Type I IFNs

The IFNs are classified into type I (> 20 members), type II (IFN-y), and type III (three types of IFN-A). IFN-y is produced by natural killer (NK) and natural killer T (NKT) cells stimulated by IL-12, while type I and III IFNs are generally produced in response to viral infections.76 Type I IFNs form part of the most diverse family cytokines, and upon binding to the interferon-a/(3 receptor (IFNAR), induce transcriptional modulation of over 1000 genes with diverse biological properties as part of the innate immune response.76

The IFNAR receptor consists of two transmembrane protein chains (IFNAR1 and 2), associated to the cytoplasmic Janus Kinase 1 (JAK1) and tyrosine kinase 2 (TYK2). In the canonical signal transduction pathway, STAT1 (signal transducer and activator of transcription 1) and STAT2 proteins are phosphorylated, bind interferon regulatory factor 9 (IRF9), and this complex translocates to the nucleus to activate ISGs.77 However, this signal transduction pathway is not isolated, and it is extensively interconnected with signaling pathways from the innate immune system involved in pattern recognition, including the Toll-like receptors (TLRs), RIG-I like receptors (RLGs), NOD-like receptors, and C-type lectin receptors.78

There are different mechanisms by which pathogens can activate type I IFN production, namely interaction with TLRs and cytosolic surveillance molecules. TLRs are transmembrane receptors specialized in the recognition of pathogen associated molecular patterns which are expressed in immune and some nonimmune cells. Upon binding of a ligand, TLRs dimerize and signal through the adaptor molecules myeloid differentiation factor 88 (MyD88) and TIR (Toll/interleukin-1 receptor) domain-containing adaptor protein inducing interferon beta (TRIF) (reviewed in Ref. [79]).

The signal transduction networks activated downstream of the innate immunity receptors is vast and complex and a detailed description of it is beyond the scope of this chapter. We refer the reader to the excellent reviews on the subject in Refs. [76,78,79]. However, in the following paragraphs of this section we will mention some of the molecules in the signaling networks downstream of TLRs and other cytoplasmic receptors, which are relevant to the discussion of studies about type I IFN induction during T. cruzi infection.

Among the molecules known to act downstream of MyD88 and TRIF are the interferon regulatory transcription factor 3 (IRF3) and TANK-binding kinase 1 (TBK1). IRF3 is sufficient to induce the expression of IFN-(3, and upon phosphorylation by TBK1 dimerizes and translocates to the nucleus, binding the IFN-в promoter , and driving the expression of IFN-в itself (autocrine loop) and of ISGs.

Production of type I IFNs can also occur in a TLR-independent manner. Cytoplasmic pathogens are detected by a different set of receptors, among which the retinoic acid-inducible protein I (RIG-I) and melanoma differentiation-associated

gene 5 (MDA5) are cytoplasmic receptors which recognize dsRNA of viral origin, and are required for type I IFN responses against several types of viruses. The signal transduction pathway downstream of RIG-I and MDA5 converges with that of TLRs in the activation of TBK-1, which phosphorylates IRF3.79 A variety of other DNA cytoplasmic sensors capable of inducing IFN production are known (reviewed by Gurtler and Bowie82).

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