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MIIM20002 - Microbes, Infections, Responses > Lecture 16 & 17 - Influenza > Flashcards

Lecture 16 & 17 - Influenza Flashcards

1
Q

What is influenza?

A

A specific respiratory syndrome

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2
Q

What are the symptoms of influenza?

A 
Fever
Chils
Cough
Headache
Muscle aches
Fatigue
Loss of appetite
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3
Q

What is the appearance of a chest X ray in patients with influenza?

A

Normal

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4
Q

How long does influenza infection last?

A

7 days

However, the cough may last several weeks

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5
Q

Which groups are at risk of influenza infection?

A

Young
Old
Immuno-compromised

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6
Q

How may influenza be spread?

A

Droplets from coughing / sneezing

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7
Q

How long is the incubation period for influenza?

A

1-5 days

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8
Q

Does influenza affect many people each year?

A

Yes: 10-20 % of pop.

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9
Q

What is the impact of influenza on the population

A

Burden on:
• doctors
• hospitals
• employers

It’s an economical burden

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10
Q

How many deaths due to influenza each year?

A

250,000 to 500,000

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11
Q

Describe the pathogenesis of influenza

A
  1. Droplets enter respiratory tract
  2. Virus binds to sialic acid receptors in URT
  3. Replication in epithelial cells of RT
  4. Tissue damage → inflammatory response
  5. Immune response clears the infection in immunocompetent individuals
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12
Q

To which types of cells does influenza bind once it enters the body?

A

Unciliated epithelial of the respiratory airways

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13
Q

Where does the virus replicate?

A

Epithelial cells, especially in the LARGE AIRWAYS

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14
Q

Which cytokines are inducted in the inflammatory response to influenza?
What is their effect?

A

IL-1 → fever

IFN → malaise, head and muscle aches

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15
Q

Is the ciliated epithelium of the airways infected by influenza?

A

Initially, no.

Later on in the infection, this does occur

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16
Q

What does infected of the ciliated infection sometimes lead to?

A

Secondary bacterial pneumonia

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17
Q

What are the causes for pneumonia?

A

Primary viral: rare

Secondary bacterial: more common, esp. in elderly

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18
Q

To which family does Influenza virus belong?

A

Orthomyxoviridae

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19
Q

Describe the genome of Influenza

A

-ve sense
ssRNA
segmented

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20
Q

How many types of influenza are there?

A

3: A B and C

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21
Q

What can we say about the three types of influenza?

A

They show no immunological cross-reactivity

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22
Q

How do we differentiate the different types of virus?

A

Antibodies to the internal antigens of the virus

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23
Q

What do types A and B do?

A

Cause human influenza

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24
Q

Which types of influenza can infect other species?

A

Type A

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25
Q

How many RNPs does influenza have?

A

8

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26
Q

Which proteins does influenza have?

A

HA: haemagglutinin
NA: neuraminidase
M1: matrix protein
M2: matrix protein (channel)

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27
Q

What is the structure of the viral RNP?

A

-ve sense ssRNA
Protein
3 polymerase subunits

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28
Q

What is the structure of HA?

A

Trimer

Head with a binding pocket for Sialic acid

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29
Q

What is the structure of NA?

A

Tetramer

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30
Q

What is different about the different subtypes of Type A influenza?

What is the same?

A

Same: internal proteins

Different: HA and NA

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31
Q

How many subtypes of HA are there?

A

16

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32
Q

How many subtypes of NA are there?

A

9

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33
Q

What is an influenza subtype?

A

eg. H1N1

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34
Q

What is the ancestral host of influenza A?

A

Aquatic birds

All subtypes are endemic in birds

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35
Q

Which other animals can be infected by influenza?

A

Pigs

Horses etc.

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36
Q

Which subtypes of influenza are currently in the human population?

A

H1N1

H3N2

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37
Q

How are influenza viruses named?

A 
Type
Place of isolation
Isolate number at that place
Year of isolation
Subtype
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38
Q

Describe the replication cycle of influenza virus

A
  1. HA binds to sialic acid
  2. RME into endosome
  3. Endosome becomes more acidic
  4. HA changes conformation
  5. Virus leaves endosome, RNPs go to the nucleus
  6. Replication, transcription, translation
  7. Budding out of cell, acquiring HA and NA
  8. NA cleaves Sialic acid receptor on host cell
  9. Tryptase clara action → active virion disseminates
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39
Q

What allows the viral membrane to fuse with the endosomal membrane, so that the RNPs are released into the cytosol?

A

Tryptase clara must cleave one amino acid on HA

HA can now change conformation in the low pH conditions of the endosome → fusion

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40
Q

What produces Typtase clara?

Where?

