Fundamentals II: 10:00 - 11:00 Scribe: Susan Whitt

Fundamentals II: 10:00 - 11:00 Scribe: Susan Whitt

Thursday, November 5, 2009 Proof: Jake Nolen

Dr. Morrow Virology Page 1 of 9

I.  Introduction: The DNA-RNA-Protein Pathway [S1]:

a.  Introduction to viruses: This virus group we’re going to talk about are plus strand RNA viruses. My name is Casey Morrow. I’m the same guy who talked yesterday for those of you who weren’t here.

b.  In order to help you out we’re going to start with one of the slides we showed yesterday to acquaint you with what we mean by plus strand RNA viruses.

c.  This is the cartoon that depicts the dogma of molecular biology. DNA to RNA to protein.

d.  We talked yesterday about DNA viruses and RNA viruses. What we’re going to talk about today are plus strand RNA viruses. So we’re going to focus basically on starting from right here. We call it a messenger RNA. Remember the definition of plus stranded RNA viruses are that they have the same sense as a messenger RNA. This is going to give you a big clue to the common feature of the replication process for all of these viruses that I”ll highlight throughout the lecture.

II.  Plus-strand RNA Viruses [S2]

a.  So what are plus strand RNA viruses? Plus strand RNA viruses have genomes comprised of RNA. Wow, I wanted to hit you with something really hard early in the morning here. They have no DNA in their replication cycles. That’s a very important point. They don’t need the nucleus of the cell in order to go through their replication process. So there’s no DNA, it’s just RNA.

b.  In most cases, the replication cycle takes place in the cytoplasm of the cells.

c.  No involvement of the transcription machinery in the nucleus; so, the plus-strand RNA viruses produce their own enzymes for RNA transcription and replication, which recognize RNA as the template. So it’s got to be able to recognize it’s own RNA to replicate.

d.  The plus-strand RNA viruses do use the host cell’s translation machinery to generate viral proteins. So that means all of the stuff that’s used in translation these viruses use and they’re going to steal that away from the host cell in order for the replication process.

e.  Many plus-strand RNA viruses produce numerous viral proteins from a single “gene.” This is the polyprotein and I am going to show you the same slide I showed you yesterday. But a polyprotein and a protease that the virus encodes to process out this polyprotein.

III.  Types of Plus-Strand RNA Viruses with single-stranded, non-segmented plus-strand genomes [S3]

a.  We’re going to talk about 2 types of plus strand RNA viruses. Most of the talk is going to be centered on class I, which encompass Picornavirus which include rhinovirus and poliovirus as well as flavivirus which include West Nile Virus, which I’m sure a lot of you have hear of.

b.  Type II, which is a much larger RNA virus that we’ll talk about in the last few slides, is contained with Coronaviruses and the virus that you’ve heard about is the SARS virus. We’re going to talk a little bit about the SARS virus.

c.  The main difference between these viruses are found right here in the types of mRNAs. Type I has a single mRNA. Type II, this Coronavirus, has multiple mRNAs. There’s a long polyprotein in both of these but in the Coronavirus as we’ll see they also have some small mRNAs to help them express their viral genomes.

d.  It’s also important to remember that these plus strand RNA viruses have no polymerase in the virion and the RNA itself is infectious. The reason why the RNA itself is infectious is the first step in the replication proess will be translation All it has to do is hit ribosomes and it will start the process of replication. Ww’ll talk about this in a minute. I just want to caution you, not all plus strand RNA viruses are like this (do no have polymerase in virions). Retroviruses which you’ll hear about are also plus strand RNA viruses but they have a DNA intermediate and they do have an enzyme in the virion called reverse transcriptase.

