Type I interferons are inducible and are synthesized by many cell types after infection by diverse viruses. Almost all types of cells can produce IFN-α and IFN-β in response to activation of several innate sensors. For example, type I interferons are induced by RIG-I and MDA-5 (the sensors of cytoplasmic viral RNA) downstream of MAVS, and by signaling from cGAS (the sensor of cytoplasmic DNA) downstream of STING (see Sections 3-10 and 3-11).
C-reactive protein binds phosphocholine on bacterial surfaces, acting as an opsonin, and also activating complement Serum amyloid protein
IFN-˜, IFN-°Virus-infected host cells virus
Fig. 3.35 Interferons are antiviral proteins produced by cells in response to viral infection. The interferons IFN-α and IFN-β have three major functions. First, they induce resistance to viral replication in uninfected cells by activating genes that cause the destruction of mRNA and inhibit the translation of viral proteins and some host proteins. These include the Mx proteins, oligoadenylate synthetase, PKR, and IFIT proteins. Second, they can induce MHC class I expression in most cell types in the body, thus enhancing their resistance to NK cells; they may also induce increased synthesis of MHC class I molecules in cells that are newly infected by virus, thus making them more susceptible to being killed by CD8 cytotoxic T cells (see Chapter 9). Third, they activate NK cells, which then selectively kill virus-infected cells.
However, some immune cells seem to be specialized for this task. In Section 3-1 we introduced the plasmacytoid dendritic cell (pDC). Also called interferon-producing cells (IPCs) or natural interferon-producing cells, human plasmacytoid dendritic cells were initially recognized as rare peripheral blood cells that accumulate in peripheral lymphoid tissues during a viral infection and make abundant type I interferons (IFN-α and IFN-β)—up to 1000 times more than other cell types. This abundant production of type I interferon may result from the efficient coupling of viral recognition by TLRs to the pathways of interferon production (see Section 3-7). Plasmacytoid dendritic cells express a subset of TLRs that includes TLR-7 and TLR-9, which are endosomal sensors of viral RNA and of the nonmethylated CpG residues present in the genomes of many DNA viruses (see Fig. 3.11). The requirement for TLR-9 in sensing infections caused by DNA viruses has been demonstrated, for example, by the inability of TLR-9-deficient plasmacytoid dendritic cells to generate type I interferons in response to herpes simplex virus. Plasmacytoid dendritic cells express CXCR3, a receptor for the chemokines CXCL9, CXCL10, and CXCL11, which are produced by T cells. This allows pDCs to migrate from the blood into lymph nodes in which there is an ongoing inflammatory response to a pathogen.
Interferons help defend against viral infection in several ways (Fig. 3.35). IFN-β is particularly important because it induces cells to make IFN-α, thus amplifying the interferon response. Interferons act to induce a state of resistance to viral replication in all cells. IFN-α and IFN-β bind to a common cell-surface receptor, known as the interferon-α receptor (IFNAR), which uses the JAK and STAT pathways described in Section 3-16. IFNAR uses the kinases Tyk2 and Jak1 to activate the factors STAT1 and STAT2, which can interact with IRF9 and form a complex called ISGF3 that binds to the promoters of many interferon stimulated genes (ISGs).