Lecture 16 & 17 - Influenza Flashcards
(109 cards)
1
Q
What is influenza?
A
A specific respiratory syndrome
2
Q
What are the symptoms of influenza?
A
Fever Chils Cough Headache Muscle aches Fatigue Loss of appetite
3
Q
What is the appearance of a chest X ray in patients with influenza?
A
Normal
4
Q
How long does influenza infection last?
A
7 days
However, the cough may last several weeks
5
Q
Which groups are at risk of influenza infection?
A
Young
Old
Immuno-compromised
6
Q
How may influenza be spread?
A
Droplets from coughing / sneezing
7
Q
How long is the incubation period for influenza?
A
1-5 days
8
Q
Does influenza affect many people each year?
A
Yes: 10-20 % of pop.
9
Q
What is the impact of influenza on the population
A
Burden on:
• doctors
• hospitals
• employers
It’s an economical burden
10
Q
How many deaths due to influenza each year?
A
250,000 to 500,000
11
Q
Describe the pathogenesis of influenza
A
- Droplets enter respiratory tract
- Virus binds to sialic acid receptors in URT
- Replication in epithelial cells of RT
- Tissue damage → inflammatory response
- Immune response clears the infection in immunocompetent individuals
12
Q
To which types of cells does influenza bind once it enters the body?
A
Unciliated epithelial of the respiratory airways
13
Q
Where does the virus replicate?
A
Epithelial cells, especially in the LARGE AIRWAYS
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
15
Q
Is the ciliated epithelium of the airways infected by influenza?
A
Initially, no.
Later on in the infection, this does occur
16
Q
What does infected of the ciliated infection sometimes lead to?
A
Secondary bacterial pneumonia
17
Q
What are the causes for pneumonia?
A
Primary viral: rare
Secondary bacterial: more common, esp. in elderly
18
Q
To which family does Influenza virus belong?
A
Orthomyxoviridae
19
Q
Describe the genome of Influenza
A
-ve sense
ssRNA
segmented
20
Q
How many types of influenza are there?
A
3: A B and C
21
Q
What can we say about the three types of influenza?
A
They show no immunological cross-reactivity
22
Q
How do we differentiate the different types of virus?
A
Antibodies to the internal antigens of the virus
23
Q
What do types A and B do?
A
Cause human influenza
24
Q
Which types of influenza can infect other species?
A
Type A
25
How many RNPs does influenza have?
8
26
Which proteins does influenza have?
HA: haemagglutinin
NA: neuraminidase
M1: matrix protein
M2: matrix protein (channel)
27
What is the structure of the viral RNP?
-ve sense ssRNA
Protein
3 polymerase subunits
28
What is the structure of HA?
Trimer
| Head with a binding pocket for Sialic acid
29
What is the structure of NA?
Tetramer
30
What is different about the different subtypes of Type A influenza?
What is the same?
Same: internal proteins
Different: HA and NA
31
How many subtypes of HA are there?
16
32
How many subtypes of NA are there?
9
33
What is an influenza subtype?
eg. H1N1
34
What is the ancestral host of influenza A?
Aquatic birds
All subtypes are endemic in birds
35
Which other animals can be infected by influenza?
Pigs
| Horses etc.
36
Which subtypes of influenza are currently in the human population?
H1N1
| H3N2
37
How are influenza viruses named?
```
Type
Place of isolation
Isolate number at that place
Year of isolation
Subtype
```
38
Describe the replication cycle of influenza virus
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
39
What allows the viral membrane to fuse with the endosomal membrane, so that the RNPs are released into the cytosol?
Tryptase clara must cleave one amino acid on HA
HA can now change conformation in the low pH conditions of the endosome → fusion
40
What produces Typtase clara?
| Where?
Clara cells
In the small airways (bronchioles)
41
Why does influenza only infect cells of the respiratory tract?
Needs Typtase clara action to be able to get out of the endosome
Clara cells are only found in the respiratory tract
42
What is the structure of a collectin?
Protein
43
What is the function of collectins?
They bind to carbohydrate side chains of HA and NA
This prevents the influenza from binding to the host cell
44
How do collectins interact with the complement cascade?
Collectin binding triggers the lectin pathway
→ opsonisation
→ MAC in infected cells
45
What are the early innate defences against Influenza?
Collectin binding
46
What are the late innate defences against influenza?
```
Viral infection triggers:
IFN-a
IFN-B
IL-1
IL-6
TNF-a
```
Inflammation
Viral immunity
47
What are the type 1 interferons?
IFN-alpha
| IFN-beta
48
What are the roles of type 1 interferon?
* binds to uninfected cells → antiviral function of cell, so it is protected from infection
* induction of NKs
* Upregulation of MHC I
49
Which cells release the cytokines in the anti-viral inflammatory response?
Why?
When viruses are taken up by macrophages and DCs, they start to produce all these cytokines
50
Describe the function of NK cells
1. Recognise virally infected cells through receptors that recognise 'stress' (decreased MHC I expression)
2. Release toxic granules → apoptosis
51
Are NK cells enough to clear a viral infection?
No, it just keeps the infection in check
To clear the virus we need an adaptive IR
52
In general, how does the adaptive immune response fight influenza infection?
CD8+ cells:
• kill virally infected cells
• recognition of internal antigens
Antibody:
• against HA and NA
53
Are CD8+ cells cross-reactive between Influenza types A and B?
Why / why not?
No, however, they are cross-reactive between subtypes.
