* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Prions—Still a Mystery!
Survey
Document related concepts
Meningococcal disease wikipedia , lookup
Brucellosis wikipedia , lookup
Marburg virus disease wikipedia , lookup
Sexually transmitted infection wikipedia , lookup
Onchocerciasis wikipedia , lookup
Chagas disease wikipedia , lookup
Oesophagostomum wikipedia , lookup
Schistosomiasis wikipedia , lookup
Neglected tropical diseases wikipedia , lookup
Leptospirosis wikipedia , lookup
Eradication of infectious diseases wikipedia , lookup
African trypanosomiasis wikipedia , lookup
Surround optical-fiber immunoassay wikipedia , lookup
Transcript
SCIENCE & TECHNOLOGY Prions—Still a Mystery! By Max Sherman In 1975, when Lewis Thomas, physician, scientist and medical writer, was asked to make a list of the Seven Wonders of the Modern World, he chose scrapie disease, now known to be caused by a proteinaceous infectious particle (prion), as number four.1 To quote Thomas, “The scrapie agent seems the strangest thing in all biology.” His reason was that the disease can propagate from a few infectious units to billions in just one year despite the absence of DNA or RNA. Without DNA or RNA, there was a serious question regarding the mode with which the agent replicated and survived. Prions, which even in 1975 showed evidence of being all protein, appeared to violate the central dogma of molecular biology: genetic information flows from nucleic acids to proteins.2 Even though 35 years have passed since Thomas’ list was first published, and he is no longer living, prions remain one of nature’s wonders. In the past three decades, no hypothesis has been proven to explain the protein-only composition of prions, their chemical composition and the mechanism for their formation in the neurons of infected hosts.3 This article reviews the major prion diseases, regulatory matters pertaining to animal tissues and sterilization methods. Despite the progression of science, prions still present a biological conundrum and the risk to humans remains uncertain. History Prions entered the scientific lexicon in 1982, courtesy of Stanley Prusiner, a neurologist at the University of California at San Francisco. He was working on some esoteric maladies that were known as “slow virus” diseases. Prusiner told the scientific community that they were caused by prions, a term he coined by blending “protein” and “infection.” (Logically, the word should have been proin, but Prusiner, with melodious intent, transposed the o and the i to make it more terrific.4) Prion diseases, however, were noted much earlier. The earliest written record of scrapie in English sheep first appeared in the 1730s, but the disease was already prevalent in central Europe. A kuru outbreak occurred in the 1950s, which was observed only among the highland tribes in New Guinea. In 1959, William J. Hadlow of the Rocky Mountain Laboratory of the National Institute of Allergy and Infectious Diseases suggested that scrapie and kuru might be related. However, it was not until the 1960s that scientists experimentally transmitted kuru to chimpanzees. This demonstrated the transmissible nature of prion diseases. Crueutzfeldt-Jakob disease (CJD) was first described in the early 1920s and classified with other degenerative brain diseases, the infectious nature of CJD was not established until 1928. Diseases As mentioned above, prions are unconventional infectious agents that cause rare but fatal neurological illnesses such as scrapie, kuru, CJD and bovine spongiform encephalopathy (BSE). Scrapie, the disease listed by Thomas, is an infectious, neurodegenerative disorder affecting the central nervous system (CNS) of sheep. (The name scrapie comes from the tendency of afflicted sheep to scrape off much of their wool.) It is a close cousin to BSE in cattle, chronic wasting disease in cervids (deer family), as well as kuru, fatal and sporadic familial insomnia, Gerstmann-Straussler syndrome and CJD and variant CJD (vCJD) in humans. Each is a brain disease marked exclusively by a deposition in the CNS of prions.5 A unique feature of these diseases is that they can have three different origins: sporadic, inherited and infectious. The clinical epidemiological and neuropathological features can be very different, but they are classified together because the key molecular event appears to be the same: a misfolding of the prion protein. The damage is thought to occur when abnormal prion protein (PrPSc) molecules gain access to the brain and cause normal prion protein to change shape to the abnormal form. (Normal prion protein (PrPc) is encoded by a gene on human chromosome 20, is expressed in the brain, and in its normal form is probably a receptor.6) The misshapen protein molecules clump together and accumulate in brain tissue, causing a severe loss of neurons, gliosis (excessive development of neuroglia tissue) and a spongiform appearance. Regulatory Focus 45 a German medical journal.9 