Interferon

Interferons are important components of the immune system that trigger cellular defences in response to infection by viruses or bacteria and tumour formation (…)

Interferon

Interferons are important components of the immune system that trigger cellular defences in response to infection by viruses or bacteria and tumour formation.

Discovery

The phenomenon of viral interference is known since 1935, when researchers found that an animal infected by a virus became resistant to infection by other viruses. However, the explanation only came in 1957 when Alick Isaacs and Jean Lindenmann showed that cells in contact with an inactivated virus release a soluble substance that protected the healthy cells of a subsequent infection. In this experiment, they added the Influenza virus (flu virus) inactivated by heat in a culture of chorioallantoid membrane cells from hen’s egg and they incubated at 37° C for 24 hours. Next, they transferred the supernatant of this first culture in a second culture free from viruses and returned to incubate for 24 hours. Finally, they added a suspension of live Influenza virus and found that these didn’t multiply. So, they concluded that the supernatant contained a substance secreted by cells in contact with the virus and that it was “assimilated” by healthy cells causing interference on virus infection. This substance was then designated Interferon (IFN).

Types of interferons

Interferons belong to a cytokine subset. In humans, there are three types of interferons classified mainly according to their structure and respective receptors:

  • Type I IFN – Group that includes IFN-α (IFN-alpha) and IFN-β (IFN-beta), among others. Interferons are non-glycosylated proteins that bind to the same type of receptor, IFNAR (IFN-α receptor).

In humans, there are 13 varieties of IFN-α, encoded by genes located on chromosome 9.  They are produced by leukocytes, macrophages, endothelial cells, tumour cells and mesenchymal cells in response to viral or bacterial infections and tumour cells.

IFN-β is encoded by a single gene located on chromosome 9 and is produced by fibroblasts, endothelial cells, macrophages, and epithelial cells in response to stimuli by viruses or foreign nucleic acid.

Type I IFN share many properties, including the structural homology and act by inhibiting viral replication and increasing the expression of MHC Class I molecules in the cell itself (infected) and in neighbouring cells, being important in the regulation of innate and adaptive immunity.

  • Type II IFN – Group that includes IFN-γ (IFN-gamma), encoded by a single gene located on chromosome 12 and produced by Th1 subpopulation of T lymphocytes , CD8 T lymphocyte and NK cells in response to microbial antigens and stimulation by IL-12 (Interleukin 12).

Although they inhibit viral replication, the structure and mode of action of IFN-γ differ from other types of interferons. IFN-γ is essential for cellular immunity once it stimulates differentiation of macrophages and therefore they are also called macrophage-activating factor. It’s an important imunomodulador, being responsible for the increased phagocytosis; it also activates neutrophils, increases the cytotoxic action of NK cells, stimulates the expression of molecules of MHC Class I and II and of co-stimulators and induces the production of antibodies complement fixing IgG1 and IgG3.

  • Type III IFN – Group set up by the family of IFN-λ (IFN-lambda), set of three proteins also designated interleukins 29, 28A and 28B (IFN-λ1, λ2 and λ3, respectively) are encoded by three genes located on chromosome 19 and produced mainly by dendritic cells and macrophages after viral or bacterial infection. IFN-λ have an activity similar to IFN-α.

Antiviral mechanism

Interferons have a much more complex activity than the one described initially by Isaacs and Lindenmann. They are produced in response to the appearance in the body of a wide variety of antigens and other cytokines and play an important role in anti-tumour defence. However, the function which is perhaps best described is the antiviral activity.

Interferon is the first active defence against a viral infection. Their production is induced by the presence, in the infected cell, of a double-stranded RNA, a type of nucleic acid non-existent in normal human cells and that is part of some viral genomes, resulting from replication of viral genetic material (either DNA or RNA). Interferons are excreted into the extracellular fluid and will fix itself, in neighbouring cells and in their respective receptors, where they activate several antiviral protein coding genes. The two main routes with direct antiviral activity is the production of a protein kinase, which inhibits phosphorylation of IF-2 (initiation factor) and blocks the translation of proteins, and the synthesis of 2 ‘5 ‘-oligoadenilato synthetase that activates an endonuclease involved in the degradation of viral RNA. The infected cell dies by apoptosis in a programmed manner and viruses are unable to replicate. The activity of interferons is also the cause of systemic symptoms associated with many viral infections, such as the malaise, myalgias, headache and fever.

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References:

  • Cha, L. et al. (2014). Interferon-alpha, immune activation and immune dysfunction in treated HIV infection. Clinical & Translational Immunology. 3, p1-6.
  • DeFranco, A.L. et al. (2007). Immunity: The Immune Response in Infectious and Inflammatory Disease. New York: New Science Press.
  • Dussurget, O. et al. (2014). The bacterial pathogen Listeria monocytogenes and the interferon family: type I, type II and type III interferons. Frontiers in cellular and infection microbiology. 4 (50), p1-12.
  • Egli, A. et al. (2014). The impact of the interferon-lambda family on the innate and adaptive immune response to viral infections. Emerging Microbes & Infections. 3, p1-12.
  • Karper, L.H. et al. (2014). Immunomodulatory activity of interferon-beta. Annals of Clinical and Translational Neurology. 1 (8), p622-631.
  • Parham, P. (2000). The immune system. New York: Garland Publishing. p219-220.
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