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+ MICB 202 Final > Virology Chapter 7-9: Orthomyxoviruses (Influenza) > Flashcards

Virology Chapter 7-9: Orthomyxoviruses (Influenza) Flashcards

1
Q

What type of genome do orthomyxoviruses have?

A

segmented (-) single-standed RNA genome

composed of 8 molecules

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2
Q

Which type of influenza causes pandemics?

A

influenza A

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3
Q

How are influenza viruses transmitted?

A

respiratory route

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4
Q

What is the structure of the virus particle?

A
  • enveloped (lipid bilayer)
  • viral glycoproteins embedded in membrane – spike proteins
  • helical
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5
Q

What are the two types of glycoproteins in virus’ envelope?

A
  • hemagglutinin (H)

- neuraminidase (N)

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6
Q

How does replication cycle begin?

A

virus attaches to sialic acid found on host cell glycoproteins

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7
Q

What does neuraminidase (N) do?

A

virus uses it to detach from host cell by digesting the sialic acid after replication cycle is complete

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8
Q

What are the two other important envelope proteins?

A
  • M2

- M1 (lines inside of envelope)

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9
Q

What does the M2 envelope protein do?

A

ion channel that allows protons (H+) to enter into interior of virus particle

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10
Q

What does the M1 envelope protein do?

A

allow nucleocapsid, envelope, and glycoproteins to assemble correctly during late stages of replication cycle

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11
Q

What is important in the releasing of virus’ genome from M1 protein at the early stages of the replication cycle?

A

acidification process

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12
Q

What is the structure of the virus particle genome?

A

10 genes distributed on 8 pieces of (-) RNA molecules

(two pieces encode two proteins)

each segment is replicated and transcribed independently

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13
Q

What does each RNP (segment of the influenza genome) consist of?

A
  • (-) RNA
  • coated with nucleoproteins (NP)
  • RDRP complex (PA, PB1, and PB2)
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14
Q

What are the segments of the influenza genome called?

A

ribonucleoproteins (RNPs)

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15
Q

How are influenza A viruses classified by subtype?

A

based on properties of their H and N surface proteins

  • 18 different H subtypes
  • 11 different N subtypes
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16
Q

How are influenza viruses named?

A

human origin:

  1. virus type
  2. geographic site where it was first isolated
  3. strain number
  4. year of isolation
  5. virus subtype (for A viruses only)

ie. seasonal influenza A (H3N2) = A/Perth/16/2019

non-human origin:

  1. virus type
  2. species of host
  3. geographic site where it was first isolated
  4. strain number
  5. year of isolation
  6. virus subtype (for A viruses only)

ie. avian influenza A (H1N1) = A/duck/Alberta/35/7

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17
Q

Who does influenza A infect?

A

humans, animals, and birds

pigs and birds are particularly important reservoirs

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18
Q

What is the host cell receptor for influenza? Where can it be found?

A

sialic acid (N-acetylneuraminic acid)

  • cell surfaces
  • mucus
  • URT in mammals
  • usually GI tract in domestic and wild birds
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19
Q

Why is the natural environment for influenza virus in the URT for mammals?

A

virus is dependent on protease (tryptase Clara) in respiratory secretions to activate H protein so that virus can release its genome into the cell

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20
Q

What is the anti-receptor for influenza virus?

A

hemagglutinin (H)

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21
Q

What does RDRP do?

A
  • degrade host cell mRNA
  • reserve 5’ cap to use as primer for synthesis of viral mRNA
  • can adopt a second conformation that allows it to synthesize full length (+) RNA to be used as template for synthesis of RNA for genome of progeny virus
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22
Q

Where do influenza viruses replicate?

A

epithelial cells of entire respiratory tract

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23
Q

What destroys cells lining the respiratory tract?

A
  • virus replication

- immune response to infection

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24
Q

What causes the symptoms associated with URT infections?

A
  • epithelial damage

- cytokines produced during immune response to virus

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25
Q

What can cause pneumonia?

A
  • influenza virus – especially if it infects alveolar epithelia
  • secondary infection caused by bacteria of microbiota
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26
Q

How can new influenza strains arise?

A

change in genes encoding H and/or N proteins by:

  • antigenic drift
  • antigenic shift
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27
Q

What is antigenic drift?

