Influenza Viruses – Orthomyxoviruses

by Sean Elliott, MD

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    00:01 The orthomyxoviridae viruses.

    00:05 The orthomyxoviridae our large, enveloped viruses with a helical capsid, such as you can see on the colored scanning electron micrograph to the right.

    00:15 They are or they have a linear, single-stranded, negative-sense, segmented RNA genome, and thus must carry an RNA-dependent RNA polymerase.

    00:26 They're able to replicate within the nucleus, even though they have their own RNA polymerase.

    00:32 The important viruses in this family are the influenza viruses, types A, B, and C.

    00:39 And these, of course, will be quite familiar to you as the cause of pandemic and epidemic flu.

    00:46 What is the structure of the influenza virus? And in fact, it is well known for having both hemagglutinin and neuraminidase glycoproteins, which you see identified on the cartoon in the right side.

    00:59 Both are present at the surface of the virus, and both have different medical implications.

    01:06 Both can be targets, though, for identification, and in the case of neuraminidase, a target for treatment.

    01:13 Within the helical capsid are also nucleoproteins, and also, the RNA-dependent RNA polymerase, the RDRP.

    01:23 In addition, influenza A especially, contains M1 and M2 proteins important for virion assembly.

    01:31 And then for M2, it's a target for some other antiviral drugs.

    01:38 How do we think about these influenza viruses, and specifically, how do they serve as examples for antigenic drift and shift? Now, to explain the concepts of drift and shift, you first need to know that as you sit here watching this, hopefully, very exciting session, you yourself are mutating.

    01:58 Well, in fact, your DNA or your RNA are undergoing constant point mutations.

    02:05 In human beings, we have a repair mechanism which corrects or fixes those mutations. And so, if I suddenly change a T to an A, it'll be changed back to a T.

    02:17 Influenza, both A and B, does not have such a repair mechanism.

    02:22 And so, those natural spontaneous mutations that the influenza genome undergoes, are not repaired.

    02:30 As these mutations occur, and each one by itself has no major effect, but as they continue to occur and accumulate, then ultimately -- and this may be a period of hours, days, weeks, months -- ultimately, there may be sufficient mutations within a genome or a gene, which actually changes the transcription of that gene and changes the protein product.

    02:55 So, it's minor changes, and when they occur, they will change the hemagglutinin or the neuraminidase genes, which will change the antigenic recognition of the influenza A, and we have the effect of a new virus affecting the world leading to an epidemic.

    03:13 So, antigenic drift, slow, gradual, very much like an iceberg drifting slowly, slowly, slowly on the ocean.

    03:22 In direct contrast is antigenic shift. This is a dramatic change, and it involves reassortment of different genes between different influenza viruses.

    03:33 And this may be from a reassortment between a human strain and an animal strain.

    03:39 For example, the avian flu, if you all remember that outbreak, was a reassortment between poultry and between the human strain.

    03:49 Most of the reassortment occurs, sorry to tell you this, between humans and pigs.

    03:54 Yes, we share some interactions with our dear friends, the pig kingdom.

    03:59 So, as a reassortment occurs between those 2, then we get in the space of a rapid reassortment, so, you know, days to weeks, a brand new, significantly different or shifted influenza, especially influenza A, which nobody has seen, and it's completely separate from prior viruses out there.

    04:21 So there is no antibody recognition whatsoever.

    04:24 When that happens, then one has a pandemic.

    04:27 Not just a limited blip of flu occurring during the winter season, but worldwide, many more cases, higher severity, higher numbers, etc.

    04:37 And this most recently happened in 2009 with the influenza H1N1 pandemic.

    04:45 Now, the problem with these antigenic shifts is that they can occur dramatically, meaning there's a lot more virus out there, and that increases the ability to be affected with 2 strains at the same time.

    05:00 And when that occurs, that further allows mixing of genome segments to occur, not just in humans that are, thankfully, inefficient mixing pots, but in other animals. Again, the pig is an ideal mixing pot for such interagency to occur.

    05:17 So that means that hybrid viruses can continue to occur in the setting of a pandemic.

    05:22 Basically, a whole lot influenza, which all of us are susceptible to.

    05:27 So, let's look at the diseases caused by the influenza viruses, and we break these down into classic influenza in adults and in children.

    05:37 Children may, as you will see, present a little bit more dramatically, and children are also very effective mixing pots because their immunity is slightly less mature.

    05:48 And that also allows for them to have higher viral expression and for them to be highly contagious.

    05:55 So, both adults and children have a incubation period with influenza of just 1-3 days. It's a very short process.

    06:04 The transmission, of course, very effective through respiratory droplets, hence the public health recommendations to cover the cough and sneeze into the crook of the arm.

    06:16 Clinical manifestations.

    06:18 Prodrome for both is from maybe 3- 24 hours, not days, but hours.

    06:25 Children may not report the malaise or headache because they're too busy doing other things, having fun, eating dirt, etc.

    06:33 But when disease occurs, then both adults and children will have fever, but the children will have a higher fever.

    06:42 Adults have the fever along with the myalgias, so severe muscle aches.

    06:46 They may have a dry, nonproductive cough.

