Interferons Induction of synthesis Induction of antiviral activity Antiviral activities induced by interferons  and  Antiviral activities induced by interferons  Viral defenses against interferon responses

 Interferons  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  Type II interferon:  146–amino acid glycoprotein, immune modulator  Labile at pH 2  Interferon-  : 1 gene in humans, made in lymphocytes and macrophages 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. 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. Interferons

 Antiviral activities induced by interferons  and   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 2  (eIF-2  ). Interferons

 Antiviral activities induced by interferons   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  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. 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 Interferons

 Interferons , , and  are made by different cells and have distinct functions

 Transcription of interferon genes is activated by virus infection or double-stranded RNA Interferons Fig The interferon system.

 Transcriptional activation occurs by binding of transcription factors to interferon gene enhancers Interferons Fig Transcriptional activation of the interferon gene.

Interferons

 Interferon signal transduction is carried out via the Jak-Stat pathway Interferons Fig Interferon signal transduction.

 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 Interferons

Fig Antiviral activity directed by 2, 5-oligo(A) synthetase and ribonuclease L.

Interferons Fig Mechanism of antiviral activity directed by PKR.

 Interferons have diverse effects on the immune system  The adaptive immune system Interferons Fig Antibody production by B cells.

Interferons Fig Generation of helper (Th) and cytotoxic (Tc) T lymphocytes.

Interferons Fig Cell lysis by cytotoxic T lymphocytes.

 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  INF  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  Antibodies  Antigens  B lymphocytes  Caspases  Chemokines  Complement  Cytokines  Cytotoxic T lymphocytes  Epitopes  Interferons  Interleukin-1  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