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Virology > Lecture 9: Influenza Viruses > Flashcards

Lecture 9: Influenza Viruses Flashcards

1
Q

influenza virus structure

A
  • Enveloped particles, quasi-spherical or filamentous
  • envelope is derived from host membrane by budding
  • segmented genome
  • Compact helical nucleocapsids
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2
Q

influenza virus types

A
  • A: is most common to infect humans
  • type A-D
  • Multiple subtypes within each virus type distinguished by variations in the surface glycoproteins –hemagglutinin (HA) and neuraminidase (NA)
  • Myxoviruses split into paramyxo and orthomyxo, with different structure and replication cycles
  • Orthomyxoviridae have two
    additional genera:
  • Thogotovirus (transmitted by
    ticks)
  • Isavirus (infects fish,
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3
Q

influenza virus infections of the respiratory tract

A
  • can lead to secondary bacterial infections (e.g. pneumonia) by providing easier access
  • causes a loss of the ciliated epithelium and disrupts mucociliary flow (flow of mucus and debris along the epithelial lining of the respiratory tract)
  • gets moved by cilia on epithelial cells
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4
Q

influenza virus genome

A
  • Segmented negative sense ssRNA genome (6-8 different segments)
  • multiple helical nucleocapsids
  • each of the segments needs to be present for virus to be packaged correctly
  • contains ssNCR = Segment specific
    non-coding region on each gene
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5
Q

Segment 1 protein function (influenza genome)

A
  • binds to cap structures on cellular pre-mNAs
  • part of transcriptase complex
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6
Q

Segment 2 protein function (influenza genome)

A
  • cleaves cellular pre-mRNAs to create primer
  • RNA polymerase activity for transcription and replication
  • enhances apoptis in immune cells
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7
Q

Segment 3 protein function (influenza genome)

A
  • part of transcription and replication complexes
  • exact role unknown
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8
Q

Segment 4 protein function (influenza genome)

A
  • hemagglutinin:
  • major surface glycoprotein
  • receptor binding
  • mediates membrane fusion at low pH
  • antigenic determinant
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9
Q

Segment 5 protein function (influenza genome)

A
  • nucleocapsid protein
  • binds to and encapsidates viral RNA
  • control functions in RNA synthesis
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10
Q

Segment 6 protein function (influenza genome)

A
  • neuraminidase:
  • major surface glycoprotein
  • receptor destruction
  • dissociation of virus aggregates
  • antigenic determinant
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11
Q

Segment 7 protein function (influenza genome)

A
  • matrix protein: interacts with envelope, nucleocapsids and NS2
  • integral membrane protein: ion channel activity essential for virus uncoating and maturation
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12
Q

Segment 8 protein function (influenza genome)

A
  • nonstructural protein that down-regulates host cell mRNA processing
  • nonstructural protein that directs nuclear export of viral nucleocapsids
  • interacts with M1
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13
Q

influenza virus proteins

A
  • 8 of the influenza virus genome segments code for a total of 11 different viral proteins (alternative splicing)
  • 9 of the proteins are packaged into viral particles
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14
Q

Uni-12 and Uni-13

A
  • highly conserved sequences
    (universal primers) that are
    self-complementary
  • could act as primer for various polymerases
  • helps genome interact with proteins and packaging of genome
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15
Q

genome segments 1- 6

A
  • each encode for a single protein: three are RNA polymerase subunits (PA, PB1, PB2), envelope glycoprotein HA, neuraminidase (NA)
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16
Q

genome segments 7 and 8

A
  • Alternate splicing can occur in mRNA transcribed
  • yields different proteins
    Segment 7:
  • Matrix protein M1
  • Envelope protein M2
    Segment 8:
  • Non-structural proteins NS1 and NS2
17
Q

Viral hemagglutinin (HA)

A
  • binds to cell surface receptors and
    mediates fusion with endosome
  • binds to sialic acid residues on cell surface receptors of
    various cell types (muco-proteins)
  • forms trimers on virus surface mediate fusion of viral envelope
    with the endosomal membrane
  • N-terminal is exposed to the outside of the virion with a hydrophobic transmembrane domain near the C-terminal
18
Q

what facilitates membrane fusion for influenza viruses?

A
  1. activation by cleavage by cellular proteases (cellular furin or trypsin)
  2. conformational changes after acidification in endosome
19
Q

activation by cleavage by cellular proteases (cellular furin or trypsin) (membrane fusion)

A

Cleavage of HA by cellular proteases into 2 subunits:
- HA1 is the surface subunit, binds to sialic acid
- HA2 is anchored in the viral envelope, contains the
hydrophobic fusion peptide

20
Q

conformational changes after acidification in endosome (membrane fusion)

A
  • viral protein M2 forms an ion channel that facilitates release of nucleocapsids from the virion
  • allows protons to enter the interior of the virus (virus acidification)
    weakening the interaction of M1 (matrix protein) with the nucleocapsids
21
Q

