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.

    05:49 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.

    08:34 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.

    08:58 The diagnosis of influenza is best performed via nucleic acid detection methods, which have both high sensitivity and specificity.

    09:06 These exist as conventional PCR, such as RT-PCR and multiplex PCR.

    09:12 That Multiplex PCR typically will detect other respiratory viruses and respiratory bacterial pathogens.

    09:19 Time to complete these PCR tests usually is from one to 8 hours, and they have, as noted, very high sensitivity and very high specificity.

    09:27 They can differentiate influenza A and B and also can differentiate the subtypes of Influenza A, such as H1N1 versus H3N2.

    09:37 Another detection method is a rapid nucleic acid detection, and this typically can take from 15 to 30 minutes to complete.

    09:44 So a point of care test, for example, in an emergency department.

    09:48 This can differentiate and detect influenza A and B, but it cannot sub differentiate the influenza A subtypes.

    09:55 Other tests exist such as antigen detection assays.

    09:58 These are rapid from 15 minutes up to immunofluorescence assays taking one to 4 hours.

    10:04 Unfortunately, false negative results are common, so these should only be used as screening tests.

    10:10 Viral culture is possible but is not useful because it takes a long time and is really only used for public health reasons and for serologic excuse me for therapeutic testing purposes.

    10:22 Serology itself is not useful because it doesn't distinguish very actively active versus past infection.

    10:29 Prevention. Vaccination, vaccination, vaccination.

    10:34 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.

    11:08 Treatment of influenza if started with an antiviral drug, it must be started within 48 hours of onset of symptoms to have any discernible, proven impact on the outcome.

    11:19 However, these treatment track drugs can also be used for post-exposure prophylaxis.

    11:25 The classes of antiviral drugs for influenza are the neuraminidase inhibitors.

    11:31 These inhibit the influenza virus neuraminidase enzyme, which prevents release of viral particles from infected cells.

    11:39 These drugs are active against both Influenza A and B.

    11:42 And examples include oseltamivir and oral medication zanamivir, which is inhaled and of course contraindicated if the patient has chronic lung disease such as asthma or COPD, and then peramivir, which is given intravenously.

    11:56 The next class of influenza treatment are the endonuclease inhibitors.

    12:01 These inhibit initiation of mRNA synthesis and are active also against influenza A and B. Baloxavir, an oral drug is and is an example of this class.

    12:12 And then the Adamantanes which target the M2 protein of influenza A only. This protein forms a protein channel in the viral membrane and is essential for viral replication.

    12:24 So of course preventing it from acting will prevent viral replication.

    12:29 These drugs only are active against Influenza A, but unfortunately there are no long or useful due to high rates of resistance, both in the States and elsewhere.

    12:38 The two drugs that are examples in this class though, are amantadine and rimantidine.

    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. Hemagglutin
    2. Nucleocapsid protein
    3. M1 protein
    4. M2 protein
    5. Neuraminidase
    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. Polymerase chain reaction
    2. Hemadsorption test
    3. Serologic testing for antibodies
    4. Viral culture

    Author of lecture Influenza Viruses – Orthomyxoviruses

     Sean Elliott, MD

    Sean Elliott, MD

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