A group of progressive degenerative diseases of the CNS has been shown to be caused by infectious agents with unusual physical and chemical properties, which are now known as prions. The Nobel Prize in Medicine for 1997 was awarded to Stanley Prisoner for his work in identifying the role of prions in disease. Prions cause bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep, and five fatal CNS diseases in humans (Table 20–2). Prions can be the etiologic agents of inherited, communicable, or sporadic diseases. The pathogenesis of these illnesses is not well understood, but the pathologic and clinical features are similar. Varying degrees of neuronal loss and astrocyte proliferation occur. The diseases are known as “spongiform” encephalopathies or transmissible spongiform encephalopathies (TSE) because of the vacuolar changes in the cortex and cerebellum (Figures 20–1 and 20–2). The incubation periods for these diseases are months to years, and their courses are protracted and inevitably fatal.
Appearance of brain with spongiform encephalopathy. (Left) Normal brain. (Right) Brain infected with a prion. Note the sponge-like appearance. (Reproduced with permission from Nester EW: Microbiology: A Human Perspective, 6th edition. 2009.)
Spongiform changes. (Reproduced with permission from Connor DH, Chandler FW, Schwartz DQ, et al: Pathology of Infectious Diseases. Stamford, CT: Appleton & Lange, 1997.)
Prions affect animals and humans
✺ Cause neuronal loss and spongiform changes in brain
A prion is a “small proteinaceous infectious particle” that is not inactivated by procedures that destroy nucleic acids (Table 20–3). They have diameters of 5 to 100 nm or less and can remain viable even in formalinized brain tissue for many years. They are resistant to ionizing radiation, boiling, and many common disinfectants. Recognizable virions have not been found in tissues by electron microscopy, and the agents have not been grown in cell culture.
A prion is composed of a protein encoded by a normal cellular gene, PrP, in the brain which is located on chromosome 20. The protein, designated PrPc, is converted from a normal form (designated as NP in Figure 20–3) into a disease-causing form by a change in posttranslational conformational process to a protein designated PrPsc (designated as PP in Figure 20–3). Brain extracts from scrapie-infected animals contain PrPsc, which is not found in the brains of normal animals; PrPsc is the prion that is responsible for transmission and infection. The conformational change is also the way in which prions increase in number; that is, contact with PrPsc results in a conformational change of the normal prion host cell protein, PrPc or NP, and the formation of additional abnormal or infectious prion protein, PrPsc or PP (Figure 20–3). Production of PrPsc prions and the consequent pathology result from this process. During scrapie infection, prion protein may aggregate into amyloid-like birefringent rods and filamentous structures termed scrapie-associated fibrils (Figure 20–4), which are found in membranes of scrapie-infected brain tissues. The amino acid sequence of different prion proteins in different animal species differ from one another and transmission across species usually does not occur. Specifically, ingestion of tissue from sheep or elk infected with abnormal prions has not been documented to lead to human disease. Tissue from infected cows did, however, transmit variant CJD (see following text).
Proposed mechanism of how prions are converted to abnormal proteins. The normal and abnormal prion proteins differ in their tertiary structures. (Reproduced with permission from Nester EW: Microbiology: A Human Perspective, 6th edition. 2009.)
Amyloid-like fibrils (scrapie-associated fibrils) observed in brain extract of a patient with Creutzfeldt–Jakob disease. (Reprinted with permission from Bockman JM, Kingsbury DT, McKinley MP, et al: Creutzfeldt-Jakob disease prion proteins in human brains. N Engl J Med. 1985; 312:73-82.)
✺ Prion is an infectious agent comprised of protein without any nucleic acids
Infectious agents resist inactivation
Prion, PrPc, is encoded by a normal cellular gene
✺ Conformational changes convert normal prion protein (PrPc) to infectious prion protein (PrPsc), which increases the numbers of PrPsc resulting in prion disease
How does few infectious prion protein molecules become many infectious prion protein molecules and cause CJD without any replication?
Think ➮ Apply 20-3. Infectious prions interact with normal prions to change their conformation and make them infectious prions in a long duration and causing varying degrees of neuronal loss and astrocyte proliferation occurs resulting in spongiform encephalopathies.
Kuru was a subacute, progressive neurologic disease of the Fore people of the Eastern Highlands of New Guinea. The disease was brought to the attention of the Western world by Gadjusek and Zigas in 1957. Although the illness was localized and decreasing in incidence, its study has thrown light on the transmissibility and infectious nature of similar encephalopathies. Epidemiologic studies indicated that kuru usually afflicted adult women, or children of either sex. The disease was rarely observed outside the Fore region, and outsiders in the region did not contract the disease. The symptoms and signs were ataxia, hyperreflexia, and spasticity, which led to progressive dementia, starvation, and death. Pathologic examination revealed changes only in the CNS, with diffuse neuronal degeneration and spongiform changes of the cerebral cortex and basal ganglia. No inflammatory response was apparent. Inoculation of infectious brain tissue into primates produced a disease that caused similar neurologic symptoms and pathologic manifestations after an incubation period of approximately 40 months. Epidemiologic studies indicated that transmission of the disease in humans was associated with ingestion of a soup made from the brains of dead relatives and eaten in honor of the deceased. Clinical disease developed 4 to 20 years after exposure. Since the elimination of cannibalism from the Fore culture, kuru has disappeared.
Women and children of the Fore people of New Guinea
Transmissible to primates
Associated with cannibalism
Creutzfeldt-Jakob disease (CJD) is a progressive, fatal illness of the CNS that is seen most frequently in the sixth and seventh decades of life. The initial clinical manifestations are a change in cerebral function, usually diagnosed initially as a psychiatric disorder. Forgetfulness and disorientation progress to overt dementia and the development of changes in gait, increased tone in the limbs, involuntary movement, and seizures. These manifestations resemble those of kuru. The disorder usually runs a course of 4 to 7 months, eventually leading to paralysis, wasting, pneumonia, and death.
