Dr Margaret Hunt

 BACTERIOLOGY IMMUNOLOGY MYCOLOGY PARASITOLOGY VIROLOGY
    

 INTERFERON
 

v-h2.jpg (43722 bytes) Interferon response to an acute virus infection

Interferons play an important role in the first line of defense against viral infections. They are part of the non-specific immune system and are induced at an early stage in viral infection – before the specific immune system has had time to respond.

Interferons are made by cells in response to an appropriate stimulus, and are released into the surrounding medium; they then bind to receptors on target cells and induce transcription of  approximately 20-30 genes in the target cells, and this results in an anti-viral state in the target cells. 

TYPES OF INTERFERON:

TYPE I interferon:

Interferon-alpha (leukocyte interferon) is produced by virus-infected leukocytes, etc

Interferon-beta (fibroblast interferon) is produced by virus-infected fibroblasts, or virus-infected epithelial cells, etc

Interferon-a (a family of about 20 related proteins) and interferon-b are particularly potent as antiviral agents. They are not expressed in normal cells, but viral infection of a cell causes interferons to be made and released from the cell (that cell will often eventually die as a result of the infection). The interferon binds to target cells and induces an antiviral state. Both DNA and RNA viruses induce interferon but RNA viruses tend to induce higher levels. Double-stranded RNA produced during viral infection may be an important inducing agent. Other stimuli will also cause these interferons to be made: e.g. exogenous double-stranded RNA, lipopolysaccharide, other components of certain bacteria.

TYPE II inteferon

            Interferon-gamma  (immune interferon) is produced by certain activated T-cells and NK cells.

Interferon-gamma is made in response to antigen (including viral antigens) or mitogen stimulation of lymphocytes.

 

interferon.jpg (72628 bytes) Effects of interferon

INTERFERON-alpha AND INTERFERON-beta (TYPE I INTERFERONS)

These interferons induce about 20-30 proteins, and the function of many of these is not fully understood. However, three of the proteins that appear to play an important role in the induction of the anti-viral state have been intensively studied. Expression of one of these proteins (2’5’ oligo A synthase) results in activation of the second of these proteins (a ribonuclease) which can break down mRNA, and expression of the third protein (a protein kinase) results in inhibition of the initiation step of protein synthesis. These activities target viral protein synthesis, but also result in inhibition of host protein synthesis. Thus it is important that these proteins are only made and activated when needed.

Interferon treatment induces the synthesis of the inactive form of these proteins in the target cell. Double-stranded RNA is needed for activation of these proteins. It directly activates 2’5’ oligo A synthase and protein kinase R, and indirectly activates ribonuclease L (since this needs 2'5'oligo A, the product of 2’5’ oligo A synthase, for activation). Thus, these potentially toxic pathways are only activated in the interferon-treated cell if double-stranded RNA is made, this will usually only happen if virus infection actually occurs. The activation of these proteins may sometimes result in the death of the cell, but at least the progress of the infection is prevented.

 

 

OTHER EFFECTS OF INTERFERONS

The pathway described above is by no means the only way that interferons protect cells against viruses and other pathogens. 

All three interferons increase expression of class I MHC molecules and thus promote recognition by cytotoxic T cells. All three interferons can activate NK cells which can then kill virus-infected cells. 

Interferon-gamma increases expression of class II MHC molecules on antigen-presenting cells and thus promotes presentation of antigens to helper T cells. Interferon-gamma can also activate the ability of macrophages to resist viral infection (intrinsic antiviral activity) and to kill other cells if they are infected (extrinsic antiviral activity). 

Interferons have many other effects on gene expression, not all of which are understood. 

THERAPEUTIC USES OF INTERFERONS

Interferons-alpha and -beta have been used to treat various viral infections. One currently approved use for various types of interferon-a is in the treatment of certain cases of acute and chronic hepatitis C and chronic hepatitis B.

Interferon-gamma has been used to treat a variety of disease in which macrophage activation might play an important role in recovery, eg. lepromatous leprosy, leishmaniasis, toxoplasmosis.

Since interferons have anti-proliferative effects, they have also been used to treat certain tumors such as melanoma and Kaposi’s sarcoma.

 

   

SIDE EFFECTS OF INTERFERONS

Common side effects of interferons:

            fever, malaise, fatigue, muscle pains

High levels of interferons can cause kidney, liver, bone marrow and heart toxicity.

 

VIRAL DEFENSES AGAINST THE NON-SPECIFIC AND SPECIFIC IMMUNE SYSTEMS

Not surprisingly, some viruses have developed defenses against the interferon-induced antiviral response and other aspects of the immune defense system. For example, viruses may code for proteins which block interferon binding to cells, inhibit the action of the interferon-induced protein kinase, inhibit NK function, interfere with cell surface expression of MHC, block complement activation, prevent the host cell committing apoptosis, etc.

 

 

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