M2 protein and membrane fusion

A
  • relatively small protein
  • forms a tetramer
  • creates a small pore in envelope
  • External N-terminal domain, a transmembrane domain and a larger internal domain (base)
  • Tryptophan (W41) ‘gate’ is locked through molecular interaction with Asp (D44), stays closed until right conditions
  • opened by addition of proton to a histidine residue (H37)
  • causes conformational change, then H+ conductance.
22
Q

nuclear entry of the nucleocapsids

A
  • Nucleocapsids enter the nucleus where mRNA synthesis and RNA replication occur
  • NPs wrap the RNA into an unusual twin helical conformation with a central loop
  • also contain a trimer of RNA polymerase proteins: PA, PB1, PB2
  • NPs and RNA polymerase proteins contain nuclear localization signals that interact with cellular importin-α, allows for nuclear entry
23
Q

steps in RNA replication and synthesis

A
  • orthomyxoviruses replicate in the nucleus, complicating the machinery required for viral replication
    1. Import of nucleocapsid into the nucleus through nuclear pore complex
    2. Viral mRNA synthesis
    3. Export of viral RNA and translation in cytosol
    4. and 6. Import of newly synthesized viral proteins (early and late proteins)
    5. Replication to antigenome and genome
    7. Export of new nucleocapsid to the
    cytoplasm
24
Q

primers for synthesis of viral mRNAs

A
  • “cap-stealing” mechanism
  • Capped 5’ ends of cellular pre-mRNAs are used as primers
  • Viral transcription machinery cannot make mRNA on its own, uses cellular premRNAs
  • PB2 recognizes capped cellular pre-mRNA
  • PB1 acts as a nuclease AND polymerase →cleaves bound pre-mRNA at an ‘A’ or ‘G’ 10- 13nt from the 5’ cap and adds complementary
    nt
  • Capped fragment is used as a primer for synthesis of viral mRNAs
25
Q

generation of poly (A) tail

A
  • Each genomic RNA segment contains a stretch of poly-U
  • Viral mRNAs terminate in poly(A) tail
    generated by “stuttering” transcription
  • After reaching poly-U, RNA polymerase pauses and stutters → reads through polyU multiple times → generates poly-A tail
26
Q

what is generated from transcription of influenza viruses?

A
  • set of 8 viral mRNAs:
  • Segments 1-6 are exported directly to cytoplasm
  • Segment 7 and 8 undergo alternative splicing in the nucleus
27
Q

alternative splicing in influenza viruses

A
  • Segment 7 and 8 undergo alternative splicing in the nucleus
  • ratio of unspliced to spliced mRNAs is 9:1
  • Unspliced RNAs yield M1 and NS1 (abundant)
  • Spliced RNAs create M2 and NS2 (less abundant)
28
Q

Amount of NP in nucleus and balance of transcription and replication

A
  • NP binding to growing RNA chains, [NP] drops in the nucleus
  • Drop in [NP]: more mRNA synthesis to make more NP, imported into nucleus
  • Possible mechanism: NP does not bind to capped mRNA with cellular 5’ sequences but does bind to uncapped genome RNA
  • more NP = more replication
  • drop in NP = switch to transcription
29
Q

what does genome replication create?

A
  • ‘+’ strand (antigenome) complexed with NP
  • produces nucleocapsids with antigenome RNA
  • no ‘stuttering’
  • creates full-length copy (mechanism
    poorly understood)
  • copied to genome RNA in a similar mechanism
30
Q

Import of newly synthesized viral proteins (early and late proteins) (RNA replication and synthesis)

A
  • Newly made M1 is imported into nucleus and forms a complex with newly made nucleocapsids
  • NS2 binds to M1
31
Q

Export of new nucleocapsid to the
cytoplasm (RNA replication and synthesis)

A
  • Nucleocapsids are exported from the nucleus in a complex with matrix protein (M1) and NS2
  • NS2 contains a nuclear export signal
  • recognized by exportins
  • export of complexes to cytoplasm
32
Q

influenza virus assembly

A
  • Viral envelope proteins transverse through ER and Golgi to assemble in the plasma membrane and direct
    budding of virions
  • HA, NA, M2 are directed to plasma membrane via Golgi network and accumulate in lipid raft
  • Cytoplasmic tails of HA, NA and M2 interact with M1 that is on nucleocapsids
  • Viral proteins recognize and interact with specific RNA sequences in the nucleocapsid and become packaged in the virion
  • one copy of each genome segment is packaged
33
Q

influenza virus release

A
  • budding occurs
  • Neuraminidase (NA) cleaves sialic acid, the cellular receptor that binds to viral HA
  • interaction of ribonucleocapsids with HN and HA proteins form a bud at the cell surface
  • bud grows with HA protenis gatherings in the tubule part
  • M2 depolarizes the membrane, s involved in ‘pinching’ the budding virions from the plasma membrane
34
Q

Influenza A virus subtypes

A
  • divided into subtypes based on HA and NA proteins
  • 18 subtypes of HA (HA 1 → HA
    18)
  • 11 subtypes of NA (NA 1-→ NA 11)
  • Most subtype combinations infect birds, two subtypes circulate between humans (H1N1 and H3N2)
35
Q

Influenza B virus subtypes

A

not divided into subtypes

36
Q

antigenic change

A

prevents lifetime immunity and can occur in two ways:
1. Antigenic drift
2. Antigenic shift

37
Q

antigenic drift

A

slow, continuous accumulation of (point) mutations (mutation of single nucleotide)

38
Q

antigenic shift

A
  • reassortment (exchange) of genes
    during a mixed infection with two or
    more subtypes
  • genome segments can combine
  • potentially create a new subtype that has a potential for pandemics
  • can increase or decrease pathogenesis depending on combination

Virology (16 decks)

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