Influenza Flashcards

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1
Q

What are the symptoms of seasonal influenza?

A
  • subclinical to severe
  • fever/chills
  • cough
  • headache
  • muscle aches
  • fatigue
  • loss of appetite
  • lasts ~7 days
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2
Q

How is influenza spread?

A

droplet infection from coughing and sneezing

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3
Q

What is the incubation period of influenza?

A

1-5 days

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4
Q

What is the infectious period of influenza?

A

5-6 days

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5
Q

Who is more at risk of getting influenza?

A
  • young
  • elderly
  • w/underlying chronic heart, lung, renal, or metabolic conditions
  • obese
  • pregnant women
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6
Q

What is the pathogenesis of seasonal influenza?

A
  • viral droplets enter respiratory tract
  • virus vinds ti sialic acid on receptors on non-ciliated respiratory epithelium
    • SA alpha2-6 linkage to galactose in humans
    • found elsewhere but virus remains localized to RT
  • replicates in epithelial cells of U and LRT, esp in large airways
  • tissue damage as a result of virus killing epithelial cells and the resulting inflammatory response
  • production of cytokines:
    • IL-1 from SCs and macros –> fever
    • IFN –> lethargy, aches
  • later, infects ciliated epithelium of trachea and bronchi
    • leads to secondary commensal bacterial infections
      • H. influenzae, S. aureus, S. pneumoniae)
        • death from bacterial pneumonia esp in elderly
  • rarely infects parenchyma directly (viral pneumonia)
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7
Q

What is the general structure of inluenza viruses?

A
  • orthomyxoviridae family
  • enveloped virus
  • genome is segments of ssRNA -ve sense
    • tf carries its own RNA-dep RNA-pol on infection
  • 3 genomically different types: A, B, C (mild)
    • differetniated by Abs to the internal Ags
  • Types A & B cause human influenza
  • only type A can infect other species
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8
Q

What are the critical features of the influenza envelope?

A
  • hemagglutinin (HA), the dominant glycoprotein in the envelope surface
  • nueraminidase, NA
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9
Q

What is the structure of the influenza genome?

A
  • 8 segments of -ssRNA
  • each twisted in a panhandle structure with a nucleoprotein around it
  • each carry a RNA-dep RNA-pol
  • each encodes at least one gene
  • there are 10+ proteins depeniding on the strain
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10
Q

Which part of the influenza virus interacts with sialic acid on receptors?

A
  • hemagglutinin and neuraminidase
  • HA binds SA and gets the virus into the cell
  • NA cuts SA to free viruses that bud out of the host cell
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11
Q

What are the Type A influenza subtypes?

A
  • all Type A share similar internal proteins but differ in HA and NA they encode
    • this generates the different subtypes:
    • HA = H1-H16
    • NA = N1-N10
    • named accordingly eg H5N1
  • all subtypes of HA and NA are found on viruses endemic in avian species as they are the ancestral host of influenza A
  • H1N1, H2N2, and H3N2 have previously become endemic in humans
  • currrently H1N1, H3N2, and Type B are the only circulating viruses that are endemic in humans
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12
Q

How does influenza enter the cell and start the replication cycle?

A
  • viral hemagglutinin binds sialic acid linked to a galactose on its receptor (unknown) on the surface of a non-ciliated respiratory epithelial cell
  • virus is taken up by receptor-mediated endocytosis
  • as the endosome pH drops, HA changes conformation
    • viral envelope fuses with the endosomal membrane
    • forms a pore
    • releases the 8 viral RNPs (ribonucleoproteins, panhandle genome segments)
  • 8 viral RNPs enter nucleus
  • viral RNA is amplified to produce mRNA
  • mRNA leaves the nucleus to produce proteins
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13
Q

How are influenza viruses assembled in the host cell?

A
  • the hemagglutinin and neuraminidase are glycosylated proteins and therefore go through the ER and golgi –> host cell membrane
  • proteins are made eg nucleopeptide, RNA-dep RNA-pol
    • these are shunted back to the nucleus to form the RNPs
  • RNPs exit the nucleus
  • come up underneath the host cell membrane
  • bud off with envolpe containing HA and NA
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14
Q

How is the influenza virus released from the host cell?

A
  • viral RNPs bud out of the host cell membrane with HA and NA in their envelope
  • the NA will naturally target sialic acid on receptors on the host cell
  • tf NA snips sialic acid off receptors as it exits the host cell to prevent re-binding by the HA
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15
Q

What has to happen to newly-formed influenza virus for it to be infectious?

A
  • it must be cut by tryptase Clara, present only in the RT
  • occurs at a cleavage site to reveal a hydrophobic fusion peptide
  • only viruses that have undergone this cut can undergo the endosomal pH change required to fuse and form a pore for RNP escape
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16
Q

What is the adaptive immune response to influenza virus infection?

A

CD8+ cytotoxic T cells:

  • kill virus-infected cells
  • important in recovery by keeping viral load down
  • recognize peptides derived from the internal antigens
    • these are conserved within Type A tf CD8s recognize Type A subtypes (but do not see Type B)
  • CD8 T cell immunity is not long-lived but can be boosted by repeated exposure

antibody:

  • develops predominantly to HA but also to NA
  • speeds viral clearance
  • Abs bind HA, tf it cannot bind to its recetors
  • Ab & complement cascade promote lysis, phagocytosis of virus
  • pre-existing Abs will protect against infection in the same season and next by neutralizing the incoming virus
    • Ab response to infecting strain is lifelong
    • but rendered ineffective by antigenic drift
17
Q

What is the common site for favourable mutation in antigenic drift of influenza virus?

