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Yr 2 Sem 1 > Virology > Flashcards

Virology Flashcards

1
Q

What is a virus?

A

Very small obligate intracellular parasite - non living.
Can have either single/double stranded RNA/DNA genomes
Capsid encoding organisms.

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2
Q

How were viruses first distinguished from other microorganisms?

A

1892 Ivanovsky ground up leaf tissue + filtered it -> filtered liquid had agent of disease not the concentrated filtrate

1898 Beijerinck repeated but said filterable agent was not a small bacterium

Electron microscope allowed for x100,000-fold magnification

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3
Q

What does the Baltimore classification scheme demonstrate?

A

7 genome types based on replication strategies - all must make mRNA that can be translated by host ribosomes.

DNA genomes - 2kb ssDNA Circovirus -> 2.8 Mb Pandoravirus

RNA genomes - 1.7kb -ssRNA hepatitis -> 31kb -ssRNA Coronavirus

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4
Q

Escape/progressive hypothesis for viral origins

A

Mobile genetic elements exited one cell + entered another via acquisition of structural protein.
Retrotransposons move via RNA intermediate like retrovirus.

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5
Q

Reduction/regressive hypothesis for viral origins

A

Viruses degenerate so retain genetic info for parasitic way of life -> loss of previously indispensable genes + reduction in genome size

  • obligate intracellular parasites (Chlamydia + Rickettsia bacteria) evolved from free living ancestors, cant make ATP or proteins
  • Mimivirus has relics of genes encoding tRNAs, aminoacyl tRNA synthetase + TFs so previously non-parasitic BUT evidence of horizontal gene transfer
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6
Q

Virus first hypothesis for viral origins

A

Independent entities evolved parallel/before cellular life from self-replicating mols in RNA world BUT all viruses need cellular host for replication

  • 1st replicating mol had RNA not DNA, maybe circular ssRNA of ribozymes could infect first cells
  • complex enveloped DNA virus became resident of emerging eukaryotic cell (endosymbiotic event)
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7
Q

What is the general structure of a virus?

A

Metastable structures (non-covalent bonding)
- extracellular virions stable to protect genome
- intracellular virion must open to release genomic contents

Watson + Crick 1956 EM studies showed rod vs spherical viruses - later helical & icosahedral symmetry.

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8
Q

TMV structure

A

Helical, +ssRNA 6.4 kB, single protein capsid
Each protein subunit binds 3 nucleotides + adjacent subunits, hollow helix w/ pore.

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9
Q

Parvovirus structure

A

60 subunits, very small (18-26nm) - 12 pentons/capsomers at vertices
3 subunits per face in head-head + tail-tail gives rotational symmetry.
T=3

Subunit proteins about 100kDa -> larger viruses need increased subunit number + increase triangulation value.

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10
Q

Triangulation values + icosahedral structure with examples

A

Always 12 pentamers but number of hexamers varies w/ size.

T=1, 20 faces + 60 subunits
T=3, 60 faces + 180 subunits
T=4, 80 faces + 240 subunits

  • Nodamura virus (T=3), coat proteins defined by occupancy of structurally distinct environments.
  • Brome mosaic virus (T=3), pentons + hexons composed of same subunit.
  • Adenovirus (T=25), pentons + hexons composed of different subunit proteins.
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11
Q

What is the role of glycoproteins in membrane bound viruses?

A

Membrane from host cell but studded w/ glycoproteins in bilayer -> most are oligomers
e.g. influenza HA is trimeric

Glycoproteins act as receptors, antigenic determinants + mediators of cell fusion.

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12
Q

Examples of Membrane bound viruses

A

Measles (-ssRNA) helical sym, membrane has HA & fusion protein (F)

Herpes simplex (dsDNA) has icosahedral sym.

Influenza: 8 separate helical nucleocapsids interact w/ ribonuclear proteins -> organise each RNA into helix, further folding by viral P proteins (sequence specific) at 5’ & 3’ end.
Matrix protein holds structure together.
Has HA to bind respiratory epithelial cells + NA enzyme allows exit

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13
Q

What are the requirements for replication to occur in a cell?

A

Susceptible cells have functional receptor for given virus - may or may not support replication (HIV cant infect primate cells)
-> resistant cells have no receptor

Permissive cells can support replication.