A

Clara cells

In the small airways (bronchioles)

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41
Q

Why does influenza only infect cells of the respiratory tract?

A

Needs Typtase clara action to be able to get out of the endosome

Clara cells are only found in the respiratory tract

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42
Q

What is the structure of a collectin?

A

Protein

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43
Q

What is the function of collectins?

A

They bind to carbohydrate side chains of HA and NA

This prevents the influenza from binding to the host cell

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44
Q

How do collectins interact with the complement cascade?

A

Collectin binding triggers the lectin pathway

→ opsonisation
→ MAC in infected cells

45
Q

What are the early innate defences against Influenza?

A

Collectin binding

46
Q

What are the late innate defences against influenza?

A 
Viral infection triggers:
IFN-a
IFN-B
IL-1
IL-6
TNF-a

Inflammation
Viral immunity

47
Q

What are the type 1 interferons?

A

IFN-alpha

IFN-beta

48
Q

What are the roles of type 1 interferon?

A
  • binds to uninfected cells → antiviral function of cell, so it is protected from infection
  • induction of NKs
  • Upregulation of MHC I
49
Q

Which cells release the cytokines in the anti-viral inflammatory response?
Why?

A

When viruses are taken up by macrophages and DCs, they start to produce all these cytokines

50
Q

Describe the function of NK cells

A
  1. Recognise virally infected cells through receptors that recognise ‘stress’ (decreased MHC I expression)
  2. Release toxic granules → apoptosis
51
Q

Are NK cells enough to clear a viral infection?

A

No, it just keeps the infection in check

To clear the virus we need an adaptive IR

52
Q

In general, how does the adaptive immune response fight influenza infection?

A

CD8+ cells:
• kill virally infected cells
• recognition of internal antigens

Antibody:
• against HA and NA

53
Q

Are CD8+ cells cross-reactive between Influenza types A and B?

Why / why not?

A

No, however, they are cross-reactive between subtypes.

CD8+ cells recognise internal proteins, which are conserved between influenza subtypes

54
Q

Are the antibody and CD8+ cell response against influenza long lasting?

A

Antibody: lifelong

CD8+ cell: not long lived (can be boosted by repeat exposure)

55
Q

If our antibodies against HA and NA are lifelong, why do we get continual infection with influenza?

A

Antigenic drift

56
Q

Describe the mechanism of antigenic drift

A
  1. Error in replication
  2. No proof-reading
  3. Single amino acid changes in viral proteins (inc. HA and NA)
  4. Antibodies can no longer bind
  5. Resistant strains are selected for
57
Q

How many antigenic sites are there on HA?

A

5

58
Q

Where does neutralising Ab bind to HA?

A

The 5 antigenic sites surrounding the receptor binding pocket

59
Q

In general, when does an epidemic of influenza come about?

A

When all 5 antigenic sites mutate

The population has no pre-existing antibodies to this strain

60
Q

Antigenic drift brings about new viral …

A

Strains within a subtype

61
Q

Evolution of influenza is a … process

A

Linear

62
Q

Why is evolution of influenza described as linear?

A

Once a new strain is created through mutation, it replaces all older strains

63
Q

Describe the evolution of the H3 subtype

A

From 1968 to 1987, there were mutation at the five sites, such that the globular head became completely different

64
Q

When is influenza present in the population?

A

Throughout the year

In winter, however, there are peaks

65
Q

How often do we see epidemics of seasonal influenza?

A

Every 2-3 years

66
Q

Why is surveillance of influenza important?

A
  • Detection of new antigenic variants that could cause an epidemic
  • Vaccine production
  • New strains
  • Checking antibody levels to see how effective the vaccines are
67
Q

Why is rapid diagnosis important?

A

Rapid anti-viral therapy

68
Q

What are the three groups of lab diagnosis?

What is the time frame for each?

A

Rapid: hours
Culture: days
Detection of antibody responses: days-weeks

69
Q

How is rapid diagnosis of influenza performed?

A

Reverse transcriptase - PCR

‘X/pect’ test for antigen

70
Q

What does rapid diagnosis tell us?

A

Type A vs. Type B

71
Q

What does culture tell us?

A

Subtype and strain analysis

72
Q

How is culture analysis performed?

A

Embryonated eggs with specific reference antibodies

Haemagglutination-inhibtiion test

73
Q

Why do we detect for antibody responses?

A

To evaluate the success of a vaccine

74
Q

How do we detect for antibody responses?

A

Haemagglutination-inhibition test with patient’s serum + virus

75
Q

Describe the process of the Haemagglutination-inhibtion test

A
  1. Chicken RBCs with sialic acid
  2. Add virus
  3. Virus binds to sialic acid receptor
  4. Agglutination → sinking, ‘button’

If there are antibodies present, the virus will not bind to the RBCs → no button

76
Q

Differentiate between a positive H-I test and a negative

A

Antibodies present: no agglutination, button

No Ab: agglutination, no button

77
Q

How does the H-I assay let us subtype the virus?