A

minor changes in H and/or N glycoproteins due to accumulation of changes in amino acid sequence

results in minor antigenic differences

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28
Q

During antigenic drift, what are the changes in H and/or N proteins?

A

mutations (base-substitutions) caused by viral RDRP

  • unlike DNA polymerases, RNA polymerases do not have proof-reading function, therefore have higher rates of mutation
  • changes result in H and N that are immunologically similar to previous strain, therefore existing antibodies MIGHT still be effective at neutralizing the virus
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29
Q

What is the result of antigenic shift?

A

new virus strain with novel H and/or N proteins that are immunologically distinct (existing antibodies will not be able to neutralize the virus)

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30
Q

During antigenic shift, what causes the changes in H and/or N proteins?

A

arise from the genetic re-assortment of previously circulating human and animal Influenza viruses

  • H and N are encoded on different RNA segments of Influenza genome
  • if host cell is infected with two different influenza viruses (simultaneously), there can be a high frequency of re-assortment, producing different combinations of H and N variants
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31
Q

How is antigenic shift possible in influenza virus?

A

influenza virus’ genome is segmented

32
Q

When does influenza A undergo antigenic drift and antigenic shift?

A

antigenic drift: continuously – accounts for most of the changes between flu seasons

antigenic shift: occasionally – accounts for major pandemics
- after a new pandemic influenza strain has evolved, it may undergo antigenic drift and evolve into a seasonal influenza strain

33
Q

Antigenic Shift, then Drift

A
  • after re-assortment process has occurred, if virus became established in humans, virus would begin to drift like any other seasonal influenza virus
  • during drift, small antigenic changes in H protein generated by mutation are selected to increase immune evasion of virus particle
34
Q

What are asymptomatic reservoirs of influenza viruses?

A

ducks and other water birds

35
Q

How are pigs susceptible to both human and avian influenza viruses?

A

respiratory epithelial cells of pigs have receptors that express both types of sialic acid moieties that pigs and humans differently carry

  • dual infections can occur and re-assortment of gene segments can give rise to new strains
  • pigs are therefore a mixing bowl for generation of new strains of influenza viruses
  • new strains can be transmitted back to humans
36
Q

What is used for influenza control and prevention?

A
  • antiviral drugs

- vaccines

37
Q

What are plug drugs?

A

antivirals that block active site of N protein – without this site, virus is unable to cleave sialic acid and escape from cell to infect a new host

ie. Zanamivir and Oseltamivir – sialic acid analogues

38
Q

What are ion channel inhibitors?

A

antivirals that block release of influenza virus genome into cytoplasm by affecting M2 ion channel

ie. Amantadine and Rimantadine

39
Q

How are new vaccines produced?

A

by genetic re-assortment to produce a strain with the desired H antigen

  • cell cultures can be used
  • recombinant DNA technology can be used
40
Q

What type of vaccine do pharmaceutical companies often create?

A

trivalent vaccine

  • two influenza A strains
  • one influenza B strain
41
Q

What are the current vaccines being used?

A
  • whole virus (WV) vaccine – contains intact but inactivated virus
  • subvirion (SV) vaccine – contains isolated envelope portion of virus
  • surface antigen (SA) vaccines – contain isolated H and N glycoproteins
42
Q

Describe the secondary response to influenza infections.

A
  • B cells that recognize H or N antigens will become activated and differentiate into memory B cells
  • upon re-infection with same Influenza strain, secondary response generates lots of anti-H and anti-N antibodies
  • anti-H antibodies are particularly important because they bind to H protein and neutralize virus before it can bind to host cell
43
Q

Why would antibodies against the H protein be more effective at neutralizing the influenza virus than antibodies against the N protein?

A
  • H protein extends out of virus particle more than N protein (it is taller)
  • 5x more copies of H protein than N protein
  • H protein is what virus uses to attach to cells, so antibodies against H would stop virus from binding to cell surface
44
Q

Where do influenza viruses replicate?

A

host cell nucleus

45
Q

Can the host cell RNA polymerase read the virus’ genome template?

A

no – viruses must package their own RNA polymerases, and have genes that encode them

46
Q

Where does assembly of the virus particle start and end?

A

starts wth assembly of RNPs in the nucleus

ends in cytoplasm, near plasma membrane of the cell

47
Q

Attachment of Virus Particle and Entry of Virus Genome

Describe the interaction between the virus particle and the receptor sialic acid (SA) on mucoproteins of epithelial cells.

