-22 Viroids and prions are infectious agents that are very different from viruses.

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  • Viroids are plant pathogens are small RNAs, but these RNAs do not code for any protein products. Viroids are therefore just a site for replication and they steal virtually everything else from the host.
  • Prions are infectious proteins and contain no nucleic acid. Instead, they cause their own amplification by altering the host cell to produce a normal cell protein, which the prion than converts to an altered, infectious form.

We will now take a short aside to round out your knowledge of the very small and harmful. Work in the latter half of the 20th century revealed that viruses are not the smallest or the simplest parasites of organisms; several other classes of parasitic molecules exist.

Let us first remind ourselves that there is nothing magic about the typical virus organization, which is a bit of nucleic acid encoding a few proteins, a coat to protect the nucleic acid from the environment, and a site or mechanism for replication of the nucleic acid. The only properties an infectious agent really needs to have are the ability to infect and be replicated. As we have seen, infection often requires rather little, especially if the host helps, which means that you might only need to be replicated in a host. As you will see in the following cases, this simple requirement is satisfied by some remarkable agents (it is difficult even knowing what general name to call them). Are these just obscure curiosities? They are if you feel that Mad Cow disease is a curiosity. We have probably not appreciated these diseases until fairly recently, in part because they were so different from what we could imagine an infectious agent could be, and also because they cause very slowly developing diseases. These slow diseases are also technically difficult to study as an infectious disease process. The future will no doubt reveal more entities that fail to conform to our old image of a infectious agent.

Viroid replication

Figure 19.33. Viroid replication. Replication begins with entrance into the cell. Once inside, the RNA is taken to the nucleus and recognized by host factors, which copy the RNA. A single-stranded (-) copy of the RNA is created and this is subsequently used as a template for continuous rounds of (+) strand synthesis. Positive strands leave the nucleus and are free to leave the cell. The (+) strand can also lead to smaller pieces of RNA being created that interfere with host cell metabolism. (The (+) and (-) are somewhat of a misnomer since neither strand codes for protein and the nomenclature is merely a convention.

One amazing form of infectious agent is the viroid, which are important plant pathogens. About 30 different viroid sequences are known, causing damage to important crops including potatoes, tomatoes, citrus trees, avocados and peaches. As shown in Figure 19-33, RNA genomes viroids are about 246-375 nucleotides long; they are single-stranded, circular molecules and have extensive intramolecular base pairing to protect themselves from single-strand nucleases. As you might guess from the very small size, viroids do not code for any proteins and depend upon the host for their replication. But here is a problem: viroids are RNA and there should not be an RNA-dependent RNA polymerase in a normal cell. The answer to this paradox is that the viroids linearize and then recruit the host DNA-dependent RNA polymerase for replication. The RNA polymerase travels around the viroid RNA multiple times, making a long RNA strand containing multiple copies of the genome. This copy is then replicated again to generate an oligomeric copy of the viroid, which is then cleaved to make the monomeric circular viroid. The site of replication is in the nucleus or in the chloroplast of the plant, depending upon the specific viroid. Their main impact on a plant is to direct their own replication and in the process waste the resources of their host. A large number of viroid molecules floating around in a plant cell understandably wrecks havoc on its metabolism. This in turn weakens the plant, lowering yields of important crops. Unlike satellite viruses, viroids do not depend upon a helper virus to replicate. Viroids are spread by mechanical damage of plants in farming and evidence is also pointing at the participation of insect vectors, such as aphids, in spreading these diseases.

An even more unusual disease-causing agent is the prion, which is a normal protein in an abnormal conformation. For many years, fatal degenerative diseases of the central nervous system have been known that cause affected animals to have neurological symptoms, such as loss of coordination. Autopsies of these animals revealed holes in the brain that were called spongiform encephalopathy. Sheep and goats infected by one type of this disease become irritable and sometimes develop an intense itch that causes them to rub off their coat, giving the disease the name scrapie. Similar diseases have been identified in elk, deer, mink, cats, and cows. Humans suffer from three diseases that fall into these categories, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease and fatal familial insomnia. The cause of these encephalopathies could not be attributed to a bacterium or a virus, but transmission of the disease was possible by injection of the extracts of a diseased brain into the brain of a test animal. There also seems to be an inherited component to these diseases.

In 1972, Stanley Prusiner lost a patient to Creutzfeldt-Jakob disease and began to investigate scrapie as a model of this human disease. He showed that the agent lacked nucleic acid and apparently contained only protein, leading him to name it prion (a play on the terms protein and virion). Claiming that an infectious agent lacked nucleic acid was nothing short of heretical, and Prusiner and his colleges were met with intense skepticism. Subsequent work has confirmed the original hypothesis, however, and changed how we think about infectious agents. The infectious form of the prion protein is abbreviated PrP.

Where does this protein come from? PrP could be attributed to a single protein that was traced to a single gene in mammals. Amazingly, the sufferers of this disease make the infectious agent themselves. In healthy animals, PrP is a normal cellular protein that carries out an unknown normal function. However, scrapie PrP causes changes in the brain that lead to encephalopathy. Figure 19-35 shows the structure of normal human PrP. The difference between the normal and scrapie PrP is the way the protein folds. Normal PrP and scrapie PrP have different shapes, with scrapie PrP being much more resistant to degradation by cellular proteases than is normal PrP. It is thought that the accumulation of PrP in the lysosomes of brain cells somehow kills them and when these cells die, they cause the characteristic holes in the brain seen in spongiform encephalopathy. The disease is contagious because scrapie PrP is able to convert normal PrP to the diseased form by protein-to-protein interactions. In other words, scrapie PrP forces normal PrP to change shape. The disease spreads as scrapie PrP moves from cell to cell using normal cell transport systems.

A molecular model of a prion

Figure 19.35. A molecular model of a prion. A molecular model of a prion. Prions are small proteins that change from a normal state, to a disease-causing state. The disease they cause involve not nucleic acid and are transmitted only by the protein itself.

An example of the havoc prions can cause is Mad Cow disease. Gerald A. H. Wells and John W. Wilesmith identified the condition in 1986 in England, after it began causing cows 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, some of which were probably infected with the scrapie PrP. The British government banned the use of animal-derived feed supplements in 1988 and animals with Mad Cow disease were destroyed. Because of these actions the epidemic has peaked. Some worry that there may be a link between the mad cow disease epidemic and the human prion malady Creutzfeldt-Jakob disease. During the mad cow epidemic, there was an increase in Creutzfeldt-Jakob disease, but no causal evidence has been discovered.

A recent concern in the United States has been the emergence of another prion disease, chronic wasting disease in wild deer. The disease causes similar symptoms and can be spread within a population of deer. The mechanism of spread is not clear at this time, but it will be more difficult to contain this epidemic, since it is carried by wild deer that cannot be as easily tracked as domesticated cattle.

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1. Even though viroids do not encode proteins, they still coat themselves with protective proteins.

True
False


2. Prions replicate using a nucleic acid intermediate.

True
False


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