A
  • sites on HA or NA that neutralizing antibodies bind to
    • if the Ab can no longer recognize the mutated protein sequence
  • leads to that strain of virus being selected for
    • eg can have multiple strains even within H1 with slight mutative differences that confer a selective advantage for infection of hosts
  • there are 5 antigenic sites surrounding the receptor binding pocket
    • once all 5 have mutated, majority of population have no antiboides
    • this results in an epidemic
  • new strains replace older strains (linear evolution)
18
Q

What are the targets of vaccine-induced immunity?

A
  • Abs produced to the vaccine will target HA to block viral attachment, and NA to block viral release
19
Q

What does the influenza vaccine contain?

A
  • inactivated forms of 3 different influenza viruses ie the most recent circulating strains of:
    • Type A: H1N1 and H3N2
    • Type B
20
Q

What type of immune response does the influenza vaccine induce?

A
  • the vaccine is inactivated therefore it induces Ab formation but not cytotoxic T-cell responses
21
Q

What are the targets of influenza antiviral drugs?

A
  • ion channel blockers
    • inhibit the M2 ion channel on the influenza virus, preventing the RNPs from escaping the endosome in the host cell
  • NA inhibitors
    • block NA from snipping sialic acid off receptors on the host cell
    • this impairs the virus from being released from the host cell
22
Q

How do ion channel blocker influenza antivirals work?

A
  • eg amantadine and rimantadine (except for H5N1)
  • block the influenza virus M2 ion channel
  • normally M2 allows the H+ that is decreasing the pH of the endosome to pass into the viral cell through the pore that is formed when the endosomal and viral membranes fuse
  • this H+ is required to induce a conformational change that unlocks the RNPs for release via the fusion pore into the cytoplasm
23
Q

Amantadine & Rimantadine

A
  • influenza antivirals (adamantanes)
  • block M2 ion channel to inhibit uncoating of influenza A virus in the endosome
  • NOT ACTIVE AGAINST TYPE B
  • oral, daily administration
  • tx in children, propx in nursing homes to prevent outbreaks
  • not used widely in the community because drug-resistant influenza mutants arise
    • the M2 protein also mutates via drift, can cause epidemics
24
Q

Relenza (Zanamivir) & Tamiflu (Oseltamivir)

A
  • influenza antivirals
  • block the action of NA by binding to its active site and blocking its enzymatic activity to release viral particles from host cells
  • ACTIVE AGAINST INFLUENZA TYPE A AND B
  • reduce duration and severity of the flu
  • DO NOT STOP INFECTION
  • only effective if administered within 2 days of developing symptoms
  • administration is 2x daily:
    • Relenza: inhalation by mouth
    • Tamiflu: orally administered prodrug (activated in liver –> lungs)
  • some older H1N1 strains show resistance to Tamiflu; susceptible to Relenza
  • they are analogs of sialic acid
25
Q

What is antigenic shift?

A
  • sudden appearance of a new HA (sometimes NA) subtype of a Type A influenza virus within the human population
    • occurs ~10 years, usually zoonoses from birds, sometimes pigs
  • because we have no Abs to these new HA (NA)s, these strains have pandemic effects
  • 1-2 AA change in receptor binding pocket of HA switches it from a2-3 (avian) bound sialic acid specificity on receptors to a2-6 sialic acid specificity on human receptors
    • influenza jumps from the avian population to humans
26
Q

Why are pandemics rare?

A
  • human influenza virus sees sialic acid bound alpha2-6 to galactose (human RT)
  • avian influenza virus sees sialic acid bound alpha2-3 to galactose (bird RT and GIT)
  • this normally prevents zoonosis of avian influenza to humans
    • ​just 1-2 AA changes can convert HA receptor binding sites from being a2-3 (avian) specific to a2-6(human) specific = zoonosis –> pandemic
  • pigs have both of these lined SA receptors in their respiratory tract and can act as a mixing vessel
    • can produce a dangerous combination if a human strain and an avian strain coinfect
    • get specificity for human a2-6 in the pig (or first few infected humans) with the HA and NA of the avian strain to which we are niave
      • this can be a deadly, pandemic combination
27
Q

Swine-origin H1N1

A
  • 2009
  • respiratory symptoms as in seasonal flu
  • not highly lethal
    • most deaths people had underlying conditions
  • far greater ability to replicate in lungs compared to seasonal
    • tf younger adults getting viral pneumonia
    • deaths in younger people
  • pregnant women, obese, and inigenous pop’ns most susceptible
  • susceptible to NA inhibitors
    • resistant mutants developing to seasonal H1N1
  • replaced seasonal H1N1 tf now included in Aus vaccine
28
Q

avian H5N1

A
  • mutated in birds to become very virulent and endemic in the bird population
  • not yet endemic in the human population
  • it is a highly pathogenic avian influenza
    • it can have systemic effects because it doesn’t depend on tryptase clara and therefore is not restricted to the RT
  • can be lethal in humans
  • even lethal in eggs in which it is grown
  • first cases in 1997 (halted), 2003 (re-emergence)
    • indonesia has most cases and highest fatality rate (82%)
  • susceptible to NA inhibitors but people are not always treated in time