A mad cow in America

spongiform encephalopathyA dairy cow in California is the fourth known American case of mad cow disease, which is caused by prions, infectious agents composed only of protein (the story hit the press the day after my lecture on this type of illness). Unlike viruses, prions have no nucleic acid and no protective coat. But virologists know all about them because, as Stanley Prusiner once said, there was a time when only virologists believed that they existed.

Prions are found in mammals and in fungi, but only in mammals are they infectious and pathogenic. All mammals make normal forms of the prion protein (PrPc) which is found in many tissues including the nervous system. The pathogenic form, called PrPSc, is a structurally altered form of PrPc. The PrPSc protein, named after the first prion disease studied, scrapie in sheep, causes PrPc to undergo a structural transformation to the pathogenic form. The PrPSc protein becomes deposited in amyloid fibrils in the brain, leading to neurodegenerative diseases known as transmissible spongiform encephalopathies (TSE), after the sponge-like appearance of the brain observed in afflicted animals (image).

There are three different ways to acquire a TSE. One is by infection: a human consumes meat that contains PrPSc, or receives a corneal transplant from a donor with an undiagnosed TSE . The PrPSc proteins make their way to the brain where they cause the host’s PrPc to misfold and become the pathogenic PrPSc. The more PrPSc that is made, the more the normal PrPc is converted to the pathogenic form. After an incubation period of many years, the host develops an invariably fatal neurodegenerative disease characterized by dementia in humans. There is also a familial form, in which mutations in the gene encoding PrPc are inherited; these cause the PrPc protein to misfold to form the pathogenic form. In the sporadic form PrPc spontaneously converts to PrPSc without any known mutation or infection.

TSEs occur in different forms with varied symptoms and pathology. There are TSEs of humans (Creutzfeld-Jacob disease, fatal familial insomnia, Gerstmann-­Sträussler syndrome, Kuru) cows (bovine spongiform encephalopathy or mad cow disease), sheep and goats (scrapie), deer, elk, and moose (chronic wasting disease), and of a variety of other mammals.

This brings us back to the mad American cow, the first in the US since 2006. It died on a dairy farm and was tested for BSE as are 40,00o other cows each year in this country. The reason why this is big news is that back in the 1990s there was an outbreak of human TSE in the United Kingdom caused by consuming beef from animals with BSE. The cows acquired BSE by being fed processed animal byproducts as protein supplements, which unknowingly contained pathogenic prions. Bt the time the disease was detected in cows, contaminated meat had already entered the human food chain. Cows are routinely tested for BSE precisely to avoid a similar outbreak of human TSE.

The dead cow apparently had atypical BSE – that is, it was not a consequence of eating contaminated meat and it was not an inherited disease. Atypical BSE is caused by strains of prions distinct from other forms. This is good news because it means that the feed that the cow was receiving was not contaminated with pathogenic prions. Furthermore, the cow was not destined for meat production; it was a dairy cow that had died and was selected for random sampling.

Could the milk produced by this cow and consumed by humans pose a risk for transmission of a TSE to humans? It is known that ewes with scrapie shed infectious and pathogenic prions in their milk. However cows with BSE have  much less PrPSc accumulation in peripheral tissues, and in particular lymphoid tissues which include the mammary glands. It seems unlikely that cow milk contains prions, but it is a question worth revisiting. Pathogenic prions are highly resistant to heat, ultraviolet irradiation and other extreme conditions, so would certainly survive the pasteurization process.

TWiV 153: Rabid reindeer and protective prions

svalbardHosts: Vincent Racaniello, Alan Dove, and Rich Condit

Vincent, Alan, and Rich review an outbreak of rabies in arctic foxes and reindeer in Norway, and a prion that makes you go antiviral.

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BillVirolution by Frank Ryan

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TWiV 93: Our infectious inbox

Hosts: Vincent Racaniello, Alan Dove, and Rich Condit

On episode #93 of the podcast This Week in Virology, Vincent, Alan, and Rich answer listener questions about lab procedures, prokaryotes, endogenous retroviruses, the iPad and teaching, prions, mimivirus, splitting water with viruses, and the polio outbreak in Tajikistan.

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Virology lecture #24: Unusual infectious agents

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TWiV #78: Darwin gets weird

Hosts: Vincent Racaniello, Alan Dove, Dickson Despommier, and Rich Condit

Vincent, Alan, Dickson, and Rich talk about treating arthritis with a tanapox virus protein, Darwinian evolution of prions in cell culture, and the connection between cold weather fronts and outbreaks of avian H5N1 influenza in Europe.

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TWiV 71: Please Mr. Postman

Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, and Rich Condit

Vincent, Dickson, Alan, and Rich answer listener questions about maternal infection and fetal injury, viral gene therapy, eyeglasses and influenza, filtering prions from blood, eradication of rinderpest, Tamiflu resistance of H1N1 influenza, bacteriophages and the human microbiome, H1N1 vaccine recalls, human tumor viruses, RNA interference, and junk DNA.

