Prion Diseases Notes 2024 PDF

Prion Diseases part 1 Judd Aiken [email protected]  Animals Humans Scrapie (Sheep and goats) Creutzfeldt-Jakob Disease (CJD) Bovine Spongiform Encephalopathy Variant CJD Chronic Wasting Disease (cervids) Kuru Tra...

Prion Diseases part 1 Judd Aiken [email protected]  Animals Humans Scrapie (Sheep and goats) Creutzfeldt-Jakob Disease (CJD) Bovine Spongiform Encephalopathy Variant CJD Chronic Wasting Disease (cervids) Kuru Transmissible Mink Encephalopathy Fatal Familial Insomnia Feline Spongiform Encephalopathy Gerstmann-Straussler-Scheinker Camel Spongiform Encephalopathy Syndrome Prion Diseases Prion Diseases Spongiform Degeneration Transmissible Infection highest: brain & spinal cord other sources: lymphatic Accumulation of PrPTSE Long Incubation Period Extended Preclinical Stage Prion Diseases Fatal No Cure Extreme Resistance to Inactivation  Infected Animals Generate Millions to Billions of Infectious Prions Mice 0.1-1 Billion Infectious Units/ gram brain tissue Mink 1-10 Million Infectious Units Hamsters 1-10 Billion Infectious Units: i.c. route Deer ? Cattle 1-10 Million Infectious Units/gram brain tissue ~0.01-.1 million oral infectious units ~4000 oral infectious units (brain)  Prion Disease: Long Incubation Diseases Humans (CJD, vCJD) Years to decades Cattle, Deer, Sheep Years Rodent Models  Prion Protein (PrP) A normal host protein expressed on cell surface of neurons, glia, and other peripheral cells ~ 250 Amino Acids with 2 glycans and a GPI anchor +H -COO- 3N- Signal Metal Hydrophobic GPI Peptide Binding Core Signal Repeats Sequence  +H -COO- 3N- PrionProtein Signal Metal Hydrophobic GPI Peptide Binding Signal Repeats Core Sequence PrPC PrPCWD ( PrPSc) -Non-infectious -Infectious form - Cell surface -Same a.a. sequence as PrPC - Metal homeostasis -Resistant to degradation - Necessary for prion infection  PrPC Prion replication: PrPSc Converting PrPC to PrPSc Prion Diseases part 2 part 2 Healthy or Infected? Protozoa, Helminths, Fungi Bacteria Viruses Prion Disease Eukaryotic Prokaryotic DNA or RNA Protein + Protein coat Nucleic Acid Detection Protein Detection  Detecting Prion Diseases (factors) Infectious agent Abnormal protein PrPSC No virus to culture or detect No bacteria to characterize Antibody Response None useful Serology not appropriate Extended Preclinical, Short Clinical Years Deer (chronic wasting disease) Cattle (bovine spongiform encephalopathy) Sheep (scrapie) Decades Humans (Creutzfeldt Jakob Disease)  Protease Resistance a means of distinguishing normal from abnormal prions Uninfected Normal form of prion protein (PrPC) PrPC + proteinase K = No protein Prion Infected Normal Form of prion protein + PrPCWD PrPCWD + PrPC + proteinase K = PrPCWD  Protease Resistance: a means of distinguishing normal from abnormal prions Uninfected Infected + PrPC PrPC PrPSC Proteinase K Proteinase K PrPSC Western Blot Analysis: Distinguishing PrPC from PrP CWD CWD+ CWD- 32 kDa PK - + - + - + - + 50 ug/ml proteinase K (PK) 30 minutes PrP Antibody: 6H4 Obex Staining (CWD) No detectable Obex score 1 Obex score 4 Infectious Prions Resist: Chemical inactivation Acids Base Detergent Extreme conditions (1 N NaOH) will inactivate Standard Sterilization Methods Autoclaving---medical sterilization (120 o C 20 min) Extreme conditions (autoclaving at 134 C for 1 hour) will inactivate UV and gamma irradiation levels that inactivate most bacteria and viruses Relevance? Environmental Persistence Contamination of surgical instruments Survival through rendering process Cooking does not inactivate Laboratory Inactivation  Prion Diseases part 3 Judd Aiken  Scrapie: A disease of sheep and goats  Scrapie abriefhistory First recorded case in UK: 1732 First case in Canada in 1938 U.S. in 1947 Worldwide Distribution Scrapie Eradication decades of failure current approaches successful Scrapie Transmission https://www.agric.wa.gov.au/ Contagious Scrapie infectivity present in fluid and tissue from the placentas of infected ewes Environmentally persistent >15 years  PRNP Gene +H -COO- 3N- 136 154 171 ARR resistance to scrapie VRQ susceptible to scrapie VRQ/VRQ highly susceptible ARR/ARR highly resistant Controlling Scrapie: Canadian Food Inspection Agency (CFIA) Program Scrapie is a Reportable Disease Suspect cases must be reported to a CFIA veterinarian immediately Sheep documented with scrapie and all animals exposed to the same birthing environment must be destroyed Producers compensated for loss of their animals Producers that want to minimize the risk of scrapie in their sheep flock can consider selective breeding for genetic resistance to scrapie.  