A

initially, interaction is of low affinity

however, there is high avidity because of multiple low affinity interactions

48
Q

Attachment of Virus Particle and Entry of Virus Genome

How does influenza virus enter the epithelial cell?

A

receptor-mediated endocytosis

49
Q

Attachment of Virus Particle and Entry of Virus Genome

What occurs prior to receptor-mediated endocytosis of the virus particle? Why?

A
  • virus’ H proteins (H, H0) are modified by cleavage by protease tryptase Clara
  • cleavage of H0 to H1 and H2 is necessary for full infectivity of the virus
  • H1 binds to SA on mucoprotein
  • H2 remains integrated in envelope bilayer
50
Q

Attachment of Virus Particle and Entry of Virus Genome

What does the N terminal portion of H2 have?

A

fusion peptide

critical for subsequent fusion events of the endosome membrane and virus’ envelope

51
Q

Attachment of Virus Particle and Entry of Virus Genome – Process

A
  1. Virus particle binds to sialic acid on mucoproteins
  2. Virus’ H proteins (H, H0) are modified by cleavage by protease tryptase Clara
  • H0 is cleaved into H1 and H2
  • H1 binds to SA on mucoprotein
  • H2 remains integrated in envelope bilayer
  1. Receptor-mediated endocytosis
  2. Endosome is acidified, resulting in conformation change in H protein
  3. Fusion peptide (of H2) is inserted into endosome membrane
  4. Two lipid bilayer structures (endosome membrane and virus envelope) fuse together
  5. Virus’ genome is released into cell cytoplasm
  6. Interior of virus particle is acidified by movement of protons through M2 channel in envelope
  7. RNPs are released from M1 protein lining inside virus envelope, and enter nucleus through nuclear pore
52
Q

Attachment of Virus Particle and Entry of Virus Genome

What does NP do?

A
  • have special targeting sequence that gets genome into nucleus
  • protect genome from RNA nucleases
53
Q

Transcription of Genome – Process

A
  1. Influenza RNA polymerase complex anchors 5’ end of genomic (-) strand RNA
    - 5’ end of viral RNA template is not released during transcription
  2. Cap-stealing to obtain primer for RNA polymerase complex
  3. Synthesis of (+) strand RNA using (-) strand as template by adding the complementary nucleotides to cap/host cell derived nucleotides – start from 3’ end
  4. Near end of transcription (5’ end of (-) RNA template), polyadenylation sequence is read multiple times by RNA polymerase (stutters) – polyA tail formed
54
Q

Transcription of Genome

What is used as the template?

A

(-) strand of RNA is used as the template by viral RNA polymerase complex to synthesize mRNA

55
Q

Transcription of Genome

What is the primer for the influenza RNA polymerase complex?

A

cap-stealing

  • RNA polymerase binds to host cell mRNA molecule near 5’ end, and uses its endonuclease to cleave 5’ cap from mRNA
  • rest of the host cell mRNA is released
56
Q

Transcription of Genome

What are two distinct advantages of cap-stealing to synthesize viral mRNA?

A
  • mRNA that is produced has many features of a cellular mRNA (5’ methylated cap, polyA tail) that enable it to bind to, and be translated by, cell’s ribosomes
  • host cell mRNA is degraded, and competition for ribosomes has been eliminated
57
Q

Transcription of Genome

Why is the mRNA produced called the incomplete (+) strand? Why is it incomplete?

A

entire sequence of genomic (-) RNA is NOT copied into mRNA

  • mRNA is incomplete because of “panhandle” structure that is formed when complex anchors to 5’ end of viral (-) strand RNA
  • results in the last 15–22 nucleotides of (-) RNA not being copied into mRNA
58
Q

Translation: Synthesis of Virus Proteins

Where does translation occur?

A

cytoplasm

59
Q

Translation: Synthesis of Virus Proteins

What do ribosomes bound to ER translate?

A

viral mRNAs that specify viral envelope proteins

60
Q

Translation: Synthesis of Virus Proteins

What do cytoplasmic ribosomes translate?

A

all other mRNAs – not those that encode envelope proteins

61
Q

Translation: Synthesis of Virus Proteins

Which synthesized proteins return to the nucleus? Why?