✺ Progressive disease, usually occurring among elderly
✺ Clinical manifestations include altered cerebral functions characterized by changes in gait, increased tone in the limbs, involuntary movement, and seizures
CJD is found worldwide, including the United States, with an incidence of disease of one to two case(s) per million per year. The mode of acquisition is unknown, but it occurs both sporadically (85%) and in a familial pattern (15%). Infection has also been transmitted by dura mater grafts and corneal transplants, by contact with contaminated electrodes or instruments used in neurosurgical procedures, and by pituitary-derived human growth hormone. The latter was responsible for more than 100 cases. The incubation period of the disease is approximately 3 years to more than 20 years. The agent of CJD has not been transmitted to animals by inoculation of body secretions, and no increased risk of disease has been noted in family members or medical personnel caring for patients.
✺ Course of the disease 4 to 7 months leading to paralysis, wasting, pneumonia, and death
✺ One to two case(s) of CJD per million people annually in the United States
It has been transmitted to chimpanzees, mice, and guinea pigs by inoculation of infected brain tissue, leukocytes, and certain organs. High levels of infectious agent have been found, especially in the brain, where they may reach 107 infectious doses per gram of brain tissue. Nonpercutaneous transmission of CJD has not been observed, and there is no evidence of transmission by direct contact or airborne spread.
✺ Mode of acquisition of CJD; Sporadic: 85%; Familial: 15%
Brains from patients with CJD have the birefringent rods and fibrillar structures noted in kuru and scrapie (Figure 20–4). Identification of PrPsc and antibodies directed against it may become a useful diagnostic adjunct to neuropathologic examination of brain tissue. Pathologic examination of brain tissue is the only definitive diagnostic test.
Pathology identical to kuru
Scrapie-like structures seen in brain
There is no effective therapy for CJD, and all cases have been fatal.
The small risk of nosocomial infection is related only to direct contact with infected tissue. Stereotactic neurosurgical equipment, especially which was used in patients with undiagnosed dementia, should not be reused. In addition, organs from patients with undiagnosed neurologic disease should not be used for transplants. Growth hormone from human tissue has now been replaced by a recombinant genetically engineered product. Recommendations for disinfection of potentially infectious material include treatment for 1 hour with 2N NaOH or by autoclaving at 132°C for 60 to 90 minutes. Others recommend even more extensive treatment such as combining these two procedures to ensure inactivation.
Nosocomial infections preventable by avoidance of potentially infectious materials, careful sterilization
Bovine Spongiform Encephalopathy (“Mad Cow Disease”) and “Variant Creutzfeldt-Jakob Disease”
BSE was identified in 1986 in cow in the United Kingdom, causing them to become uncoordinated and unusually apprehensive. The source of the emerging epidemic was soon traced to a food supplement that included meat and bone meal from dead sheep. Between 1986 and 2004, 180 000 cases of BSE in cattle were confirmed in the United Kingdom. To combat BSE, the British government banned the use of animal-derived feed supplements in 1988, and the epidemic among cattle, which peaked at nearly 40 000 cases in 1992, decreased to less than 4000 new cases in 1997. By February 2002, most European countries had reported cases of BSE, but new infections have ceased as a result of imposing tight controls on cattle feed. The United States had been spared, as measured by over 19 000 cattle brain examinations. The incubation period in cattle was determined to be 2 to 8 years. In addition to the incoordination and apprehension, the cows exhibited hyperesthesia, hyperreflexia, muscle fasciculations, tremors, and weight loss. Autonomic dysfunction was frequently manifested as reduced rumination, bradycardia, and other cardiac arrhythmias. Unfortunately, the prion that causes BSE survived the heat of cooking and was transmitted to humans who inadvertently consumed infected bovine neural tissue or bone marrow (both are sometimes found in processed meats, depending on the rendering procedures used).
Source was meat and bone meal from sheep in cattle feed
✺ BSE prion survived heat during cooking
Transmitted to humans by consuming prion contaminated bovine neural tissue, bone marrow, meat, processed meat
Globally, over 220 humans with “variant CJD,” have been reported, with a majority of them, 177 cases, in the United Kingdom, 27 cases in France, and 4 cases in the United States. In all the four cases reported in the United States, infection most likely occurred outside the United States, including United Kingdom (two cases), Saudi Arabia (one case), and Europe and/or the Middle East (one case). The cases frequently present in young adults as psychiatric problems progressing to neurologic changes and dementia, with death in an average of 14 months. It appears that destruction of diseased cattle and the changes in livestock feeds have prevented further cases.
✺ Variant CJD apparently transmitted by infected bovine tissues to humans
✺ Clinical manifestations and outcome similar to CJD
Gerstmann-Straüssler-Scheinker (GSS) disease is similar to CJD, but occurs at a younger age (fourth to fifth decade). Cerebellar ataxia and paralysis are common, but dementia is less often seen. The disease evolves over an average of 5 years. It was originally thought to be familial, but it also occurs sporadically, very rarely. GSS has been transmitted to experimental animals. The familial nature of this disease raises the question of vertical transmission versus inherited susceptibility.
Gerstmann-Straüssler-Scheinker disease similar to CJD but evolves more slowly
This is a recently recognized familial (inherited) prion disease in which a syndrome of sleeping difficulty is followed by progressive dementia. It occurs in patients aged 35 to 61 years, culminating in death within 13 to 25 months. In almost all cases, this disease is caused by a specific mutation in the prion protein. The infectious agent has been transmitted to experimental animal models.
Sleeping difficulties progressing to dementia