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Virology > Influenza > Flashcards

Influenza Flashcards

0
Q

What is the difference between influenza A, B and C?

A

C only has 7 segments whereas A and B have 8.
Influenza A nearly always infects humans and nearly all mammals and avian species.
All cause severe disease but only A has caused pandemics.

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1
Q

What type of virus is influenza?

A

A negative strand, segmented, orthomyxoviridae, RNA virus.

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2
Q

Describe the exterior morphology of influenza?

A

80-120 nm in diameter pleomorphic virus particles, with outer membrane derived from the host cell.
3 membrane proteins; NA, HA and M2. All tetrameric a part from HA which is a trimer.

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3
Q

Give the segment number and name for each segment?

A

1: PB1
2: PB2
3: PA
4: HA
5: NP
6: NA
7: M
8: NS

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4
Q

What is the arrangement of the 8 segments?

A

7+1 conformation.

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5
Q

What is the definition of negative and positive sense strands?

A

Negative: complimentary to the positive strand and required transcription to positive strand RNA I’m order to code for a protein.
Positive: has the ability to code for a protein.

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6
Q

What happens to the RNA segments?

A

They are linear strands that become highly structured through RNA and protein interactions- terminal RNA interactions and the genome is wrapped in a protein called nucleoprotein (NP).
NP has the ability to bind RNA and the ability to bind itself.
The RNA backbone binds via positively charged residues.

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7
Q

What is the coding compactly of the 8 segments?

A

1: PB1- RdRp
2: PB2- RdRp
3: PA- RdRp
4: HA- hemagglutinin
5: NP- nucleocapsid protein
6: NA- Neuraminidase
7: M- Matrix protein
8: NS- non structural proteins

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8
Q

What is also made during infection?

A

Additional accessory proteins

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9
Q

What are the 8 steps of the influenza life cycle?

A
  1. Virus binds sialic acid receptor via HA and is internalised.
  2. Low pH induced membrane fusion via HA.
  3. Segments released into the cytoplasm.
  4. Segments imported into nucleus.
  5. RNA synthesis.
  6. RNA/RNP export.
  7. Virus assembly at plasma membrane.
  8. Release.
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10
Q

What mediates binding to sialic acid receptors?

A

HA, encoded by segment 4, initially synthesis as HA0 in cells and HA assembles into a trimer. HA0 is cleaved to HA1 and HA2 by an intra/extra- cellular protease, HA1 forms the globular head and HA2 forms the long stable stem via a 6 helix bundle. The binding site is on the globular head.

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11
Q

Describe the binding via sialic acid?

A

Sialic acid is linked to galactose in two ways alpha 2-6 (mainly human influenza in the respiratory tract) and alpha 2-3 (avian influenzas in the gut).

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12
Q

Describe the second step of the virus life cycle?

A

Membrane fusion to allow for the virus to be released from the endosome and the RNP segments to be released. This process is mediated by the HA proteins and it’s fusion peptide and induced by a low pH.

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13
Q

Describe the action of the fusion peptide?

A

The fusion peptide is buried in the middle of HA0, the HA1/HA2 cleavage event allows it to be positioned at a free polypeptide terminus and be active. The pH5 triggers a conformational change flipping the fusion peptide upwards and inserting it into an endosome membrane. Further pH changes bring the 2 membranes together.

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14
Q

What mediates RNP release?

A

M2 viroporin which allows the influx of protons breaking the matrix layer releasing the segmens.

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15
Q

Can RNP diffuse into the nucleus for RNA synthesis?

A

No, an active process is required. Individual NP molecules have 2 import signals, only NLS1 is exposed on formed RNPs which recruits importin alpha p, recruiting importin beta which together bind nuclear pores allowing RNPs to enter through.

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16
Q

What are the two steps of RNA synthesis?

A

Transcription: negative sense input genome to positive sense mRNA to generate a coding strand for translation.
Translation: positive sense anti-genome to negative sense input genome and vica versa to amplify the number of negative stranded genome segments.