IV.  Picornavirus Diseases [S4]

a.  We’re going to talk about picornavirus disease. Picornaviruses were named by an old way of naming viruses and it’s not very original but it actually helps you remember. Pico which is small RNA viruses. These are going to be one of the smallest RNA viruses that we’re going to talk about. They cause a significant amount of disease. Poliomyelitis, we’ll talk a lot about this.

b.  Hepatitis A virus. This is the Hepatitis virus you get when you go down to the gulf and eat those oysters that didn’t quite look right, and the next day all of a sudden your eyes are turning a little yellow and you’re not feeling well. This is a liver hepatitis. It’s different than Hepatitis B and C, you get rid of this Hepatitis A virus.

c.  Coxsackieviruses are named after a town in New York called Coxsackie, NY, where they were first isolated. This is a virus that is similar to poilio virus in terms of its transmission. It’s transmitted by a fecal-oral route. It causes a different type of disease. It causes disease when it gets to a secondary organ, and it likes to replicate in heart tissue. When it affects children it causes significant heart damage and can be a problem.

d.  There are other different types of viruses called Enteroviruses because these are enteric viruses. These viruses generally you don’t come into contact with unless you have a small kid in daycare. Sometimes they get hand-foot-mouthvirus where they get a conjunctivitis in their eyes and it can be a very painful virus if you get it.

e.  Echoviruses are viruses that generally do not cause too much disease.

f.  Different than Enteroviruses which are stable in your GI tract--they’re transmitted in a fecal-oral manner that we’ll talked about, are Rhinoviruses. These are viruses that infect your nose and these are one of the major viruses that cause a cold. We’ll talk about these viruses during the lecture.

V.  Fecal-Oral Transmission [S5]

a.  Let’s talk a little bit about fecal-oral transmission. This is a way that a lot of viruses are transmitted, and all of the Enteroviruses are transmitted in a fecal-oral transmission.

b.  You have human fecal matter. It generally gets into sewage, land fills and gets into the water supply. Once it gets back in the water supply it can get retransmitted to humans.

c.  A Shellfish is positioned here because these shellfish have a tendency to concentrate particles in water. That’s what they do, that’s how they feed. By concentrating particles in water they become nice reservoirs for Picornaviruses and especially Hepatitis A.

d.  You can also transmit these viruses on your hand, which can then also get to either your food or the water supply.

e.  We’re going to talk a lot about this because this is one of the early things that probably your grandparents had to deal with with polio virus.

VI.  Enterovirus Pathogenesis: Target Tissues [S6]

a.  This slide depicts the general pathogenesis of Enteroviruses. You don’t have to memorize this slide, but you should have a sense of what some of these viruses do. Viruses such as Hepatitis A, polio, and coxsackie we’ll focus on.

b.  You ingest these viruses. Most of the time they grow in your throat, you swallow them, they go through your gut and then are shed in your stool and that’s the end of the story. Then they’re retransmitted.

c.  A small portion of the time the viruses actually become viremic. We talked about this yesterday. You can identify viruses in the blood. This is an important point because once they get in the blood they can go around to the rest of the tissues in the body and this is where they cause most of the disease. For example, echo virus, coxsackie virus, and hand-foot-and-mouth disease you can get in the skin you get a rash. You can actually see this in children when they get this hand-foot-and-mouth disease.

d.  Echo and coxsackie virus will go to muscle. One of the biggest muscles in your body is the heart. It gets into the heart and causes damage in the heart. And you can get severe myocarditis and pericarditis.

e.  We’re going to talk about polio virus. Polio has a prediliction when it gets in the blood to go the the central nervous center. It can cross the blood-brain barrier. What cell does polio like to replicate in when it gets into your nervous system? A motor neuron. That’s not good. If it messes up your motor neurons you have paralysis. We’ll talk a lot of polio myelitis and paralysis.

f.  Hepatis A virus likes to get into the liver. It causes Hepatitis. That’s why it’s called Hepatitis A virus, but it replicates in the liver and causes destruction of the liver.

g.  Again, the point for this whole slide is most of the time the virus goes this way (points to arrow (probably arrow going down and whole left side of slide). Whenever it goes this way (probably arrow going to the left) it’ll cause pathogenesis and some form of disease