    06:50 In adults, they'll have secondary diseases including Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae caused pneumonia.

    07:00 Children may get the pneumonia, but they may also get otitis media, they may get bronchiolitis, sort of upper and lower respiratory disease. They may have croup.

    07:10 Certainly, they may have more of a gastro- intestinal component to their influenza, but that's not limited to children either.

    07:16 So you can see some cross symptoms between the 2, but if you had to distinguish adult versus childhood influenza, it's really the height and severity of the fever.

    07:29 Overall severity, although anybody who's in the middle of suffering from the flu would argue with me extensively, but overall, it's a relatively mild, minor, self-resolving process if one is immunocompetent.

    07:45 Now, those who are immunodeficient can have severe disease, which can progress to respiratory failure and death.

    07:52 Those individuals would be pregnant women, a person with known immunodeficiency, or even patients with cardiorespiratory disease.

    08:02 The rest of us may be completely asymptomatic, if we're lucky, all the way up to how -- to a very severe process, depending on how much of an immune reaction we actually have.

    08:12 The complications, and these are actually also contributors to the mortality, the death rate, associated with outbreaks of influenza.

    08:22 In adults, the bacterial super infections causing pneumonia, and also in some cases, especially with influenza B, there's a postinfluenza encephalitis.

    08:33 In children, a myositis.

    08:36 Some children who are still mistakenly treated with aspirin are at risk for Reye's syndrome or fulminant hepatic failure.

    08:44 But again, that's more due to ingestion of aspirin or so.

    08:48 So, overall, the severity depends upon age, and then to a secondary extent, the immune function of the patient.

    08:59 Now, identification. We have multiple different ways to look for influenza, really, depending on what both secretions are, the target of our sample, as well as the type of disease that we -- or the type of testing that we want to investigate.

    09:16 So, starting with the ELISA, the enzyme- linked immunosorbent assay, this is able to detect antigens expressed in nasal secretions.

    09:24 And if you're suffering from the flu right now, you know that you have plenty of nasal secretions to sample.

    09:31 If one then takes that same specimen or perhaps, like the oral mucosa, and cultures that on appropriate culture cells, that one can do a hemadsorption/ hemagglutination assay to look for presence of influenza.

    09:46 The hemagglutination inhibition is performed by antibody detection, so you can now start to identify influence A versus B.

    09:54 But in terms of getting the actual, what type of influence A is it, one has to do molecular diagnosis to look for the viral genomes to have any degree of sensitivity.

    10:05 So, I can tell you in influenza A, H1N1 versus H3N2.

    10:12 Prevention. Vaccination, vaccination, vaccination.

    10:16 Yes. An annual vaccination for influenza is created based on predictive probability in a single country looking at influenza in the other hemisphere saying, "All right." So in the States, we look at information coming from Australia to say, "Okay, they're having these strains of influenza A and B, meaning that when we have our flu season, we're more likely than not going to have the same strains." So, based on predicted endemic strains, the vaccine is created to provide coverage to those.

    10:51 Treatment.

    10:52 Amantadine and rimantadine are historic antivirals.

    10:56 They targeted the M2 protein in influenza A, but they had to be used within 24-48 hours. They actually -- to have full efficacy needed to be used at the time of onset, which of course, who knew that they had the flu at the time? Unfortunately, most currently circulating strains of influenza A are resistant to these antivirals.

    11:18 And so, instead, we use drugs which target the neuraminidase of influenza A and B, zanamivir and also oseltamivir.

    11:26 And these remain relatively effective.

    11:29 Ongoing discovery continues to create yet new antivirals to target alternate sites.

    11:35 But to this point, these antivirals have relative efficacy.

    11:39 Same caution to use these within the first 48 hours of onset because after that, the targeting of respiratory epithelium by the influenza viruses has already occurred.

    11:51 So, quite common viruses, you'll be very familiar with them, at least, by your own experiences, but hopefully, now, you can start to understand a bit more of the genetics behind how influenza causes such a problem every year.

    About the Lecture

    The lecture Influenza Viruses – Orthomyxoviruses by Sean Elliott, MD is from the course Viruses.

    Included Quiz Questions

    1. Linear, single-stranded RNA
    2. Circular, single-stranded RNA
    3. Circular, double-stranded DNA
    4. Circular, single-stranded DNA
    5. Linear, single-stranded DNA
    1. Helical
    2. Prolate
    3. Circular
    4. Icosahedral
    5. Dodecahedral
    1. A pandemic
    2. An endemic
    3. An epidemic
    4. An isodemic
    5. A syndemic
    1. ...1–3 days.
    2. ...4–7 days.
    3. ...7–10 days.
    4. ...10–14 days.
    5. ...15–18 days.
    1. Antigenic drift
    2. Antigenic shift
    3. Antigenic lift
    4. Antigenic grift
    5. Antigenic swift
    1. Enzyme-linked immunosorbent assay
    2. Hemadsorption test
    3. Hemagglutination test
    4. Hemagglutination inhibition test
    5. Reverse transcriptase-polymerase chain reaction

    Author of lecture Influenza Viruses – Orthomyxoviruses

     Sean Elliott, MD

    Sean Elliott, MD

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