The patient in the report was a 22-year-old woman being treated for a progressive dementing illness. Jakob described four older patients with a clinically similar presentation and course one year later, and during the ensuing decades, numerous cases of the disease were described clinically and pathologically.10 In 1959, Klatzo et al noted the neuropathological similarities between CJD and kuru.11 That same year, Hadlow described the similarities between kuru and scrapie, and suggested that kuru might be transmissible to animals after a long incubation period.12 During the next decade, both kuru and CJD were transmitted to apes and monkeys.13 New vCJD differs dramatically from classic CJD. In patients with vCJD, symptoms develop at a mean age of 26 years—nearly four decades earlier than patients with the classic sporadic disease. The new variant was linked to exposure to BSE, or “mad cow” disease, in British beef. During the period from November 1986 (when BSE was first identified as a separate disease entity) until December 1995, an estimated 155,600 head of cattle in almost 33,000 herds were diagnosed with BSE in the UK. The epidemic peaked in January 1993 at almost 1,000 new cases per week. As of 2004, it was estimated that four million cattle were infected over the course of the BSE epidemic and there were 155 vCJD cases worldwide, all of whom have died. The only affected US resident, whose probable vCJD case was identified in 2002, was a 22-year-old woman who had moved from the UK to Florida in 1992.14 Because of the long incubation period, cases due to mad cow beef will likely surface well into the future.15 All of the diseases have a long incubation period, and lead to dementia and death. There is no treatment and, thus, no cure.7 Kuru, the first human malady to be labeled a slow virus disease, came to the attention of Western doctors only in the 1950s: it was the primary cause of death among the Fore, a cannibalistic New Guinea tribe. In 1966, Carleton Gajdusek and Joe Gibbs proved that like scrapie, kuru was infectious; chimps inoculated with the brain tissue of human victims developed kuru-like symptoms and died. The spread of the disease was attributed to the endocannabalistic funeral practices of the tribe in which relatives prepared and consumed the tissues (including the brain) of deceased family members.8 Male members of the Fore tribe participated little, if at all, in these feasts, with the result that kuru at its peak predominantly affected women and children. Classic CJD is the most prevalent of the spongiform diseases. It occurs spontaneously in one out of a million people, 10% of which are inherited mutations in the prion protein gene (PRPN). The disease was first described by Alfons Jakob in 1920 in a paper published in 46 February 2011 Regulatory Issues On 20 March 1996, the British government announced that new information about BSE suggested a possible relationship between the disease and 10 cases of a newly identified form of CJD in humans. The US Food and Drug Administration (FDA), on 9 May 1996, issued a notice to manufacturers of drug/biological/ device products recommending avoidance of materials from cattle born, raised or slaughtered in countries where BSE was known to exist. The agency stated its belief that the rapid spread in cattle was caused by feeding them certain infected cattle and sheep tissues. FDA has published two rules to protect animals and consumers against BSE. The 1997 final regulation prohibited the use of most mammalian protein in feed given to cows, sheep and goats, and required process and control systems to ensure that feed does not contain the prohibited tissue. This rule, Title 21 Part 589.200, called the Ruminant Feed Ban became effective on 4 August 1997. In 2008, FDA published a regulation that strengthened the 1997 rule by prohibiting the use of certain cattle-derived materials that have the highest risk for carrying the agent thought to cause BSE. These materials are the brains and spinal cords from cattle 30 months of age and older. The 2008 rule, Title 21 Part 589.2001, called the Enhanced Feed Ban, became effective on 27 April 2009. Sterilization The transmissible agent of vCJD (PRPSc) is not readily destroyed by conventional sterilization, and transmissions by neurosurgical equipment including instruments and EEG depth electrodes, and in recipients of pituitary growth hormone, dura mater or corneal grafts have been reported.16 Iatrogenic (resulting from the action of a physician) transmission of the CJD agent has been reported in more than 250 patients worldwide.17,18 Unfortunately, the incubation period of vCJD is unknown but could be several decades, thus it is unlikely that any iatrogenic cases have yet emerged.19 Previous work indicated that prion protein bound to steel wire was resistant to most conventional reprocessing procedures, including enzymatic cleaning, fixatives, acidic treatments, and autoclaving (steam at 134C for 18 minutes