathology

Western blots are also distinct

The problem

Viral/Bacterial strain

Inoculate a host with strain X. Subsequently isolate strain X

Inoculate the same host with Y . Subsequently isolate strain Y

???

TSE strains

Inoculate a host with prion strain A. Subsequently isolate strain A

Inoculate the same host with strain B. Subsequently isolate strain B

???

Problems for the prion hypothesis

The same strain can be isolated from different host

Different host species have different PrP sequences - so strain can't be determined by the PrP amino acid sequence

The same host can be infected with different strains

A host only has one/two PrP types so strain cannot be determined by PrP amino acid sequence

Glycoforms

At least 8 prion strains have diff PrP^Sc conformations, suggesting that theological properties of prions are enciphered in conformation

Different strains also have unique combinations of glycoforms that are maintained upon transmission to mice

Species barrier

Transmission of agents limited by species barrier , characterised by extended incubation times which notable decrease as the agent is passaged though individuals of the recipient species

A large species barrier means a large infectious dose is needed for inoculum