Transcript Introduction to Virology

Interferons
Interferons
Induction of synthesis
Induction of antiviral activity
Antiviral activities induced by interferons a and b
Antiviral activities induced by interferons g
Viral defenses against interferon responses
Interferons
 Interferons
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Type I interferon:
 165–amino acid glycoproteins with antiviral activity
 Stable at pH 2
 Interferon-: 13 genes in humans, made in leukocytes and
other cells
 Interferon-: 1 gene in humans, made in fibroblasts and
epithelial cells
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Type II interferon:
 146–amino acid glycoprotein, immune modulator
 Labile at pH 2
 Interferon-g: 1 gene in humans, made in lymphocytes
and macrophages
Interferons
 Induction of synthesis
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Induced by virus infection and double-stranded
RNA.
Interferon regulatory factors (IRF) activated by
phosphorylation.
IRF bind to interferon genes, activating
transcription.
Interferon mRNAs are unstable; short burst of
interferon synthesis.
Interferons are secreted into the extracellular
medium.
Interferons
 Induction of antiviral activity
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Interferons interact with specific receptors on the
surface of target cells.
Binding leads to dimerization of receptors,
phosphorylation and activation of Jak kinases.
Jak kinases phosphorylate Stat proteins, which
dimerize and transit to nucleus.
Stat proteins bind to interferon-stimulated genes
in nucleus and activate transcription.
More than 100 cellular genes are activated by the
Jak-Stat pathway.
Interferons
 Antiviral activities induced by interferons a
and b
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Mx proteins suppress replication of negativestrand RNA viruses.
2, 5-oligoadenylate synthetase activates
ribonuclease L, which degrades host and viral
mRNAs.
Double-stranded RNA-dependent protein kinase
(PKR) inactivates protein synthesis by
phosphorylating initiation factor 2a (eIF-2a).
Interferons
 Antiviral activities induced by interferons g
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Expression of major histocompatibility protein (MHC) class I
promotes development of cytotoxic T cells leading to
killing of virus-infected cells.
Expression of MHC class II promotes antibody responses
against viral proteins.
Activation of proteasomes increases immune display of viral
peptides.
Synthesis of interleukin-2 promotes development of Th1 cells,
leading to cytotoxic response and killing of virus-infected cells.
Activation of macrophages leads to killing of microbes via nitric
oxide pathway.
Switch of B-cell production from immunoglobulin M to
immunoglobulin G2 generates soluble antibodies against virus
proteins.
Interferons
 Viral defenses against interferon responses
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Homologues of interferon-regulatory factors block
transcription of interferon genes.
Viral proteins inhibit activation of interferonstimulated genes.
Small viral dsRNAs block activation of dsRNAdependent protein kinase (PKR).
Viral proteins that bind to dsRNA reduce
activation of PKR.
Soluble homologues of cytokine receptors block
cytokine production and inhibit B-cell activation
and antibody production.
Interferons
 Virus-infected cells secrete interferons, which
protect nearby cells against virus infection
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Released from virus-infected cells, binds to receptors on
nearby uninfected cells
Stimulate transcription of genes encoding proteins with
antiviral activities
INF induced by one kind of virus can inhibit replication of
different virus types
Species- dependent
 Interferons are a first line of host defense against
viruses but therapeutic use has been limited
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Most effective at initial stage of virus infection
Therapeutically administered INF leads side effects and
short-lived antiviral effects
Interferons
 Interferons a, b, and g are made by different
cells and have distinct functions
Interferons
 Transcription of interferon genes is activated
by virus infection or double-stranded RNA
Fig. 31.1 The interferon system.
Interferons
 Transcriptional activation occurs by binding
of transcription factors to interferon gene
enhancers
Fig. 31.2 Transcriptional activation of the interferon gene.
Interferons
Interferons
 Interferon signal transduction is carried out
via the Jak-Stat pathway
Fig. 31.3 Interferon signal transduction.
Interferons
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Antiviral activities induced by interferon
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The Mx proteins.
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Able to hydrolyze GTP, function not known
Inhibits viral RNA polymerase activity
2, 5-oligo(A) synthetase and ribonuclease L.
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Activated 2,5-oligo(A) synthetase produce 2,5-oligo(A)
2,5-oligo(A) binds and activates ribonuclease L
Degrades host and viral mRNAs
Double-stranded RNA-dependent protein kinase.
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Activated by ds RNA
Phosphorylates eIF-2
phosphorylation results in inactive complex
Block initiation of protein synthesis
Interferons
Fig. 31.4 Antiviral activity directed by 2, 5-oligo(A)
synthetase and ribonuclease L.
Interferons
Fig. 31.5 Mechanism of antiviral
activity directed by PKR.
Interferons
 Interferons have diverse effects on the
immune system
 The adaptive immune system
Fig. 31.6 Antibody production by B cells.
Interferons
Fig. 31.7 Generation of helper
(Th) and cytotoxic (Tc) T
lymphocytes.
Interferons
Fig. 31.8 Cell lysis by cytotoxic
T lymphocytes.
Interferons
 Interferons stimulate antigen processing and
presentation
 Interferon and the development of CD4positive helper T-cells
 The role of interferon in macrophage
activation and cellular immunity
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INFg stimulates macrophage activation
 Effects of interferons on antibody production
 Interferons regulate cell growth and
apoptosis
Interferons
 Viruses have developed numerous strategies
to evade the interferon response
Interferons
 Conclusion: interferons are a first line of
defense against virus infection
Key Terms
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Antibodies
Antigens
B lymphocytes
Caspases
Chemokines
Complement
Cytokines
Cytotoxic T lymphocytes
Epitopes
Interferons
Interleukin-1
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Jak-Stat pathway
Macrophages
Major histocompatibility
complex (MHC) proteins
Natural killer cells
2, 5-oligo(A) synthetase
PKR (double-stranded RNAdependent protein kinase)
Plasma cells
Proteasomes
Ribonuclease L
T-cell receptors
T lymphocytes
Toll-like receptors
Viral interference