Interferon

Interferons (IFNs) are signaling proteins that cells release in response to viruses and other threats, switching on hundreds of antiviral genes in nearby cells and coordinating the immune response. They are among the body's earliest defenses against infection, acting within hours, long before antibodies or T cells are ready.

Interferons were discovered in 1957 by Alick Isaacs and Jean Lindenmann, who found that cells exposed to inactivated influenza virus released a substance that protected other cells from infection. They named it after its ability to interfere with viral replication.

Interferons are grouped into three types according to the receptors they use:

• Type I interferons include several IFN-α subtypes (13 in humans), IFN-β, and a few others. Almost any infected cell can make them, but plasmacytoid dendritic cells produce them in especially large amounts. They act through a receptor (IFNAR) found on nearly all cells.
• Type II interferon has a single member, IFN-γ, produced mainly by T cells and natural killer cells. Rather than acting as a direct antiviral alarm, it chiefly activates macrophages, boosts antigen presentation by the major histocompatibility complex, and steers immunity toward fighting intracellular pathogens.
• Type III interferons (IFN-λ) act through a receptor found mainly on epithelial cells lining the airways, gut, and liver. They provide targeted antiviral protection at barrier surfaces while causing less body-wide inflammation than type I interferons.

Cells make interferon when sensors called pattern-recognition receptors detect molecules that signal infection, especially viral nucleic acids:

• RIG-I and MDA5 detect viral RNA in the cytoplasm and signal through the adaptor MAVS on mitochondria.
• cGAS detects DNA in the cytoplasm, where it should not be, and activates the adaptor STING.
• Toll-like receptors in endosomes detect double-stranded RNA (TLR3), single-stranded RNA (TLR7 and TLR8), and DNA (TLR9).

These pathways activate the transcription factors IRF3, IRF7, and NF-κB, which switch on the interferon genes.

Secreted type I interferon binds IFNAR on the infected cell and its neighbors, activating the JAK–STAT signaling pathway. The kinases JAK1 and TYK2 phosphorylate STAT1 and STAT2, which join IRF9 to form a complex called ISGF3. ISGF3 enters the nucleus and turns on hundreds of interferon-stimulated genes (ISGs). Their products attack viruses at nearly every stage:

• MX proteins trap viral components and block replication of influenza and other viruses.
• OAS and RNase L detect double-stranded RNA and destroy RNA in the cell, viral and cellular alike (see ribonuclease).
• PKR shuts down protein synthesis by phosphorylating a key translation factor.
• IFITM proteins block the fusion of viral membranes with cell membranes.

Together these create an antiviral state: cells become hostile to viral replication, more visible to killer T cells, and primed to die rather than become virus factories.

Because interferon is so effective, nearly every successful virus carries proteins that block it. Influenza's NS1 protein hides viral RNA from sensors, and many coronavirus proteins interfere with interferon production and signaling. Flaviviruses such as dengue virus and Zika virus degrade or block STAT2. These evasion strategies are one reason the same virus can be mild in one host species and deadly in another.

• Treatments: IFN-α was long used, with ribavirin, to treat hepatitis C until direct-acting antiviral drugs replaced it. It is still used for some patients with hepatitis B and certain cancers. IFN-β is a long-standing treatment for relapsing multiple sclerosis, and IFN-γ is used to reduce infections in chronic granulomatous disease.
• Too little interferon: Inherited defects in interferon pathways, or autoantibodies that neutralize type I interferons, can cause life-threatening viral infections. In 2020, researchers found such autoantibodies in at least 10% of patients with life-threatening COVID-19 pneumonia.
• Too much interferon: Excess type I interferon drives inflammation in systemic lupus erythematosus and in rare inherited "interferonopathies" such as Aicardi–Goutières syndrome. Anifrolumab, an antibody that blocks the type I interferon receptor, was approved for lupus in 2021.

Interferons show how the innate immune system buys time against viruses and shapes the adaptive response that follows, a key theme in immunology and vaccine design.