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TWiV 67: Wasting deer and the Hulk rabbit

Hosts: Vincent Racaniello, Alan Dove, and Marc Pelletier

Vincent, Alan, and Marc talk about chronic wasting disease of deer caused by prions, blocking the semen-derived enhancer of HIV infection with surfen, and making green transgenic rabbits using a lentiviral vector.

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A case of Creutzfeldt-Jacob disease

histology_bseThe other day I learned that a friend’s relative had recently succumbed to Creutzfeldt-Jacob disease (CJD). He told me that he had been diagnosed with the ‘infectious’ form of the disease. What does this mean?

CJD is one of several neurological diseases known as transmissible spongiform encephalopathies (TSEs). These diseases are characterized by progressive mental and physical degeneration, and by the presence of microscopic holes in the cerebral cortex (hence ‘spongiform’). The disease was described in humans in the 1920s, but was not shown to be transmissible until Carleton Gajdusek‘s work on kuru in Papua New Guinea. The disease is caused by a novel infectious agent, called a prion by Stanley Prusiner. Prions do not contain nucleic acid; rather it is the misfolding of this protein that causes the disease. CJD is extremely rare, occuring in 1 per million humans per year.

There are three major kinds of CJD. In the sporadic form, which accounts for about 85% of all cases, a spontaneous mutations likely occurs in the prion gene. About 15% of the cases are caused by inherited autosomal dominant mutations; 30 different amino acid changes leading to the disease have been described to date. The remainder are transmitted iatrogenically: originating as a result of medical care. These include the use of contaminated growth hormone derived from human cadavers, implantation of contaminated dura mater grafts, using electroencephalographic electrodes, and surgery with contaminated instruments. Prions are probably not transmitted by aerosol or casual contact. However, they may be transmitted through contact with infected tissue or body fluids. A major problem is that prions are not inactivated by autoclaving or boiling.

Variant CJD (vCJD), first described in March 1996, affects younger patients (average age 29 years, versus 65 years for CJD), has a longer duration of illness (median of 14 months versus 4.5 months) and is linked to consumption of food from cattle with bovine spongiform encephalopathy (BSE), or mad cow disease. More than 184,000 cows with BSE, and over 162 causes of human vCJD have been identified in the United Kingdom.

My friend’s relative died of infectious CJD – but he had no history of a medical procedure or transplant consistent with transmission of the disease. He worked in a hospital in New York City – but as a physical therapist, and therefore would not have had direct contact with body fluids. His age – less than 50 – is the best evidence that he had vCJD. When and where he had eaten contaminated food will never be known – perhaps on a trip to Europe in the past 5 years. What we do know, however, is that cases of vCJD in the US are extremely rare – only three have ever been reported. Now there are four.

TWiV # 12: Prions in milk, lemur lentiviruses, RS virus vaccine, H5N1

twiv_aa_200This Week in Virology #12 has been posted at twiv.tv.

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In this episode, Vincent, Alan, and Angela discuss Kuru, prions in milk, ancient lentiviruses found in the chromosomes of lemurs, a respiratory syncytial virus vaccine failure in the 1960s, and recent outbreaks of H5N1 influenza in chickens.

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D. Carleton Gajdusek, 85

Virologist D. Carleton Gajdusek, who was awarded the 1976 Nobel Prize in medicine for unraveling the nature of the prion disease Kuru, has died, as reported by the New York Times.

Gajdusek’s work on Kuru, a fatal encephalopathy found in the Fore people of New Guinea, proved that human transmissible spongiform encephalopathies (TSEs) could be transmitted among humans. This group of rare, slow diseases now includes Creutzfeldt-Jakob disease, Gerstmann-Straussler syndrome in humans, as well as bovine spongiform encephalopathy (BSE, or mad cow disease) and scrapie in sheep and goats. These disorders are rare, but always fatal. Gajdusek’s contribution was to understand that the fatal encephalopathy affecting the Fore people was spread among women and children by ritual cannibalism of the brains of deceased relatives. The disease stopped when cannibalism was discontinued. 

Subsequent work by others showed that the infectious agents of TSEs are highly unconventional because they lack nucleic acid genomes. Stanley Prusiner called the agent of scrapie a ‘prion’ and suggested that an misfolded form of the protein causes the fatal encephalopathy. The genomes of many animals, including humans, carry a gene called prnp (encoding the PrP protein) which is essential for the pathogenesis of TSEs. In the simplest case, the misfolded PrP protein (PrPsc) converts normal PrP protein to more copies of the pathogenic form. The altered protein may be acquired by infection, by inheritance of the prnp gene with an autosomal mutation, or sporadically. It is believed that Kuru was established in the small Fore population when the brain of an individual with sporadic CJD was eaten.

I met Dr. Gajdusek briefly in the 1980s when he presented a seminar at Columbia. We were in a room alone for about 5 minutes, awaiting the arrival of other participants in the post-seminar dinner. In that short time it became clear that he was extremely intelligent, but not at all interested in my work on poliovirus, much to my disappointment.