Interferons

1
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
2
Interferons

• Interferons
• Type I interferon
• 165amino 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
• Type II interferon
• 146amino acid glycoprotein, immune modulator
• Labile at pH 2
• Interferon-g 1 gene in humans, made in
  lymphocytes and macrophages

3
Interferons

• Induction of synthesis
• 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.

4
Interferons

• Induction of antiviral activity
• 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.

5
Interferons

• Antiviral activities induced by interferons a and
  b
• Mx proteins suppress replication of
  negative-strand 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).

6
Interferons

• Antiviral activities induced by interferons g
• 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.

7
Interferons

• Viral defenses against interferon responses
• Homologues of interferon-regulatory factors block
  transcription of interferon genes.
• Viral proteins inhibit activation of
  interferon-stimulated genes.
• Small viral dsRNAs block activation of
  dsRNA-dependent 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.

8
Interferons

• Virus-infected cells secrete interferons, which
  protect nearby cells against virus infection
• 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
• Most effective at initial stage of virus
  infection
• Therapeutically administered INF leads side
  effects and short-lived antiviral effects

9
Interferons

• Interferons a, b, and g are made by different
  cells and have distinct functions

10
Interferons

• Transcription of interferon genes is activated by
  virus infection or double-stranded RNA

Fig. 31.1 The interferon system.
11
Interferons

• Transcriptional activation occurs by binding of
  transcription factors to interferon gene
  enhancers

Fig. 31.2 Transcriptional activation of the
interferon gene.
12
Interferons
13
Interferons

• Interferon signal transduction is carried out via
  the Jak-Stat pathway

Fig. 31.3 Interferon signal transduction.
14
Interferons

• Antiviral activities induced by interferon
• The Mx proteins.
• Able to hydrolyze GTP, function not known
• Inhibits viral RNA polymerase activity
• 2, 5-oligo(A) synthetase and ribonuclease L.
• 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.
• Activated by ds RNA
• Phosphorylates eIF-2
• phosphorylation results in inactive complex
• Block initiation of protein synthesis

15
Interferons
Fig. 31.4 Antiviral activity directed by 2,
5-oligo(A) synthetase and ribonuclease L.
16
Interferons
Fig. 31.5 Mechanism of antiviral activity
directed by PKR.
17
Interferons

• Interferons have diverse effects on the immune
  system
• The adaptive immune system

Fig. 31.6 Antibody production by B cells.
18
Interferons
Fig. 31.7 Generation of helper (Th) and cytotoxic
(Tc) T lymphocytes.
19
Interferons
Fig. 31.8 Cell lysis by cytotoxic T lymphocytes.
20
Interferons

• Interferons stimulate antigen processing and
  presentation
• Interferon and the development of CD4- positive
  helper T-cells
• The role of interferon in macrophage activation
  and cellular immunity
• INFg stimulates macrophage activation
• Effects of interferons on antibody production
• Interferons regulate cell growth and apoptosis

21
Interferons

• Viruses have developed numerous strategies to
  evade the interferon response

22
Interferons

• Conclusion interferons are a first line of
  defense against virus infection

23
Key Terms

• Jak-Stat pathway
• Macrophages
• Major histocompatibility complex (MHC) proteins
• Natural killer cells
• 2, 5-oligo(A) synthetase
• PKR (double-stranded RNA-dependent protein
  kinase)
• Plasma cells
• Proteasomes
• Ribonuclease L
• T-cell receptors
• T lymphocytes
• Toll-like receptors
• Viral interference

• Antibodies
• Antigens
• B lymphocytes
• Caspases
• Chemokines
• Complement
• Cytokines
• Cytotoxic T lymphocytes
• Epitopes
• Interferons
• Interleukin-1