A

The antibodies used in the test are for different subtypes and strains

Agglutination or lack of in the presence of certain antibodies will indicate the subtype

78
Q

What are the antibody targets of the H-I test?

A

HA and NA

79
Q

Which types of influenza viruses are contained in the influenza vaccine?

A

Type A:
• H1N1
• H3N2

Type B

80
Q

How in the influenza vaccine administered?

A

Intramuscularly

81
Q

Which people are strongly advised to get the influenza vaccine?

A 
Elderly
Young
Chronic heart, lung, kidney disease
Cancer / diabetes sufferes
Immunosuppressed
Health workers
82
Q

How is the influenza vaccine made?

A

Viruses are grown in eggs
Purification
Chemical inactivation

83
Q

Who can’t take the influenza vaccine?

A

People with egg allergies

84
Q

What type of vaccine is the influenza vaccine?

A

Split virus vaccine

85
Q

Which responses are induced by the influenza vaccine?

Why?

A

B cell
CD4+ cell

No CD8+ cell response

This is because it is a inactivated virus

86
Q

Does the influenza vaccine work well?

A

Young and healthy: 70%

Elderly: less

87
Q

Why must the vaccine be made again every year?

A

Because there are new strains every year due to antigenic drift

88
Q

What are the targets of antiviral drugs?

A
  • M2 ion channels

* Neuraminidase

89
Q

Describe how M2 ion channels work

How is this targeted by an antiviral drug?

A
  1. Ion channels pump H+ into the virus
  2. Conformational change of HA
  3. Fusion of virus with endosome
  4. Release of RNPs

By blocking the ion channel, there is no fusion, and the virus can not release its RNPs

90
Q

What are some examples of M2 ion channel blockers?

A

Amantadine

Rimantadine

91
Q

Which types of influenza are susceptible to M2 ion channel blockers?

A

Type A

92
Q

Are M2 ion channel blocker widely used?

Why / why not?

A

They are not widely used

Because drug resistant variants readily arise

93
Q

What are some antivirals that block neuraminidase?

A

Relenza (zamamivir)

Tamiflu (oseltamivir)

94
Q

Which types of influenza are susceptible to neuraminidase inhibitors?

A

Types A and B

95
Q

What is the result of administering neuriminidase inhibitors?

A

Reduction in severity and duration

96
Q

How is Relenza administered?

A

Inhalation by mouth

97
Q

How is Tamiflu administered?

A

Oral prodrug

98
Q

Describe how neuraminidase inhibitors work

A
  1. Bind to the active site of NA
  2. NA can no longer cleave sialic acid from host cell
  3. Virions are stuck onto the host cell and can not disseminate
99
Q

For how many days is one infectious?

A

5-6 days

100
Q

Describe the bond between Sialic acid and HA

A

alpha 2-6 galactose on Sialic acid
+
HA

101
Q

Which bacteria may cause secondary bacterial pneumonia?

A

Strep. pneumoniae
H. influenzae
Staph. aureus

102
Q

Describe the structure of the Influenza virion

A 
8 RNPs
M1: matrix
M2: ion channel
Envelope
Glycoproteins: HA, NA
103
Q

Describe the symmetry of Influenzavirus

A

Helical symmetry

104
Q

Describe how the virion acquires its glycoproteins on its envelope

A
  1. The glycoproteins are made using the host machinery (ribosomes)
  2. Vesicular transport through ER and Golgi, eventually to host cell membrane
  3. Viruses bud out, acquiring the glycoproteins
105
Q

What is one way that you could describe collectins?

A

Soluble PRR:

• bind PAMPs

106
Q

Describe the stages of immune response to influenza

A
  1. Innate early
    • Collectins
2. Innate, delayed
• PAMP-PRR → DC activation
• IFN release
• Inflammatory cytokine release
• NK activation
  1. Adaptive
    • B cells produce antibodies
    • CD8+ T cells kill infected cells
107
Q

Describe cross reactivity of CD8+ T cells

A

Recognise internal antigens
Thus, broadly cross-reactive within a type

However, not crossreactive between types

108
Q

Describe the role of antibody in the immune response to influenza.

A
  1. HA and NA are present on the cell membrane of infected cells
  2. Ab binds to HA and NA
  3. Complement activation
    • lysis
    • phagocytosis
109
Q

Where are the ‘advantageous’ mutations occurring during antigenic drift?

A

At the Antigenic Sites:

• (sites on HA and NA where antibodies bind)

MIIM20002 - Microbes, Infections, Responses (32 decks)

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