Interferons and Antiviral Immunity
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Direct answer
Interferons are cytokines that virus-infected cells release to warn neighbouring cells and induce an antiviral state. Type I interferons, IFN-alpha and IFN-beta, are produced by most nucleated cells in response to viral nucleic acid. Type II interferon, IFN-gamma, comes mainly from T cells and natural killer cells and is chiefly immunoregulatory, while type III interferon, IFN-lambda, acts mainly on epithelial surfaces.
What you must remember
- Type I: IFN-alpha, made by leukocytes, and IFN-beta, made by fibroblasts, both signal through the same receptor, IFNAR.
- Type II: IFN-gamma activates macrophages and is the principal interferon of cell-mediated immunity.
- Type III: IFN-lambda uses its own receptor and acts mainly on epithelial cells of the lung and gut.
- Viral sensing: RIG-I and MDA5 in the cytoplasm and TLR3 in endosomes detect viral RNA and trigger interferon-beta transcription.
- JAK-STAT signalling: Receptor binding activates JAK1 and TYK2, which phosphorylate STAT1 and STAT2 to form ISGF3, the transcription complex that switches on interferon-stimulated genes.
- Antiviral state: Protein kinase R halts translation, OAS with RNase L degrades RNA, and Mx proteins block viral replication.
- Therapeutic uses: Interferon-alpha is used in chronic hepatitis B and in selected haematological cancers, while interferon-beta is used in multiple sclerosis.
- Species specificity: Interferons act only on cells of the same species, so animal experiments need species-matched interferons.
A relay from infected cell to neighbouring cells
The antiviral response is a relay that protects uninfected cells before the virus spreads. Exams usually ask for the order of signalling and the effector molecules, so learn it as a chain of six steps.
- Viral sensing: Pattern recognition receptors RIG-I and MDA5 in the cytoplasm, and TLR3 in endosomes, recognise viral RNA and start the response.
- Interferon-beta transcription: Transcription factors IRF3 and NF-kappa B switch on the interferon-beta gene, and the infected cell releases the cytokine.
- Receptor binding: Interferon binds IFNAR on a neighbouring cell, which activates JAK1 and TYK2 on the receptor's cytoplasmic tail.
- STAT signalling: Phosphorylated STAT1 and STAT2 combine with IRF9 to form ISGF3, which moves to the nucleus and binds interferon-stimulated response elements.
- Effector genes: Protein kinase R phosphorylates eIF2-alpha to stop translation, OAS and RNase L degrade RNA, and Mx proteins inhibit viral replication, which together form the antiviral state.
- Immune amplification: Interferon also activates natural killer cells and dendritic cells, linking the innate response to adaptive immunity.
Because the antiviral state is induced rather than preformed, a virus that blocks one step can still be controlled by the others. The NS1 protein of influenza virus is an example of a viral protein that antagonises this relay and helps the virus survive.
Where the exam tries to catch you
Interferon questions often hinge on which type acts where, and the wrong answer usually confuses type II with the early antiviral response.
- Trap: Assuming IFN-gamma is the main early antiviral interferon Correct: Type I interferons mount the early antiviral response, whereas IFN-gamma is mainly a T cell and natural killer cell product that activates macrophages.
- Trap: Assuming interferons destroy extracellular virus directly Correct: They act on neighbouring uninfected cells, which then resist infection, and do not kill virions on their own.
- Trap: Believing interferon is a universal cure for chronic hepatitis B Correct: Peginterferon gives a sustained response only in selected patients, so it is used alongside nucleos(t)ide analogues rather than replacing them.
Frequently asked questions
Which interferon is produced by T cells and natural killer cells?
IFN-gamma, the type II interferon, is produced by T cells and natural killer cells. It activates macrophages and enhances antigen presentation, so it is central to cell-mediated immunity.
Which receptor do type I interferons use?
Type I interferons, including IFN-alpha and IFN-beta, bind a common receptor called IFNAR, which activates the JAK-STAT pathway. Type III interferon uses a different receptor, the IFN-lambda receptor, and acts mainly on epithelial cells.
How does interferon make a cell resistant to virus infection?
Interferon induces interferon-stimulated genes such as protein kinase R, OAS with RNase L and Mx proteins. Together they block viral translation, degrade RNA and inhibit replication, producing the antiviral state in cells that are not yet infected.
Why is peginterferon alpha used in chronic hepatitis B?
Peginterferon alpha is used in selected patients with chronic hepatitis B to achieve a sustained off-treatment response. Its immunomodulatory and antiviral effects can produce this response in some patients, so it is considered alongside nucleos(t)ide analogues.
Which influenza protein blocks the interferon response?
The NS1 protein of influenza virus antagonises the interferon response by blocking interferon production and signalling in the infected cell. This helps the virus replicate in the host before the antiviral state takes hold.