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Virus and host cell interaction and pathogenesis Paul Zhou Institut Pasteur of Shanghai

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An insight into basic cellular and molecular biology mechanisms ... or integrated into host genome (potential oncogenesis and/or latent infection) ... – PowerPoint PPT presentation

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Title: Virus and host cell interaction and pathogenesis Paul Zhou Institut Pasteur of Shanghai


1
Virus and host cell interaction and
pathogenesisPaul ZhouInstitut Pasteur of
Shanghai
2
General consideration of virus and host cell
interaction
  • Importance
  • A key understanding of virus replication
  • An insight into basic cellular and molecular
    biology mechanisms
  • A lead to understanding causes for viral
    pathogenesis
  • A lead to the definition of antiviral strategies
  • A lead to the better viral vectors for gene
    delivery
  • Levels
  • Molecular and cellular level
  • Within a host organism spread from one cell to
    another
  • In environment transmission among individual
    organisms

3
Outcomes of viral infection of a cell
  • Nonproductive infection no viral replication
    and host cell survival with or without viral
    genome persistent as episomal DNA or integrated
    into host genome (potential oncogenesis and/or
    latent infection)
  • Nonproductive infection no viral replication
    but non-survival of host cell
  • Productive infection results in cell death
  • Productive infection without cell death (chronic
    infection)

4
Cytopathic effects of virus infection
5
Effect on host cell DNA replication
  • Inhibit host cell DNA synthesis
  • To provide the precursors for viral DNA synthesis
    such as vaccinia in cellular DNA degradation
  • To provide host cell structure and replication
    proteins for viral DNA synthesis such as HSV can
    displace cellular DNA from nuclear cage and
    recruit cellular replication proteins to viral
    structure
  • As a secondary effect of inhibiting cellular
    protein synthesis such as HSV and adenovirus
  • Induce host cell DNA synthesis
  • Induce host cell into S phase such as SV40 T
    antigen and adenovirus E1A and E1B
  • Maintain viral DNA
  • Integrate viral DNA into host cell chromosomes
    such as retrovirus
  • Maintain viral DNA as an extra-chromosomal
    circular molecule such as EBV, HHV8, and KSAV in
    latently infected cells

6
Effect on host cell RNA transcription and export
  • Inhibition of cellular transcription and export
  • DNA viruses compete for pol II polerase and
    transcription factors and inhibit Inhibit RNA
    exporting Adenovirus E1B and E4 and HSV ICP27
    and IE63
  • RNA viruses for precursors for RNA synthesis
  • Inhibit host cell RNA synthesis VSV M protein and
    TFII-D and PV and proteolytic cleavage of TATA
    binding TBP
  • Cap snatching of influenza A virus
  • Inhibit RNA processing NS1 and CPSF
  • To ensure high level transcription upon viral
    entry
  • Virally encoded RNA polymerase in virion
  • Transcription factor in virion
  • An enhancer sequence
  • To ensure high level transcription of later viral
    genes
  • Transactivators SV40 large T antigen,
    adenovirus E1A, PV E2, and HSV ICP4
  • An transcription activator for elongation during
    RNA synthesis

7
Effect on translational machinery
  • Modify initiation factor function involved in
    recruitment of the 40S ribosome subunit to mRNA
    e.g. PV 2A protease eIF-4GI and II and PABP
    dephosphorylation of eIF-4E by adenovirus, PV,
    and influenza virus shut off GRSF-1 by influenza
    virus
  • Modify initiation factor function involved in
    binding of initiator transfer RNA to the 40S
    ribosome subunit e.g. virus infection, PKR
    activation and inactivation, phosphorylation and
    dephosphorylation of eIF-2a- adenovirus VA1
    influenza NS1 and P58IPK HCV E2 and NS5A
    Vaccinia E3L and K3L HIV TAR TRBP and tat HSV
    ?34.5
  • Modify elongation factor function e.g. eEF1A and
    HIV MA and Pr55gag
  • Degrade cellular mRNA
  • HSV-2 UL41
  • dsRNA IFN RNA-dependent 2-5 oligoadenylate
    synthetase 2-5A RNase L
  • Unconventional translational strategies
  • Leaky scanning e.g. SV40 VP2 and VP3
  • Ribosome shunting e.g. intervening region of an
    mRNA is bypassed without scanning of ribosomes
    adenovirus late mRNAs
  • Translational frameshifting e.g. retrovirus,
    coronavirus, arterivirus -1 pol
  • Suppress translational termination e.g. pol ORF
  • Posttranslational RNA editing e.g. RNA specific
    adenosine deaminases A-I, I then read as G in
    codon

