Interferon (IFN)

  • The discovery:

    “One day in the library in the autumn of 1957, I came across an article in the English journal, The Proceedings of the Royal Society which greatly excited me. It was by Alick Isaacs and Jean Lindenmann from the Medical Research Council’s laboratories in London, and it had the title “Virus Interference I. The interferon”………

Isaacs and Lindenmann had studied what had been a subject for research since 1935, the phenomenon of virus interference. This is the name given when one virus is seen to block the growth of another virus when both try to infect the same cells…..

In 1943, Werner and Gertrude Henle who worked in this field in Philadelphia published a scientific article which had far-reaching consequences: they showed that a virus can produce the interference phenomenon even when it has itself been rendered incapable of growth; the virus can be inactivated by any of variety of treatments and yet still retain its capacity to interfere with another virus….

Isaacs and Lindenmann soon showed that this increase in interfering activity had nothing to do with the virus particles themselves, but resulted from some unknown factor which was released from the cells… They called the factor “interferon”… It appeared to be a protein; it could inhibit the multiplication of many different viruses; it had no direct effect on a virus outside a cell, but instead produced changes within the cell such that the subsequent growth of a virus was blocked….." [ref=1, with some modification]

  • Human Interferons

    • Type I

    • Type II

      • IFN-gamma

      • Produced by T lymphocytes

    • Type III (IFN-like molecule)

      • limitin (mouse)

      • IFN-lambda2 (IL-28A)

      • IFN-lambda3 (IL-28B)

      • IFN-lambda1 (IL-29)

 

Figure: These are "plasmacytoid dendritic cells (pDC)" isolated from PBMCs by using the CD304 (BDCA-4/Neuropilin-1) MicroBead Kit, and May-Grünwald/Giemsa stained. (image source: miltenyibiotec)


 

Type I IFN

  • Actions

    • Antiviral action shown against

      • Noncytopathic lymphocytic choriomeningitis WE strain virus

      • Maloney sarcoma virus

      • Newcastle disease

      • Influenza virus

      • Vaccinia virus

      • LCMV

      • ECMV

      • HSV

      • VSV

      • SFV

    • IFN-alpha currently used in treatment of HBV & HCV

    • Type I IFN was not detectable 2 months after primary HIV infection.

    • Activate the lytic potential and proliferation of NK and gamma-delta T cells

    • Activate NO synthesis by macrophages

    • Enhance

      • Lysis of infected cells by cytotoxic T cells or T helper type 1 cells

      • Gamma-IFN production by T lymphocytes

    • Increase class I MHC expression, thus increase recognition and lysis by cytotoxic T cells.

    • High level type I-IFN inhibits IL-12 expression.

  • Activation/ Induction (see the figure at the end of page)

    • Activated through Toll-like receptor (TLR)

      • HIV binds to TLR7 & CD4 to stimulate pDC.

      • Viral RNA & DNA can also bind to TLR3, -7, or -9.

      • Binding of TLR7, -8, and -9 trigger signal through an adaptor (Myeloid differentiation primary response protein 88 or MyD88), then to interferon regulatory factor (IRF)-7 and finally NF-kB (see fig.)

    • Through TLR-independent pathways

      • Binds to cytoplasmic sensors: retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5)

      • Leading to activation of IRF3 and finally NF-kB.

  • Mechanisms of action (see the figure at the end of page)

    • Amplifying their own expression through

      • Induction of IRF-7

      • Accumulation of plasmacytoid dendritic cells

    • Type I-IFN binds to a receptor (2 subunits: IFNAR1 & IFNAR2)

      • Leading to a phosphorylation cascade of kinases (JAK1 & Tyk2)

      • Then, to tyrosine phosphorylation of signal transducers and activators (STAT1 & STAT2).

      • Activated STAT and IRF9A form a complex (ISGF3).

      • ISGF3 translocates to the nucleus & binds to ISG (interferon-stimulated genes, containing IFN-stimulated response elements [ISRE])

      • More than 100 ISG are transcribed into proteins.

    • The ISG products are involved in the different properties of interferons such as

      • Antiviral

      • Anti-proliferative

      • Apoptosis

      • Immunomodulatory properties.

    • Main interferon-stimulated genes (ISG):

      • PKR

      • 2’-5’ Oligoadenylate synthetase

      • Mx proteins (myxovirus resistance GTPase), (note: MxA inhibits RNA polymerase of influenza virus and traps many viruses to prevent their multiplication)

      • ISG 20.

 

 Figure: Activation and Mechanisms of Action of Type-I Interferon

(image source: Marta E Alarcón-Riquelme Nature Genetics 38, 866 - 867 , 2006)