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


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

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

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

Cytopathic effects of virus infection
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
  • 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

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
  • Virally encoded RNA polymerase in virion
  • Transcription factor in virion
  • An enhancer sequence
  • To ensure high level transcription of later viral
  • Transactivators SV40 large T antigen,
    adenovirus E1A, PV E2, and HSV ICP4
  • An transcription activator for elongation during
    RNA synthesis

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
  • 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
  • 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

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Host cell responses to viral infection
  • Host response to virus at the cellular level
  • IFN production homologous and heterologous
  • 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

TLR7 and 9 pathways lead to IFNs and inflammatory
cytokines by plasmacytoid DCs
TLR3 pathways lead to IFNs and inflammatory
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Circumvent IFN responses by viruses
Outcomes of virus infection of a host
Routes of virus entry
Virus spread in a host
  • Localized versus systemic infection
  • Route of infection (contact, inhalation,
    arthropod vector bite, needle
  • Cell tropism (enveloped versus non-enveloped
  • 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

Stages of pathogenesis of flavivirus infection
The pathogenesis of mouse poxvirus
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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

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
  • 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

Entry of blood borne viruses into the CNS
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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,
  • 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

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Viral spread from a host to environment or a new
  • Sources of viral transmission
  • Respiratory, enteric, or genitourinary secretions
  • Arbovirus infection through an arthropod vector
  • Contaminated blood, body fluids and blood
  • Skin - HSV, HPV, and chickenpox
  • Milk CMV, HIV, mumps, rubella, HBV, HCV,
  • 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

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Replication and transneuronal passage of
pseudorabies virus