Atypical Classical Scrapie Scrapie Atypical Scrapie Nor98 PK treatment: low moly wt (10-12 kDa) Increased PK sensitivity More abundant in cerebellum & cortex than brain stem Identified in “scrapie-resistant” sheep A136 R154 R171 Abundance? Bovine Spongiform Encephalopathy Friesian cow, 9 years old. ~200,000 Cattle (Great Britain) 26 Cattle (North America) The cost of BSE to the Canadian cattle industry has been estimated to be around $7 billion dollars.  vCJD deaths United Kingdom 30 25 Deaths 20 15 10 5 0 | | | | | | 1995 2000 2005 2010 2015 2020 January 8, 2024 https://www.cjd.ed.ac.uk/sites/default/files/figs.pdf Rendering Industry Rendering Industry WHO estimates that half of every cow and a third of every pig is not consumed by humans North America: 50 billion pounds (non- edible animal carcasses, animal by- products) processed yearly Converted to 18 billion pounds of product: Fat commodity Meat and bone meal Value of $3 billion $6-8 billion of rendered product produced worldwide Proto credit: International feed.com Rendering Recycling: “The recycling of rendered animal products back into the feed of ruminant livestock species has had a positive impact both on the efficiency of livestock production and the availability of meat and milk for consumers at an affordable price.” Protein Supplement to Feed “Rendered animal products are distinguished by a high protein content containing amino acids that resist microbial degradation in the rumen, and for extracted animal fats that supply high energy for meat and milk production.” RENDERED PRODUCTS IN RUMINANT NUTRITION Thomas C. Jenkins, Ph.D. Department of Animal and Veterinary Sciences Clemson University The Problem? Once prion infectivity enters this food chain Prions resistant to inactivation Prion infectivity remains in meat and bone meal Infected meat and bone meal added to cattle feed  Ruminant Feed Ban prohibit the feeding of most Feed mammalian-derived proteins to ruminants prohibit the feeding of poultry litter and restaurant waste to Bans-- ruminants Canada 2007 1997 Feed Ban ---2007 (July 12, 2007) SRM are also banned from all animal feeds, pet foods and fertilizers. SRM= “Specified Risk Materials”: nervous tissue (skull, brain, spinal cord) from animals 30 months or older BSE: North America Source: CDC 26 known BSE cases 1 imported from Great Britain (Red Deer, 1993) 5 US 20 or 21 (Wash 2003) Canada A= Atypical BSE  Atypical BSE Classical BSE caused by feeding cattle contaminated feed Average age of infected cattle: 4-5 years Atypical BSE Very old cattle 10 years + Appears to be sporadic (randomly occurs) Distinguished from classical BSE by characteristics of the abnormal prion protein NOT linked to animal feed (Meat and bone meal)! Prion Diseases part 4 Judd Aiken [email protected]  Chronic Wasting Disease Contagious Prion disease Central nervous system & lymphatic Always fatal/ No treatment/No cure Complicated Detection Post mortem --- No useful live tests CWD Strains  Chronic Wasting Disease Environmental Contamination Persists in the environment for years Long Preclinical Phase Slow Spread Confined to Cervids Zoonotic? Zoonotic Potential Prion Disease Zoonotic? Scrapie No Bovine Spongiform Encephalopathy Yes Chronic Wasting Disease ? Chronic Wasting Disease --- circa 1980 2007 August, 2024 Circles= game farms Dark gray = free ranging animals CWD Saskatchewan 1996 Farmed elk Prevalence in Saskatchewan https://www.saskatchewan.ca/residents/environment-public-health-and-safety/wildlife- issues/fish-and-wildlife-diseases/chronic-wasting-disease/cwd-map  2022/2023 34.5% male mule deer 15.2 % female mule deer 10.3% male whitetails 4.7% female whitetails Healthy or Infected? How do you control CWD? No drugs/vaccines/cures Depopulation? Perhaps but attempts have not been completely successful Reduce population? Environmental component  White-Tailed Deer Very susceptible to CWD Numerous (and future?) strains Free-ranging and Captive Mule Deer Very susceptible Alberta and Saskatchewan: More prevalent than in WTD Elk Susceptible Free ranging and game farms  Moose Moose CWD: Relatively rare in North America Colorado and Wyoming Alberta Environmental transmission to moose considered likely route Appears more common in Europe Caribou (Rangifer tarandus) No cases to date (North America) Considered very susceptible  Judd Aiken [email protected]