CD8+ cells recognise internal proteins, which are conserved between influenza subtypes
54
Are the antibody and CD8+ cell response against influenza long lasting?
Antibody: lifelong
CD8+ cell: not long lived (can be boosted by repeat exposure)
55
If our antibodies against HA and NA are lifelong, why do we get continual infection with influenza?
Antigenic drift
56
Describe the mechanism of antigenic drift
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
How many antigenic sites are there on HA?
5
58
Where does neutralising Ab bind to HA?
The 5 antigenic sites surrounding the receptor binding pocket
59
In general, when does an epidemic of influenza come about?
When all 5 antigenic sites mutate
| The population has no pre-existing antibodies to this strain
60
Antigenic drift brings about new viral ...
Strains within a subtype
61
Evolution of influenza is a ... process
Linear
62
Why is evolution of influenza described as linear?
Once a new strain is created through mutation, it replaces all older strains
63
Describe the evolution of the H3 subtype
From 1968 to 1987, there were mutation at the five sites, such that the globular head became completely different
64
When is influenza present in the population?
Throughout the year
In winter, however, there are peaks
65
How often do we see epidemics of seasonal influenza?
Every 2-3 years
66
Why is surveillance of influenza important?
* 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
Why is rapid diagnosis important?
Rapid anti-viral therapy
68
What are the three groups of lab diagnosis?
| What is the time frame for each?
Rapid: hours
Culture: days
Detection of antibody responses: days-weeks
69
How is rapid diagnosis of influenza performed?
Reverse transcriptase - PCR
'X/pect' test for antigen
70
What does rapid diagnosis tell us?
Type A vs. Type B
71
What does culture tell us?
Subtype and strain analysis
72
How is culture analysis performed?
Embryonated eggs with specific reference antibodies
Haemagglutination-inhibtiion test
73
Why do we detect for antibody responses?
To evaluate the success of a vaccine
74
How do we detect for antibody responses?
Haemagglutination-inhibition test with patient's serum + virus
75
Describe the process of the Haemagglutination-inhibtion test
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
Differentiate between a positive H-I test and a negative
Antibodies present: no agglutination, button
No Ab: agglutination, no button
77
How does the H-I assay let us subtype the virus?
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
What are the antibody targets of the H-I test?
HA and NA
79
Which types of influenza viruses are contained in the influenza vaccine?
Type A:
• H1N1
• H3N2
Type B
80
How in the influenza vaccine administered?
Intramuscularly
81
Which people are strongly advised to get the influenza vaccine?
```
Elderly
Young
Chronic heart, lung, kidney disease
Cancer / diabetes sufferes
Immunosuppressed
Health workers
```
82
How is the influenza vaccine made?
Viruses are grown in eggs
Purification
Chemical inactivation
83
Who can't take the influenza vaccine?
People with egg allergies
84
What type of vaccine is the influenza vaccine?
Split virus vaccine
85
Which responses are induced by the influenza vaccine?
Why?
B cell
CD4+ cell
No CD8+ cell response
This is because it is a inactivated virus
86
Does the influenza vaccine work well?
Young and healthy: 70%
Elderly: less
87
Why must the vaccine be made again every year?
Because there are new strains every year due to antigenic drift
88
What are the targets of antiviral drugs?
* M2 ion channels
| * Neuraminidase
89
Describe how M2 ion channels work
How is this targeted by an antiviral drug?
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
What are some examples of M2 ion channel blockers?
Amantadine
| Rimantadine
91
Which types of influenza are susceptible to M2 ion channel blockers?
Type A
92
Are M2 ion channel blocker widely used?
| Why / why not?
They are not widely used
Because drug resistant variants readily arise
93
What are some antivirals that block neuraminidase?
Relenza (zamamivir)
| Tamiflu (oseltamivir)
94
Which types of influenza are susceptible to neuraminidase inhibitors?
Types A and B
95
What is the result of administering neuriminidase inhibitors?
Reduction in severity and duration
96
How is Relenza administered?
Inhalation by mouth
97
How is Tamiflu administered?
Oral prodrug
98
Describe how neuraminidase inhibitors work
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
For how many days is one infectious?
5-6 days
100
Describe the bond between Sialic acid and HA
alpha 2-6 galactose on Sialic acid
+
HA
101
Which bacteria may cause secondary bacterial pneumonia?
Strep. pneumoniae
H. influenzae
Staph. aureus
102
Describe the structure of the Influenza virion
```
8 RNPs
M1: matrix
M2: ion channel
Envelope
Glycoproteins: HA, NA
```
103
Describe the symmetry of Influenzavirus
Helical symmetry
104
Describe how the virion acquires its glycoproteins on its envelope
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
What is one way that you could describe collectins?
Soluble PRR:
| • bind PAMPs
106
Describe the stages of immune response to influenza
1. Innate early
• Collectins
```
2. Innate, delayed
• PAMP-PRR → DC activation
• IFN release
• Inflammatory cytokine release
• NK activation
```
3. Adaptive
• B cells produce antibodies
• CD8+ T cells kill infected cells
107
Describe cross reactivity of CD8+ T cells
Recognise internal antigens
Thus, broadly cross-reactive within a type
However, not crossreactive between types
108
Describe the role of antibody in the immune response to influenza.
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
Where are the 'advantageous' mutations occurring during antigenic drift?
At the Antigenic Sites:
| • (sites on HA and NA where antibodies bind)