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17
Q

Describe transcription?

A

Negative sense segment to a positive sense mRNA, which is 5’ capped and 3’ poly A tailed, and exported to the cytoplasm.
4 stages:
1) RdRp PB2 binds a cellular mRNA in the nucleus and PA steals it’s 5’ cap
2) RdRp and capped oligonucleotide bind to negative stranded RNA genome
3) RdRp PB1 uses the capped RNA to begin transcription and gets incorporated
4) RdRp moves along the template, PB1 generates a RNA transcript with a 5’ cap and 3’ poly A tail.

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18
Q

After translation what happens to the proteins?

A

Some stay in the cytoplasm for assembly and others are imported by NLS sequences into the nucleus to make RNPs

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19
Q

How are RNPs replicated?

A

Using PB1, PB2, PA and a supply of NP.

1) RdRp binds 3’ end of the RNA segment
2) RdRp travels along the segment 5’ to 3’ generating a complimentary copy
3) NP wraps the RNA as it is made so replication products are RNPs.
4) cycles of replication allow amplification of genomes.

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20
Q

What does RNP export involve?

A

2 viral proteins: M1 and NS2. RNPs associated with multiple M1 in the nucleus NS2 binds M1 via its NLS2 binding site, overriding the import signals with its export signal. This is mediated by CRM1 which binds ran-GTP and exits the nucleus via the pore complex.

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21
Q

Once in the cytoplasm what must the RNPs reach?

A

The apical surface plasma membrane with all three envelope proteins.

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22
Q

Describe how virus assembly occurs?

A

Occurs via interaction of cytoplasmic tails. Segments are selected to ensure one of each, 8 in total, segments are recruited. There are 2 models of assembly: daisy chains and master segment (thought to be a combination of both).

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23
Q

Why is virus release a complex task?

A

HA and the sialic acid receptor are required for further infection however HA on released virus can bind sialic acid on the host cell preventing the virus from spreading. NA is abundant on the virus envelops and can cleave sialic acid from the host cell ensuring the virus infects a new cells.

24
Q

How are influenza isolates named?

A

Subtype/location of first isolation/ number of isolation/ year of first isolation(information of HA and NA proteins)

Eg. A/Californa/04/2009(H1N1)

25
Q

How many HAs and NAs are there?

A

18 HAs, 9 NAs

26
Q

How are the different HAs and NAs distinguished?

A

On the basis of their reactivity with a panel of antibodies

27
Q

Give some facts on different HAs?

A

They have over 30% amino acid difference and they can infect different hosts determined by their sialic acid binding which is either alpha 2-3 or alpha 2-6 and different HA have different affinities for these but most can bind or both.

28
Q

Preferentially what sialic acid linkages will HA bind in a) avian species and b) humans? And what does this achieve?

A

a) alpha 2-3
b) alpha 2-6
A species barrier that protects humans from infection by many avian influenza species.

29
Q

Which two HAs are classed as special cases and why?

A

H5 and H7. They are extraordinarily pathogenic, knows as highly pathogenic avian influenza viruses. They are not restricted to the respiratory tract and can infect endothelial cells and cause ARFS.

30
Q

Describe HAs conserved structure?

A

HA0 is cleaved to give HA1 and HA2, HA1 is the globular head group and HA2 is the stalk C and N-terminus. The C-terminus has a membrane anchor.

31
Q

What are the different between the NAs?

A

Difference in amino acid sequence of 30% which show differences in preferred hosts dependent on their ability to cleave the sialic acid.

32
Q

How is influenza virus transmitted?

A

Virus inhalation via respiratory tract and their intended cell targets ( sneezing 1000000 virus particles per sneeze and 3-20 virus particles per breath) or direct contact of droplets that have settled on surfaces which are then transferred to mucosal cells (direct inoculation).

33
Q

Where does influenza virus target?

A

The respiratory tracts epithelial cells.