combined with enzymatic cleaning). Because of the unusual resistance of PRPSc, special decontamination procedures are needed to prevent accidental transmission. Studies have been done in an in vitro carrier assay using steel wires contaminated with the disease-associated prion protein and scrapie brain homogenates from hamsters.20,21 The wires were implanted into the brains of hamsters after treatment for decontamination and subsequently monitored for their potential to trigger clinical disease or subclinical cerebral PRPSc deposition within an observable period of 500 days. The most effective treatment consisted on incubating the wires in 1.0 M NaOH for one hour at 23 C, 2.5% NaOCl for one hour at 23C, an alkaline cleanser (used at a concentration of 1%) for 10 minutes at 55C or 0.2% sodium dodecyl sulfate (SDS) /0.3% NaOH for 10 minutes at 23C led to complete decontamination in terms of detectable infectivity, as well as to efficient removal of residual brain material from carriers.22 The authors mention that similar methods should be validated for human transmissible spongiform encephalopathy agents on different types of instrument surfaces. The most stringent chemical and autoclave sterilization methods for transmissible spongiform encephalopathies are currently outlined in Annex III of the WHO infection control guidelines.23 Final Thoughts There is still much to be learned about the mysterious and deadly prion. It was recently reported that US researchers have discovered a new form of prion disease that does not act like related illnesses, such as mad cow disease, but instead causes brain damage similar to that produced by Alzheimer’s disease. In this study, the researchers examined mice that were genetically engineered to process prion proteins in a unique way.24 Then they exposed them to scrapie. The treated mice did not develop holes in the brain like those typically caused by prion diseases. Instead, they developed plaques that resembled a form of human Alzheimer’s. If a treatment is found for this new form of prion disease, it may also be useful in Alzheimer’s disease. References 1. Thomas L. A Long Line of Cells. Book of the Month Club, New York, New York 1975. 2. Griffin BE. “Unconventional viruses or prions.” BMJ 1985;290(issue?):1765-6. 3. Suppattapone S. “What makes a prion infectious.” Science. 2010;327:1091-2. 4. Taubes G. “The game of the name is fame, but is it science?” Discover. 1986; 7(12):28-52. 5. Lemmer K, et al. “Decontamination of surgical instruments from prions. II. In vivo findings with a model system for testing the removal of scapie infectivity from steel surfaces.” J Gen Virology. 2008;89(issue?):348-358. 6. Harrison PJ,Roberts GW. “How now mad cow?” BMJ. 1992;304(issue?):929-30. 7. Ibid. 8. Kuru Information Page. NINDS website. http://www. ninds.nih.gov/disorders/kuru/kuru.htm. Accessed 17 January 2011. 9. Creutzfeldt HG. “Uber eine eigenartige herdformige Erkrankung des Zentral-nervensystems.” Z Ges Neurol Psychiatr. 1920;57(issue):1-18. 10. Bockman JM et al. “Creutzfeldt-Jakob disease prion proteins in human brains.” N Engl J Med. 1985;312(2):73-8. 11. Klatzo I et al. “Pathology of kuru.” Lab Invest 1959;8:799-847. 12. Hadlow WJ. “Scrapie and kuru.” Lancet. 1959;2:289-90. 13. Prusiner SB. “Prions and neurological diseases.” N Engl J Med. 1987;317(25):1371-81. 14. Donnelly CA. “Bovine spongiform encephalopathy in the United States—an epidemiologist’s view.” N Engl J Med 2004;350(6):539-42. 15. Prions on the trail of killer proteins. University of Utah website. http://learn.genetics.utah.edu/content/begin/ dna/prions. Accessed 17 January 2011. 16. Zobeley E et al. “Infectivity of scrapie prions bound to a stainless steel surface.” Molecular Medicine. 1999;5(issue):240-3. 17. Brown P. “Environmental causes of human spongiform encephalopathy.” In: Baker H, Ridly RM, eds. Prion Diseases., Totowa NJ, Human Press 1996:105-118. 18. Questions and Answers: Creutzfeldt-Jakob Disease Infection-Control Practices. CDC website. http://www. cdc.gov/ncidod/dvrd/cjd/qa_cjd_infection_control.htm. Accessed 17 January 2011. 19. “Iatrogenic vCJD from surgical instruments” (editorial). BMJ. 2001;322 (issue):1558-9. 20. Op cit 5. 21. Lemmer K et al. “Decontamination of surgical instruments from prion proteins: in vitro studies on the detachment, destabilization and degradation of PRPSc bound to steel surfaces.” J Gen Virol. 2004;85(issue):3806-16. 22. Op cit 5. 23. WHO Infection Control Guidelines for Transmissible Spongiform Encephalopathies. WHO website. http:// www.who.int/csr/resources/publications/bse/whocdscsraph2003.pdf. Accessed 17 January 2011. 24. Prion Disease in Mice May Help Advance Alzheimer’s. Meridian Health Wellness Center website. http://wellnesscenter.meridianhealth.com/RelatedItems/6,636679. Accessed 17 January 2011. Author Max Sherman is president, Sherman Consulting Services, Warsaw, IN. He can be reached by email by contacting [email protected]. Regulatory Focus 47