Interferons: Type I | José Ignacio Saldana, Imperial College, London, UK
Viruses have adapted strategies to overcome and evade the immune system and, in response, the host has evolved a broad range of strategies to ensure complete protection against viral infection. One of these strategies relies on the production of proteins that interfere with viral replication – stopping further transmission to, and infection of, neighbouring healthy cells. This group of cytokines were named interferons due to their ability to “interfere” with the life cycle of the virus and they are produced early during infection, even before other immune responses begin. The two best characterised interferons are: IFNα, a family of closely related molecules, and IFN-β which is a single gene product.
Interferon synthesis occurs primarily in response to viral single-stranded or double stranded RNA. These RNA molecules are either the genetic material of RNA viruses or a product of viral transcription that can be detected only after viral particles are degraded. In order to detect these viral products, cells have develop specific recognition receptors present in endosomes as it is there where degraded viruses are more abundant. One of the best described group of receptors are Toll-like receptors (TLR) 7, 8 and 3. Upon binding to viral RNA, they induce a signal that results in the production and secretion of interferons (see Figure 1). In addition, there are other cytoplasmic RNA receptors, such as the retinoic acid-inducible gene I (RIG-1), that are are also able to detect viral material outside of the endosome and induce interferon synthesis.
Figure 1. Increased expression of MHC I and viral antigen presentation induces CD8 T cell killing of the infected cell or protection from NK cells if the cell is uninfected
Interferons contribute to the resistance against viral infection by binding to a common cell surface receptor on the infected cell as well as on neighbouring uninfected cells. This triggers a cascade of signals that end in the rapid transcription of several host cell proteins that contribute to the slowing down of viral proliferation. One of these proteins is the enzyme oligoadenylate synthetase (OAS) that catalyses the synthesis of specific 2’-5’ linked nucleotides that activate a host ribonuclease that degrades viral RNA. Other products induced by interferons are the protein Mx that drives resistance to infuenza virus as well as the serine-threonine kinase (PKR) that mediates the inhibition of protein translation, restricting the production of viral proteins from the the viral genome (see diagram of target cell; Figure 1).
Another way IFNα and IFN-β protect host cells against viruses is by triggering cellular immune responses to these pathogens. Interferon stimulation of uninfected cells results in an up-regulation of the MHC class I pathway of antigen presentation, favouring the specific recognition and killing of the infected cells by CD8 T cells. Interferons can also activate NK cells which in turn can release cytokines, induce inflammation and kill infected cells.
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