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14
Q

What did Ellis & Delbruck develop in 1939?

A

Study of bacteriophages in E.coli. Multiplicity infection (10 phage:1 bacteria) - diluted to prevent further absorption.
Sample taken at intervals, virions counted using plaque assay

-> one step growth curve formulated

Avg burst size is 100 phage from 1 E.coli

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15
Q

What happens in the latent phase of a growth curve?

A

Eclipse - no viral particles detected, uncoating, viruses actively transcribed + replicating, protein synthesis starts

Intracellular accumulation - proteins + viral genome self-assemble into virions that accumulate in cytoplasm-> viruses CAN be detected

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16
Q

What happens in the rise period of a growth curve?

A

Viral particles accumulate to threshold level -> triggers lysis, virions released increasing extracellular phage conc rapidly.

BUT adenovirus bucks trend: membrane bound (needs to acquire membrane so we see extracellular virus before intracellular

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17
Q

Receptors for viral attachment

A

Protein receptors tissue specific - tropism receptors dictate host range

Carb receptors less specific - presence determines cells resistance (co-receptors can be required e.g. HIV)

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18
Q

Polio virus receptor (Pvr)

A

CD122 indentified by transfecting mouse cells w/ human cDNA library.
Polio is pseudo T=3, VP1/VP2/VP3 form subunits of capsid
-> 5 VP1 form 5-fold symmetry axis, penton has canyon in capsid which is recognition site for receptor

1 polio interacts w/ 60 receptors

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19
Q

How does Influenza virus attach to cells?

A

Via a carb receptor - HA binds -ve terminal sialic acid on surface glycoproteins

Human HA binds a2-6 sialic acid, Avian HA binds a2-3 sialic acid. Sialic acid ubiquitous.

Adhesion triggers entry across membranes -> genome injection, membrane fusion, endocytosis (dictated by whether virus enveloped or not).

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20
Q

Methods of entry by naked and enveloped viruses

A

Naked - genome injection (bacteriophages), endocytosis (adenovirus, polio)

Enveloped - plasma membrane fusion (Sendai, HIV), endocytosis followed by endosome membrane fusion (influenza)

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21
Q

Entry into cells via membrane fusion

A

Unique to membrane bound viruses.
e.g. Measles (RNA), Herpes (DNA)

Membranes fuse together emptying virion into cytoplasm - then uncoated to release nucleocapsid.

DNA must translocate to nucleus membrane via filaments to be uncoated.

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22
Q

Receptor mediated endocytosis

A

Used by both membrane bound + naked viruses.

  • Viruses bind receptor + accumulate in clathrin coated pit in membrane.
  • Pit forms enclave which is enclosed by dynamin -> clathrin coated vesicle
  • virus uncoated + released into cytoplasm
  • ligands bound to receptor remain in vesicle (pH~7.0)
  • fuses w/ endosome
  • protons added lowering pH (~6.0) + fuses w/ lysosome to be degraded
  • receptors recycled
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23
Q

Define uncoating in viral replication

A

Releasing of viral genomic material for replication to occur.
Occurs simultaneously w/ entry in measles.

  • DNA viruses complete uncoating at nuclear pore
  • RNA viruses uncoat by fusing w/ plasma membrane/endocytic vesicle membrane -> releasing genome into cytoplasm
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24
Q

How does uncoating work at the plasma membrane?

A

Enveloped RNA only e.g. Paramyxoviridae - Sendai, Measles, Respiratory synctial.

  • HA adheres to surface receptors
  • Fusion of protein F engages + viral/host membrane fuse
  • Viral nucleocapsid (-ssRNA) + viral proteins released into cytoplasm
  • Synthesis of +sense mRNA occurs followed by translation
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25
Q

What are the details of Paramyxoviridae fusion?

A

F protein synthesised as F0 precursor - cleaved to F1 & F2 (connected by disulphide bond) by host cell protease.
- fusion peptide buried between F1 & F2 subunits
- Binding of HN causes conformational change exposing fusion peptide -> highly hydrophobic so embeds in host membrane

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26
Q

How does uncoating via the formation of a pore in the endosome work?

