see also:

• immunology
• innate immunity
• adaptive immunity
• cytokines

• interferons are a group of immune system signalling proteins belonging to the group of cytokines, named as they “interfere” with viral replication and were first described in 1957
• in general, type I and II interferons are responsible for regulating and activating the immune response, in particular to viral infections, while type III interferons have important roles in both viral and fungal infections
• IFNs activate signal transducer and activator of transcription (STAT) complexes which regulate the expression of certain immune system genes - each IFN type can activate unique STATs in addition to shared STATs, and STATs then activate the Janus kinase-STAT (JAK-STAT) signaling pathway
• they can inhibit intracellular viral replication via:
  • reduction of protein synthesis in the cell via stimulating production of large amounts of protein kinase R (PKR)
  • increases destruction of intracellular RNA via stimulating production of RNAse L enzyme
  • inducing production of hundreds of other proteins—known collectively as interferon-stimulated genes (ISGs)
• they can limit viral spread via increasing p53 activity, which kills virus-infected cells by promoting apoptosis
• they can increase the expression of major histocompatibility complex (MHC) antigens and improve host immune responses by increasing antigen presentation
• they can activate natural killer cells and macrophages
• along with other cytokines, they are responsible for the viraemic symptoms of fever, myalgias, etc
• virtually all cell types can express type I and III interferons in response to viral infection of the cell, triggers include:
  • pattern recognition receptors, such as membrane bound toll like receptors or the cytoplasmic receptors RIG-I or MDA5 detecting:
    • viral glycoproteins, viral RNA, bacterial endotoxin (lipopolysaccharide), bacterial flagella, and CpG motifs
  • Toll Like Receptor 3 (TLR3) can detect viral dsRNA which can then activate the transcription factors IRF3 and NF-κB which are important for initiating synthesis of many inflammatory proteins.
• type II interferons are generally only produced by immune cells
• many viruses have found ways to reduce actions of interferons and thus cause infection such as by:
  • produce proteins that bind to IFNs and thus stop them binding to receptors
  • inhibition of IFN signaling
  • prevention of further IFN production
  • inhibition of proteins produced by actions of IFNs
  • etc

• all bind to a specific cell surface receptor complex known as the IFN-α/β receptor (IFNAR) which usually which leads to expression of proteins that will prevent a virus from producing and replicating its RNA and DNA
• they are mainly produced by circulating plasmacytoid dendritic cells but also by stimulated monocytes and macrophage, esp. in response to viral infections
• IFNα
  • production inhibited by interleukin-10
  • can be used to Rx hepatitis B virus and hepatitis C virus
• IFNβ
  • can be used to treat multiple sclerosis (MS)
• IFN-ε
• IFN-κ
• IFNω
• virus infections trigger the immune cells to release type 1 interferons which act as early messengers that warn uninfected cells and tissues that a virus is spreading
• in those with impaired type 1 interferon function, severe viral illness is much more likely to occur
• 5-15% of patients requiring admission to hospital from COVID-19 coronavirus (2019-nCoV / SARS-CoV-2) or influenza had impaired type 1 interferon responses due to the presence of autoantibodies that bind type 1 interferons (“neutralizing anti-IFN-I autoAbs”) - these occur in 2% of the population during their life time, usually at age 60-65yrs, and once developed are usually lifelong ¹⁾
  • a minority have genetic mutations which predispose to development of these auto-antibodies in early childhood

• binds to IFNGR
• IFN-γ
  • activated by interleukin-12
  • released by cytotoxic T cells and type-1 T helper cells
    • this can be triggered by mitogens
  • block the proliferation of type-2 T helper cells which results in an inhibition of Th2 immune response and a further induction of Th1 immune response

• bind to a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12)