A

PA, PB1, PB2, and NP proteins

initiate replication of genome and assembly of virus particle

catalyze synthesis of genomes for progeny virus in the nucleus

62
Q

Translation: Synthesis of Virus Proteins

How do PA, PB1, PB2, and NP proteins catalyze synthesis of genomes for progeny virus?

A

(in the nucleus)
both strands are synthesized in the form of nucleocapsids

  1. catalyze synthesis of full-size (+) RNAs
    - anti-genomic RNA – used as template for making (-) RNA
  2. catalyze synthesis of (-) RNAs
    - genomic RNA – used as nucleic acid for progeny viruses
63
Q

Replication of Genome

What is the purpose of this round of RNA synthesis?

A

create (+) strand of RNA that will be used as a template for synthesis of (-) strand RNA for virus progeny

64
Q

Replication of Genome

What does the process require?

A

RNA polymerase complex – to copy (-) strand to (+) strand

*no primer – no cap-stealing

65
Q

Replication of Genome

What does the amount of free NP protein molecules in the cell regulate?

A

switch to production of full-sized (+) RNA

66
Q

Replication of Genome – Process

A
  1. RNA polymerase complex binds to leader sequence on encapsidated (-) RNA genome to start replication
  2. (+) RNA (antigenome) is coated with NP during replication
  3. (+) RNA is replicated under same process
    - RNA polymerase complex binds to trailer sequence first
67
Q

Virus Assembly and Genome Packaging

What can be used as template for synthesis of additional viral mRNA?

A

newly made (-) strand RNA

68
Q

Virus Assembly and Genome Packaging

What stops viral mRNA synthesis?

A

binding of M1 to newly synthesized (-) strand RNA, which then induces export of progeny nucleocapsids into cytoplasm

69
Q

Virus Assembly and Genome Packaging – Process

A
  1. M1 binds to (-) strand RNA to stop viral mRNA synthesis
  2. Progeny nucleocapsids are exported to cytoplasm
  3. H and N proteins (synthesized by ER ribosomes) are transported to cell surface, and become incorporated into plasma membrane of the cell
  4. H and N drive formation of bud at plasma membrane
  5. M1 associates with cytoplasmic tails of H and N proteins
  6. M1 recruits virion RNPs and M2 to site of virus assembly
  7. (-) strands of RNA are packaged into virus progeny
70
Q

Virus Assembly and Genome Packaging

Which strand of RNA is packaged into virus progeny?

A

(-) strands

even though (+) strands are also associated with NP

71
Q

Virus Assembly and Genome Packaging

What are the two models for packaging of the segmented influenza genome?

A
  • random model: virus acquires complete genome purely through chance – no mechanism to distinguish between different genome segments, therefore more than 8 RNPs may be packaged so that virion has at least one copy of each segment (complete genome)
  • specific packaging model: mechanism ensures that only one copy of each different segment is specifically selected during viral assembly
72
Q

Virus Egress – Process

A
  1. New virus buds from plasma membrane
    - host cell membrane proteins appear to be excluded from virus particle
  2. M2 protein promotes membrane fission, resulting in detachment or released of virus bud
  3. N protein removes SA so that virus particle can be freed from the cell
    - ensures virus particle won’t reinfect same cell
73
Q

Transcription of Genome

What is the purpose of the “cap stealing” that occurs during the replication of influenza virus?

A
  • RDRP cannot synthesize (+) RNA for mRNA without primer
  • without cap-stealing, it is unable to interact with host ribosomes
  • eliminates competition with host cell mRNA for translation on ribosomes (because it destroys competition)
74
Q

Influenza Replication – Overview

A

attachment of virus particle → entry of virus genome → transcription of (-) genome → translation (synthesis of virus proteins) → replication of genome (- strand to + strand)

75
Q

Depending on what stage the infection is in, can produce two different replication products. How does the switch occur?

A
  1. Initial type is incomplete – part of genomic RNA is not replicated
  • incomplete unit is used in translation for protein synthesis
  • viral RNA polymerase requires primer – virus uses host 5’ caps taken from host cell mRNA (cap stealing)
  1. when a specific threshold of NP has been reached, viral RNA
    polymerase alters activity
  • virus stops using host 5’ caps as primer, and begins to replicate whole viral RNA unit
  • using (+) sense RNA as template, many full sized (-) sense RNA segments are made and packaged into the assembling influenza viruses

+ MICB 202 Final (20 decks)

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