A

Polio binds to PVR (CD155) + conformational change occurs.
- Pocket lipid lost & hydrophobic N termini of VP1 + VP4 displaced to surface so inserts into endosome membrane
- Pore formed which +ssRNA genome bound w/ VPg protein passes through

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27
Q

How does uncoating of the Influenza virus take place? (Stage 1: fusion)

A
  • HA1 binds receptors w/ sialic acid -> endocytosis.
  • Import of H+ ions acidifies endosome causing HA conformational change, reveals fusion peptide in HA2
  • Loop region in HA2 becomes coiled coil, fusion peptides reoriented towards endosome membrane
  • Alpha helices pack down bringing 2 membranes closer together allowing fusion
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28
Q

How does uncoating of the Influenza virus take place? (Stage 2: release of RNA genome segments)

A
  • M2 ion channel homotetramer, forms pore at low pH allowing protons to enter viral capsid
  • drop in pH causes conformational change of M1-> breaks bond which tethers vRNP to M1
  • M1-M1 bonds broken so capsid dissociates
  • release of vRNP reveals nuclear location signals allowing nuclear import
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29
Q

How does uncoating in the cytoplasm by ribosomes work?

A

e.g. Semiliki Forest virus

  • enters via clathrin-dependent endocytosis
  • acidification of endosome triggers fusion of viral + endosome membranes
  • viral nucleocapsid released into cytoplasm but still tethered to cytosolic endosome membrane
  • ribosomes bind nucleocapsid + hydrolyse
  • each ribosome binds 3-6 mols of C protein causing detachment
  • ribosomes bind +ssRNA genome & translation begins (still tethered to membrane)
30
Q

How does uncoating at the nuclear pore work?

A

e.g. stepwise in adenovirus

  • integrin contacts fiber receptor bound to penton -> triggers clathrin mediated endocytosis
  • endosome acidifies, fibres released from virus + penton bases drop off leaving only hexons
  • protein VI causes endosome lysis, embeds in membrane destabilising it
  • binds MTs in host to traffic to nuclear pore
  • hexon proteins interact w/ histone proteins
  • importin-7 + importin-B bind histone H1 -> import of protein into nucleus triggering capsid disassembly

Transportin + protein VII help DNA import

31
Q

Why is nuclear import easier for parvoviruses & hepadnoviruses?

A

Very small so can just enter via nuclear pores.

32
Q

What are the methods of leaving the host cell?

A

Naked viruses - cell lysis

Membrane bound - budding/ exocytosis as need to acquire a membrane from ER/golgi/plasma mem

33
Q

How do naked viruses leave host cells?

A

Normally results in cell lysis:
Adenoviruses + Polio shut down production of cellular proteins. Polio alters membrane permeability.
Bacteriophage release cytolytic molecules.

  • large quantities of virions accumulate prior to release
34
Q

Describe how Polio induces lysis

A

Shuts down protein synthesis:
- eIF4F which binds 5’-7-methyl guanosine CAP is cleaved by viral protease 2A (encoded by P2)
- eIF4G subunit lost from IF complex preventing cellular RNA from binding ribosomes

Alters membrane permeability of host cells -> 2Bpro is tetramer of 99aa peptide, forms pores in membrane -> lysis

35
Q

What does the Polio virus genome consist of?

A

Polio genome (T=3)

  • P1 encodes capsid units
  • P2 encodes proteins for interaction w/ the host (e.g. protease 2A)
  • P3 encodes proteins which participate in genome replication
  • IRES (internal ribosome entry site) 500bp allows ribosome binding + translation
36
Q

Describe how Polio can induce its non-lytic release in the GI tract

A
  • upon replication in polarised epithelial cells, only released from apical surface
  • virions enclosed in autophagosome vesicles (formed by 2BC & 3A proteins from Golgi membranes) - happens during late infection
  • fusion of vesicle w/ mem -> non-destructive from cell
37
Q

Where do various enveloped viruses acquire their membrane from?

A

Exocytosis - via budding

Envelope acquired from plasma membrane (influenza) or internal membranes of secretory pathway (herpes)

Can (rhabdovirus, paramyxovirus, togavirus) or can not (retrovirus) cause cell death.

38
Q

How does exocytosis take place for the influenza virus?

A

Acquires membrane from host cell membrane. Viral membrane studded w/ proteins: HA, NA + M2.
Proteins synthesised & delivered via secretory systems:
- synthesis + co-translational membrane insertion into ER
- glycosylation stars in rER + continues in Golgi - glycoproteins transported to membrane via vesicle

Virus w/ nucleocapsid migrates to virus modified membrane + buds off to form free infectious virus.