VII.  Poliovirus Pathogenesis [S7]

a.  Let’s talk about polio pathogenesis. Polio has been studied for a long time. Since the beginning of the 1900s, when it was a severe disease so the middle of the 1900s and 1950 where there was a first government effort to eradicate polio myelitis. Even today when they’re trying to rid the world of poliomyolytis. Polio myelytis is caused by poliovirus. We’ll talk abou this. There are three serotypes of polio virus.

b.  Most of the time when you get a poliovirus infection it’s an asymptomatic infection, meaning that you don’t even know you’re infected. It’s a mild disease. Maybe it seems like a little flu, a little gasteroenteritis. And that’s it. Virus is shed, you’re okay. You’re actually immunized against reinfection.

c.  There is some abortive/minor illness about 5% of the time.

d.  1-2% of the time, you get nonparalytic progression to the CNS. That is very important. That means that 1-2% of polio infections you actually get virus within the CNS but it does not cause poliomyelitis, it does not cause disease. You might get a little bit of muscle flaccid paralysis but nothing really to note.

e.  Paralytic occurs in only .1%-2% of infections. Just because you get infected with polio there’s a 99.9% chance most of the time you’re not going to get paralyzed. It’s not 100% paralysis. We’ll see how this actually confounded a lot of studies in how they were actually going to try and make a vaccine against polio.

f.  3-4 days of minor illness and then the virus infects-in paralytic poliovirus-motor neurons in the anterior horn of the spinal cord and motor cortex.

g.  It destroys these motor neurons. When it destroys these motor neurons you have paralysis. This can be permanent paralysis or this can be transient paralysis. Permanent paralysis happens a lot of times and it affects your breathing. A lot of patients you’ll see in the old literature were in iron lungs. These huge devices where the patients had to spend their entire lives, because this was the only way they could actually breathe. These are polio patients. Sometimes you actually will get paralysis and you’ll recover from paralysis. Those of you with grandparents that are still living maybe some of them actually had polio when they were young. They recovered, they were fine, and now they’re coming down with a syndrome oftentimes called post-polio paralysis. We’ll talk about this in just a few minutes.

VIII. Poliovirus Infection: Progression to CNS Disease [S8]

a.  Poliovirus Infection in the CNS: This cartoon just depicts generally what happens. You ingest it and it goes through most of the time and sometimes it actually breaks out and goes into the CNS. This is an important slide because this gives you an idea of the timeline for polio infection. These are days down here. Virus is ingested it replicates in your mouth. You get viremia. Again, there’s some minor illness. It’s not evident; it seems like what we call flu-like symptom. Then you begin to shed virus and you shed virus for a long period of time. So the virus is replicating and you’re constantly shedding the virus. This is good for the virus because this allows the virus to get retransmitted to new susceptible hosts.

b.  What protects you from polio myeltitis is right up here. You generate an antibody response to polio, meaning that these antibodies will bind to poliovirus when it’s in your blood and prevent the virus from going to secondary tissues. If the antibodies are in your secretory system, if you have secretory antibodies, and we’ll talk about those in just a second, you can actually prevent from being reinfected.

c.  Replication

IX.  Enterovirus Replication and Disease Progression [S9]

a.  Again, replication and disease progression. Primary infection in the mucosa, the Peyer’s patches, tonsils in your throat. You’re ingesting this virus. It’s going to hit the first cells so it can replicate in. Most of the time you’re swallowing the virus.

b.  It’s going through your gut. This virus is stable in pH 3. It’s stable to most enzymes that are in your gut. It lives in your gut and then you excrete this virus and you’re fine. A small percentage of the time you get viremia, infection of secondary target tissue and that’s when you start to get actual symptoms of polio myelitis.

X.  Protection by Antibodies [S10]

a.  You can be protected from polio infection-and I want to make this distinction very clearly now-from polio infection by secretory antibodies. What are secretory antibodies? Those are antibodies that are in your saliva and your mouth. Generally they are IgA antibodies. Those antibodies will bind the virus and prevent it from infecting a cell. So you will prevent against infection.