34
Q

What are the symptoms of the virus?

A

Tiredness, sore throat, runny nose, headache, fever, cough and muscle aches. All mostly due to hose immune response.

35
Q

How does the disease progress?

A

Rapid onset of symptoms- 24 hours after contact, symptoms peak at day 3 and decline due to activity of innate immune response.

36
Q

What does the timing of flu season depend on?

A

The hemisphere; incidence increase in winter so in the south May-September are peak months and in the north November- March and Equatorial regions have yearly season.

37
Q

What are the possible reasons for seasonal peaks?

A

Sunlight: UV exposure, low temperatures, low relative humidity, social behaviour- indoor overcrowding, national holidays- large gatherings of people.

38
Q

What does the severity of the virus depend on?

A

The virus in question. Seasonal flu is very low severity (0.1% deaths) but the 1918 Spanish flu has 10% deaths.

39
Q

What was the reason behind the severity of the 1918 Spanish flu?

A

It was a H1N1 polygenic virus

40
Q

What is a huge problem with influenza?

A

It can mutate easily by anti genetic drift.

41
Q

What does anti genetic drift require?

A

Depends on two influenza viruses infecting the same cell and re assortment occurring between their segments to produce a virus which has a combination of the two viruses segments.

42
Q

What is the species barrier keeping out of the human population? And why?

A

H5N1, a HPAI. As it has greater specificity for alpha 2-3 over alpha 2-6.

43
Q

How easily can the species barrier overcome?

A

Very! By one or two mutations depending on the HA.

44
Q

What are the three requirements for human to human spread?

A

The ability to enter cells of the human URT.
The ability to replicate to high numbers of URT cells.
The ability to exit cells of the URT.
- currently unable to do any of these, but it is now known to be possible.

45
Q

What two mutations allow an avian H5N1 to enter humans?

A

Q220L and G224S.

46
Q

What mutation is known to alter the peak replication temperature to increase the level of replication?

A

E647K

47
Q

How was a virus with aerosol transmission selected?

A

Experiments with ferrets found that H103Y and T156A mutations were required.

48
Q

What causes differences in pathogenicity?

A

Cleavability of the HA protein. The protease required is only available in the cells of the respiratory tract and this confines most to the respiratory tract. Some HA, such as the one in Spanish flu, are cleaved by proteases found in many cell types- H5 can be cleaved in this way.

49
Q

What system is used to look at new strains each year?

A

Global Influenza Surveillance Response System

50
Q

How was the influenza vaccine traditionally method?

A

Each expected strain is allowed to segment exchange with PR8 through reassortment. A reference strain- seed, is used to infect eggs.

51
Q

What three critical drawbacks does the traditional vaccine production method have?

A

Generation and selection of 3 reassortments is slow, dependence on egg productions, some H5N1 viruses grow poorly in eggs.

52
Q

How does the new method of flu vaccine production differ?

A

8 functional RNPs are made from cDNAs: 4 encoding flu virus proteins required and 8 encoding genome sequences.

53
Q

What are the benefits of the new way to produce vaccines?

A

Allows rapid response to new viruses, should allow a response to the most rapidly emerging pandemic, no issues with egg production, no issue with poor virus growth in eggs, no issue with egg allergy.

54
Q

What are the two current targets for anti-influenza therapeutics?

A

M2 during endosome escape and NA in release.

55
Q

What was the first anti-viral component approved?

A

Amantadine

56
Q

How do Adamantanes work?

A

Low concentration are specific for influenza A and high concentration have more general activity. Administered in early stages of infections. Work by preventing M2 ion channel activity by binding to block or close the pore.

57
Q

What are the problems with Adamantanes?

A

Many human flus are resistant due to mutations in the M2 channel itself. No longer used to treat flu.

58
Q

What drugs were made via structure based drug design?

A

Tamiflu and relenza both target pocket in NA and blocking the active site not allowing for the NA to bind and digest sialic acid which is required for release.

Virology (3 decks)

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