** matrix, capsid + replication enzymes synthesised by free ribosomes vs viral mem proteins translated on ribosomes associated w/ ER

39
Q

How does assembly & exocytosis occur in Herpes virus?

A

2 cycles of envelopment.

  • UL31 & UL34 bind lamina prteins when phosphorylated by US3 (kinase) -> catalyses disruption of nuclear lamina + promotes budding.
    UL51 helps virus leave ER, nucleocapsid has associated tegument proteins -> amass around nucleocapsid + important for replication cycle.
  • glycoproteins (gE, gI, gM, gD) interact w/ Tegument proteins in trans Golgi network
  • virus formed at Golgi + is exocytosed

**virus acquires nuclear & golgi membrane

40
Q

Maturation of virus particles

A

-> when virus becomes infectious

Viral proteins need to proteolytically processed post-assembly.
Happens late in assembly (Polio) or following release of immature virions from host cell (retrovirus)

41
Q

How are retrovirus particles rearranged after exocytosis?

A

Gag polyprotein layer beneath viral mem found in immature virus
-> cleaved by HIV protease -> infectious HIV

Protease used as drug target for HIV treatments.

42
Q

DNA packing signals

A

e.g. Polyoma & adenoviruses use short sequence repeats close to origin

SV40 in regulatory region - has 6 tandem binding sites for viral TF sp1.
Bound sp1 interacts w/ capsid proteins + stimulates assembly

Adenovirus IVa2 proteins recognises packing signals.

43
Q

RNA packing signals

A

e.g. HIV type 1 genome

signal-psi recognised nucleocapsid proteins - necessary but not sufficient for HIV packaging, only found in unspliced genomic RNA
-> binds DIS + part of DLS

TAR + poly A loops also required

44
Q

Packing of segmented genomes

A

Each of 8 genome segments in Influenza has unique signal at both ends.

Segments arranged in virus in specific pattern -> interactions between the segments

45
Q

What does virion assembly depend on?

A

Concentration - components concentrated in ‘factories’ -> internal membranes can be sites of assembly providing means of concentrating proteins

Can be either independent or dependent on host machinery.

46
Q

Host dependent assembly

A
  • chaperones catalyse/assist folding of individual proteins + assembly of capsid/nucleocapsid
  • viral proteins + nucleic acids from sites of assembly
  • host secretory pathways processes + moves viral particles
  • host nuclear import/export machinery moves viral nuclear proteins + nucleic acid in & out of nucleus
47
Q

What are the types of addresses embedded in amino acid sequences?

A

Signal - target correct membranes
Retention - remain in appropriate membranes
Nuclear localisation - go to nucleus
Nuclear export - ensure viral mRNA/ribonuclear proteins moved into cytoplasm

Components can travel short (across membrane) or long (to site of replication, or assembly) distances across the cell.

48
Q

How are protein shells assembled in viruses? (give examples)

A

Self assembly:
- from individual protein mols
e.g. Simian virus, need large excess of VP1 to VP2/3 (stoichiometry) for spontaneous formation

  • from polyprotein precursor
    e.g. Polio, gets around need for high conc. -> VP1-4 joined together, protease then cleaves bonds between subunits except VP1-4, 2 & 4 not cleaved until whole virus assembled w/ RNA genome

Assisted assembly: uses chaperones
e.g. Adenovirus, 3 protein IIs generate hexon timer, requires 100kDa L4 chaperone host cell protein

49
Q

Sequential assembly (in bacteriophage T4)

A

Genome inserted into pre-formed protein shell e.g. Herpes, Adenovirus

In bacteriophage T4:
It ensures orderly formation of viral particles + virion subunits.
Discrete intermediate structures formed, cannot proceed unless previous structure formed.
- head, tail & tail fibres formed separately by sequential reactions, then assembled in ordered manner.

50
Q

Concerted assembly (Polio in cytoplasmic compartment)

A

Structural subunits assemble productively hen nucleic acid present.

