Interferons: types, chemical nature, properties and mechanism of action

July 27, 2018

Introduction to Interferons

Interferons are low molecular weight protein, produced by virus infected cells.
These, itself induces the formation of a second protein inhibiting the transcription of viral mRNA.
These are produced by the host cell in response to the virus particle, viral nucleic acid and non-viral agents.
Non-viral agents include synthetic polynucleotides such as polyinosinic acid and polycytidylic acid (poly I:C).
These are a family of natural glycoproteins which inhibits viral replication.
Isaacs and Lindermann discovered interferon in 1957.

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A) Types of interferons

There are three antigenically and chemically distinct types of interferon. They are:

i) Type I interferons

These are acid-stable and produced by monocytes and B lymphocytes.
These comprise two major classes, leukocyte interferon (Le-IFN, IFN-alpha) released by stimulated leucocytes, and fibroblast interferon (F-IFN, IFN-beta) released by stimulated fibroblasts.
These have maximal antiviral activity.
These induce viral resistant state in human cells.

ii) Type II interferons

These are acid-labile and are also known as ‘immune’ (IFN-gamma) interferons because they are produced by T lymphocytes in the cellular immune system in response to specific antigen.
These are more active in inhibiting growth of tumour cells.
These have intermediate antiviral activity.
These are more active as a lymphokine than as an antiviral agent.

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B) Chemical nature and formation

They are glycoprotein in nature with molecular weight 20,000 to 40,000.
They do not contain any nucleic acid and are nontoxic and non-antigenic.
They can withstand heating at 37⁰C for 30 to 60 minutes.
These are inactivated by proteolytic enzymes.
Interferon α and interferon β share many properties, including structural homology and mechanism of action.
Interferon α is produced by B lymphocytes, monocytes and macrophages.
Interferon β is produced by fibroblasts and other cells in response to viral infections and other stimuli.
Interferon γ is produced by activated T lymphocytes and NK cells in the later part of infection. It is also called macrophage activation factor.

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C) Properties

Interferons have antiviral properties in adjacent, non-infected cells (as opposed to in infected cells).

i) Species specific

Interferon produced by one species can protect only cells of the same or related animal species against viral infection.
Thus, interferon produced by mouse cell in tissue culture is active only on other mouse cells but without any effect in chicken cells.

ii) Non-specificity

Interferon activity is not virus specific.
Interferon induced by non-virus (non-viral inducers) render cell resistant to infection by the same or unrelated broad spectrum of viruses.

iii) Virus susceptibility

Though all viruses are inhibited by interferon, but RNA viruses are more susceptible to interferon.

iv) Relation to recovery

During the acute phase of disease, interferon α and β combat viral multiplication and is probably responsible for recovery.

D) Mechanism of action

Synthesis of IFN- α and IFN- β begin with an hour of infection and attains maximum level in 6-12 hours.
Once synthesized, the interferons bind to specific receptors on uninfected neighbouring cells in which they inhibit viral replication.
Inhibition of replication of virions by interferon is mediated by cellular enzymes expression of which is regulated by interferons.
These antiviral proteins are not, however, activated until they bind to double stranded RNA.

I) Type I interferons

They inhibit viral protein synthesis, but cellular protein synthesis is not affected.
They inhibit viral protein synthesis by activating the under mentioned enzyme.
Two oligo-A adenylate synthetases which, in the presence of ds-RNA, synthesize an adenine nucleotide 2’- 5’ phosphordiester linkages.
The linkage product digests viral mRNA.
A 68kd protein kinase in presence of ds-RNA inactivates elongation factor-2 (EF-2) and blocks protein synthesis.
Type I interferons may block viral replication in some other stages, including budding.

II) Type II interferons

IFN- γ also possesses antiviral activity.
Induction of nitric oxide synthetase causes increase in intracellular nitric oxide concentration leading to inhibition of viral replication.

Upregulation of MHC-I and MHC-II expression

IFN- γ enhances the activation and effector function of cytotoxic T cells capable of destroying virus infected cells.

Activation and cytotoxicity

IFN- γ also enhances the activation of the monocytes, macrophages and NK cells which are capable of killing virus-infected cells by non-immune mechanisms.

References:

i) https://www.nature.com/articles/nri1604