8
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9
Host cell responses to viral infection
  • Host response to virus at the cellular level
  • IFN production homologous and heterologous
    viruses
  • Apoptosis untimely early destruction of
    infected cells may reduce virus yields
  • Restriction factors
  • Innate immune response (dendritic cells)
  • TLRs type I IFN production, inflammatory
    cytokines and dendritic maturation, TLR-3 and WNV
  • RNA helicases dsRNA produced during virus
    replication and leads t type I IFN production

10
TLR7 and 9 pathways lead to IFNs and inflammatory
cytokines by plasmacytoid DCs
11
TLR3 pathways lead to IFNs and inflammatory
cytokines
12
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13
Circumvent IFN responses by viruses
14
Outcomes of virus infection of a host
15
Routes of virus entry
16
Virus spread in a host
  • Localized versus systemic infection
  • Route of infection (contact, inhalation,
    arthropod vector bite, needle
  • Cell tropism (enveloped versus non-enveloped
    viruses)
  • Apical versus basolateral release of virus in
    polarized epithelial mucosal cells
  • Hematogenous spread
  • Primary replication in primary site
  • Regional lymph nodes
  • Efferent lymphatics
  • Thoracic duct
  • Systemic circulation (blood-brain barrier)
  • Secondary sites
  • Inside nerve (poliovirus and HSV)
  • Primary versus secondary viremias

17
Stages of pathogenesis of flavivirus infection
18
The pathogenesis of mouse poxvirus
19
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20
The magnitude and duration of viremia the
dynamic relationship between virus and host
  • Replication at the primary and secondary sites
    and circulating blood cells such as HIV in CD4 T
    cells provide a continuing source of virus input
    into the circulation
  • Macrophages in the RES, serum antibody and
    complement act in concert to facilitate viral
    clearance (the size and net charge of virus
    particles, other pathogen)
  • Replicated in macrophages (HSV, CMV, togavirus,
    flavivirus, poxvirus, lentiviruses,
    coronaviruses, arenaviruses, reovirus,
    piconavirus, rhabdoviruses, myxo- and
    paramyxoviruses)- circumvent antiviral defense of
    macrophages HLA down-regulation and inhibition
    of antiviral molecule production such as nitric
    oxide (NO)
  • Replicated in vascular endothelial cells that may
    be a factor for their organ-specific tropism
  • A correlation between the capacity of blood-borne
    neutropic viruses to generate a high-titer
    viremia and their neuroinvasiveness

21
Tissue invasion of viruses
  • Blood and brain barrier tight junctions (zona
    occludens) join capillary cells of the cerabral
    microvasculature and an underlying dense basement
    membrane, with a notable exception of choroid
    plexus
  • Transendothelial transport of free viruses across
    capillary endothelial cells such as piconavirus,
    togavirus, bunyavirus, parvovirus, retrovirus
  • Transportendothelial transport of cell-associated
    viruses such as HIV inside macrophage
  • Neural spread such as HSV, rabies virus,
    piconavirus, reovirus, coronavirus, pseudorabies
    virus, Borna disease virus and arbovirus

22
Entry of blood borne viruses into the CNS
23
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24
Patterns of viral infection
  • Acute infection symptomatic or asymptomatic
  • Persistent infection
  • Reduced CPE
  • Limit or restrict apoptosis
  • Balance between lytic versus non-lytic infection
    such as CMV nonproductive versus productive
    infection in monocytes and macrophages,
    respectively
  • The generation defective interfering (DI)
    particles to modulate wild type virus infection
  • Restrict gene expression such as EBV in B cells,
    HSV in sensory neuron and papillomavirus in basal
    skin cells
  • Maintain viral genome in dividing versus
    non-dividing cells
  • Evasion of the immune response
  • Latency such as HSV
  • Privileged sites
  • Escape mutants such as HIV
  • Decrease in MHC expression

25
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29
Viral spread from a host to environment or a new
host
  • Sources of viral transmission
  • Respiratory, enteric, or genitourinary secretions
  • Arbovirus infection through an arthropod vector
  • Contaminated blood, body fluids and blood
    products
  • Skin - HSV, HPV, and chickenpox
  • Milk CMV, HIV, mumps, rubella, HBV, HCV,
    flavivirus
  • Maternal-child transmission HIV, HBV, HCV, HSV,
    and CMV
  • Organ transplantation CMV, EBV, HIV, HTLV-1
  • Factors that influence the transmission blood
    borne viruses
  • The titers of virus in blood
  • The duration of viremic state
  • The amount of material transmitted
  • The route of transmission
  • Human practice and viral spread
  • Urbanization and globalization
  • Human behaviors sexual activity, consumption
    (domestic animals), drug addiction, etc
  • Screen human pathogens blood, body fluids, and
    blood products before releasing to the market
  • Vaccination
  • Ways to deliver baby

30
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31
Replication and transneuronal passage of
pseudorabies virus
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