For Polio:
- +ssRNA translated immediately -> produces P1-3
- P1 has VP0, VP1 & VP3, spontaneously assemble into 5S subunit + polymerises forming 14S penton
- Pentamer stabilised by protein interactions + interactions mediated by mysterate chains on N-terminus of VP0
- Pentons can self-assemble, viral genome required to catalyse proteolysis of VP0 -> VP2 & VP4
-> produces infectious Polio from provirion

51
Q

Concerted assembly of influenza A

A

HA, NA + M2 envelope proteins translated by ribosomes associated w/ ER
- delivered to plasma mem by host secretory pathway.

Ribonuclear proteins (nuclear export, M1) translated by free ribosomes, imported back to nucleus
- protein migrates to plasma mem to sites enriched w/ glycolipids, M1 protein genome binds C-terminal domain of HA
-> virus particle forms

8 genomic segments packaged into each capsid accurately

52
Q

Self assembly of viruses (give examples)

A

TMV + Polio form spontaneously from capsid subunit + RNA

HA of influenza expressed in cells can bud spontaneously + form particles

Hepatitis B (HBV) surface antigen forms into virus like particles

53
Q

What does assisted assembly require to be successful?

A

Need protein scaffolds to form capsid structure.
e.g. Herpes simplex, Adenovirus

  • they establish intermediate structures, not present in mature virus but needed for accurate assembly of icosahedral virus
  • subject to proteolytic degradation by viral proteases prior to entry of DNA genome into capsid
54
Q

Assisted assembly in Herpes simplex

A

linear dsDNA encodes approx 80 proteins, membrane bound, icosahedral capsid.
Targets mucosal epithelial cells but can lie dormant in neurones. T=16, 969 subunits

pre-VP22a self association (forms internal scaffold stimulates VP5 (hexamers + pentamers) binding followed by triplet protein (VP23 + VP19C)
VP24 protease in core activated + cleaves short C-terminal sequence from scaffold protein

-> scaffold disintegrates + is further degraded which promotes conformational change allowing DNA entry

*only 1 UL6 portal protein - allows scaffold ejection + DNA entry into virus

55
Q

List 3 requirements for ensuring successful infection

A

1) sufficient viral particles (shedding)
2) cells at primary infection site must be accessible, susceptible + permissive
3) local host of antiviral defences must be absent or initially defective

56
Q

How do virions defend against hostile environments?

A
  • large number of virions overcome sensitivity to heat, drying + sunlight
  • many virions stable at low pH & protease resistant
  • no exposure to environment via vector transmission or direct physical contact (e.g. zika, yellow fever)
57
Q

Local vs systemic infection

A

Local - replication occurs at site of infection, no systemic spread
e.g. influenza, rhinovirus

Systemic - replication occurs at primary site of infection + disseminated via blood, lymph + nerves to secondary site of infection where replicate further. Can shed back into blood + disseminate further
e.g. measles, chickenpox

58
Q

Viral entry via skin

A

Epidermis cannot support infection (dead keratinised cells)
Viral entry via skin abrasions, needle puncture, insect/animal bites
-> dermis + subdermal tissues highly vascularised

59
Q

Viral entry via respiratory tract

A

e.g. rubella, influenza, mumps measles, varicella zoster

Alveoli targeted, entry into lymphatic/blood vessels. Goblet cells in mucociliary escalator has secretory IgA - aggregates pathogens.

Viruses either affect upper or lower tract

60
Q

Viral entry via GI tract

A

Has innate defences - lysozyme in mouth, low pH + proteolytic enzymes in stomach

Systemic inc enterovirus, reovirus, adenovirus.
Localised infections inc coronavirus, rotavirus.

Polio virus binds M cells in Peyer’s patches to move across into lymphatics/blood, use it to cross epithelial mucosal barrier.

Enveloped viruses do not initiate GI tract infections except coronavirus (mainly naked)

61
Q

Viral entry via urogenital tract

A

Less well protected, has mucus + low pH.
Minute abrasions in sex may allows entry via epithelial cells.

