Microbiology, Lec 23.

Animal Viruses and Virus-like particles

Virus-like particles.

Before we look at some viral diseases let's consider a few really strange diseases that were once attributed to viruses...... (Read pgs. 388 - 389)

Viroids

One of the simplest known infectious agents is the viroid. Viroids are just small single strands of RNA (< 400 nucleotides; the smallest virus is 10x bigger) that lack a protein or membrane coat (Fig. 18.16 and 18.15). To date they have been shown to cause only plant diseases. The best known viroid diseases are potato spindle disease and Cadang disease of coconut palms.

Prions

Even stranger than viroids are Prions. Prions are infectious protein particles that cause several diseases in animals and humans. Prions are the only infectious agents that do not contain any nucleic acids. Prions are really scary because they are too small to act as antigens(even though they are proteins) and thus they go undetected in our bodies. They cause brain diseases in sheep (scrapie), cows ("mad cow disease"), humans (Kuru and Creutzfeld-Jakob disease) and other animals (Table 36.6, pg. 763). These diseases are caused by exposure to the brains of dead animals. Kuru was figured out by Gajdusek in the 1970s. He showed that it was spread (in certain tribes in New Guinea) via burial ceremonies in which women and children smeared the brains of their dead relatives on their bodies.

Mad cow disease was a big problem in Britain a few years ago because they were adding ground up sheep and cows to cattle feed. These cattle were then ground up and fed to humans (in hamburgers) and the incidence of Creutzfeld-Jakob disease in humans has gone up recently in England. One of the scariest things is that prion diseases have latent periods of up to 15 years (they used to be classified as slow viral diseases, pg. 762), so it may be a while before we know the full extent of the damage from mad cow disease. Not everyone believes that mad cow disease can be spread to humans.

How do prions cause disease and replicate without nucleic acids?

For a long time it was thought that they must be inducers or repressors of gene expression. The latest theory, however, is that they recruit proteins similar to themselves in the membranes of brain cells (show ScienceFig.). In essence, they line up next to these brain proteins and cause a conformational change that converts the brain protein into a Prion. This is still just a theory and Prusiner gave some evidence for it in his talk last spring. This idea also goes along with the fact that a symptom of prion diseases is the formation of holes in the brain tissue, resulting in a sponge-like appearance (thus the name "spongioform encephalitis" has been applied to some prion diseases).

Viruses

1) obligate intracellular parasites

2) cannot multiply on their own

3) Ultramicroscopic i.e. less than 0.2 micrometers; some as small as 20 nm.

4) They all contain some type of nucleic acid (RNA or DNA) surrounded by a protein coat (= capsid). Many viruses that attack animals also have a membrane outside the capsid

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Define a few terms that are relevant to animal viruses:

A lytic infection results in almost immediate lysis of the host cell (remember the lytic cycle in bacteriophage T4 above, and in generalized transduction as discussed in lec. 16). The common cold virus (a Rhinovirus) causes lytic infections.

In a persistent viral infection the virus keeps replicating without killing the host cell. This can happen because many viruses can leave the host cell via budding of the plasma membrane. Many different viruses can do this...

A latent infection is one in which the virus is not actively replicating in the host. The herpes simplex virus has a latent phase (see below). This is similar to the lysogenic phase for bacteriophage (lec. 16).

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Emerging Viral diseases (review Table 36.1 and see lec. 22)

Specific examples of viruses that cause disease.

Say a few things about animal viruses and then we will focus on several viral diseases of humans.

Fig. 18.3 shows just some of the major families of human viruses. Discuss + and - sense RNA viruses.......
Note the range in sizes, and that most animal viruses have a membrane (remember, most plant and bacterial viruses have just a protein capsid).

Examples of naked viruses are the smallest animal viruses, the Parvoviruses, which cause gastroenteritis and some other diseases in humans and other animals (dogs are vaccinated against a canine Parvovirus). These non-enveloped viruses range in size from 18 - 26 nm and contain a linear single-strand of DNA. Their genome size is so small (< 5000 nucleotides) that they can code for only 3 proteins and thus they can only multiply in growing cells (or if they co-occur with with Adenoviruses or other helper viruses; see Fig.) because they lack enzymes for replication (the 3 proteins they code for are capsid proteins).
Even these tiny viruses are 10x bigger than viroids.

Let's look in a little more depth at some viruses that cause diseases

Herpes

Herpes simplex virus 1 (HSV1) causes cold sores (pgs. 752-753) and HSV2 causes genital herpes (pgs. 755-756). These are some of the largest human viruses (ds DNA, 160,000 base pairs, approx. 50 to 100 genes, approx. 200 nm in diameter).
Show the life cycle of an HSV.

Note that it enters the cell by membrane fusion and that the nuclear membrane is its source of membrane for new virus particles. Otherwise the replication cycle is a lot like the T4 bacteriophage cycle we talked about in lec. 16.

These viruses are spread by intimate contact among people. Approx. 25 million Americans carry HSV2 and 90% of adults carry HSV1.
Upon initial infection, sores erupt (due to cell lysis as shown in Fig. 36.14) and then subside after a few days. The virus then is able to hang out in nerve ganglia (remain latent) for months to years. Sores can be triggered by emotional upset, uv light, immune function suppression, hormonal shifts etc. Herpes simplex viruses have probably been around a long time - Hippocrates described cold sores and how to treat them over 2000 years ago.

Influenza (flu)

is caused by a ssRNA Orthomyxovirus (Fig. 18.2, 18.3) that infects the mucous membranes of the upper respiratory tract. The Neuraminidase (NA) protein on the viral surface hydrolyzes the mucous coating allowing the Hemagglutinin (HA) to bind to glycoprotein receptors on our mucosal cells (HA can also cause agglutination of red blood cells). The virus then invades the cell via "receptor-mediated endocytosis" (see Fig. 18.4c). The HA molecules change conformation when the pH lowers in the lysosome, causing the protein coated RNA to be released into the cell cytoplasm (Fig. 18.4c). Production of viral proteins and more -RNA then takes place as shown in Fig. 18.5c. Finally, the virus leaves by "budding", taking host plasma membrane with it (Fig. 18.8).
Most of the symptoms of flu are caused by the fact that our killer cells lyse infected cells of the respiratory tract. Spread of the flu is mostly via sneezing and coughing (see Fig.35.7). The destruction of cells of the respiratory tract also leads to secondary infections by bacteria and other viruses (e.g. cold viruses).

One of the most fascinating things about the influenza virus is that it is continually evolving. Almost every year a new strain of this virus arises in Asia. See figure for a well documented pandemic in 1957 (note that the pandemics start in E. Asia). These new strains are basically just mutants (via point mutations and genetic rearrangement) of last years virus in which a few of its membrane proteins (e.g. Neuraminidase & Hemagglutinin) are slightly changed (enough so that they are new antigens and our antibodies from last year don't recognize them). The year to year minor variations in the viral membrane proteins is called "antigenic drift" whereas major changes in these proteins is called an "antigenic shift" and is the cause of very deadly flu outbreaks (e.g. 1918-1919 and 1957). During the 1918 pandemic about 20 million people died worldwide (about 80% of the American casualties during WWI were due to flu). Some scientists believe that there is genetic rearrangement among duck, swine and human flu viruses (probably in pigs) and that is how new flu strains arise. Rearrangement of human flu viruses can also occur because more than one strain of flu can infect a cell at the same time. Thus during assembly of the viruses the eight different segments of the viral genome can be mixed and matched among the various viral strains.

Explain how we can be immunized every year for the flu?