Systemic inc HIV, hepatitis B, herpes simplex can infect sensory + autonomic neurons.
Localised - human papillomavirus

Lymph provides access to blood stream -> haematogenous spread

62
Q

Compare active and passive viremias

A

Viremia is when viruses enter blood stream + can access rest of body (either free or contained within infected cells - lymphocytes)

Active - replication in tissue prior to bloodstream access

Passive - viruses enter bloodstream without replication in host tissue e.g. direct inoculation by mosquitoes, don’t replicate until they reach permissive tissue

63
Q

Compare primary and secondary viremias

A

Primary - release of virions after replication at initial site of entry into bloodstream, conc of virions low but allows spread to secondary sites

Secondary - replication at secondary sites results in large number of virions being released into blood -> spread to organs

64
Q

List the different features of neural spread

A

Neurotropic - infect neural cells via neural/haematogenous route

Neuroinvasive - can enter CNS after infection of peripheral site (low in herpes, high in mumps + rabies)

Neurovirulent - can cause disease of nervous tissue -> neurological systems -> death (low in mumps, high in herpes + rabies)

65
Q

How does neural spread take place and what are the two types?

A

Infection initiated in muscles or other innervated tissue. Can enter afferent /efferent nerve fibres + spread through axons to cell bodies + primary neurones.

  • can only replicate in cell bodies

Anterograde spread: moves along MTs using kinesin (cell body -> axon)

Retrograde spread: moves along MTs using dynein (axon -> cell body)

e.g. Rabies targets muscle cells to initiate CNS infection + replicate

66
Q

How do viruses cross the blood-brain barrier and what areas do they target for entry into brain?

A

e.g. Zika, Measles, West Nile, Polio
Can hijack lymphocytes or use transcytosis (vesicles), others replicate in endothelial cells lining blood vessel.

Meningeal blood vessel, cerebral blood vessels, choroid plexus blood vessel, meninges.

67
Q

Poliomyelitis

A

Enterovirus, Picornaviridae (+ssRNA), 3 serotypes: Brunhilde, Lansing + Leon. Pseudo T=3 non-enveloped capsid, icosahedral symmetry.

  • Humans only known reservoir, faecal/oral transmission (peaks warm months)
  • Can enter CNS + replicate in motor neurones in spinal chord

Complications : post-Polio syndrome (25%-40%) 30-40 yr interval, caused by long term damage to motor neurones

Paralytic 1% cases (flaccid paralysis).
Bulbar poliomyelitis has max fatality as brain stem neurons involved.

68
Q

Pathogenesis of Polio

A

Ingested + replicates in orapharynx + intestinal mucosal surface. Targets M cells w/ PVR CD155.
Enters via cervical/mesenteric lymph nodes -> viremia.

Can migrate to muscle (replicates) + reach motor endplate (access to CNS)

Moves down axon (12cm/day) - cytoplasmic C-terminal tail of CD155 associated w/ Tctex-1 (light chain subunit of dynein motor complex)
-> retrograde transmission

Replication:
-Polio cleaves translation initiation complex eIF4E, ribosomes cannot be recruited to capped mRNAs
- only uncapped Polio virus mRNA which has IRES is translated

69
Q

Rabies virus structure

A

Neurotropic lyssavirus, -ssRNA genome encodes 5 proteins, membrane bound, helical.

Bullet shape - glycoproteins act as adhesin, animal to human transmission. Can be transmitted via latrogenic cornea transplant or saliva (bites)

Spreads by retrograde axonal transport.
-> zoonotic virus

70
Q

Rabies pathogenesis & symptoms

A

Varied incubation 7 days - many years (depends of wound, inoculum size + distance from CNS)
Replicates in striated/connective tissue + enters peripheral nerves via NMJs (retrograde).
Can replicate in dorsal root ganglion + travels up spinal chord to brain.
Spreads to CNS in endoneurium of Schwann cells (anterograde transport)

Symptoms:
Furious form 80% infections.
Non-specific prodrome period: fever, malaise, anorexia, nausea, sore throat, myalgia + headache

  • acute encephalitic phase: hydrophobia + excitement, virus sheds in saliva
  • numb form (20%): weakness, flaccid paralysis

After onset, survival rarely > 7 days

71
Q

How does rabies virus navigate muscle cells, NMJs and enter neurones?

A

Glycoprotein timer binds nAchRs at post synaptic muscle membrane.

Entry via endocytosis, fusion w/ endosomal membrane, ribonucleocapsid released into cytoplasm.

Virus moves across NMJ to neurons + enters via neural cell adhesion molecule (NCAM)

Either via capsid release or whole virus remains in endosome + transported to cell body.

Retrograde axonal transport to cell body

Yr 2 Sem 1 (3 decks)

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