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  • Since innate immune responses represent the first defense ag

    2024-02-10

    Since innate immune responses represent the first defense against incoming infectious microorganisms, they are particularly engaged during the early stages of viral infections. Many innate defense mechanisms rely on the engagement of pattern recognition receptors (PRRs) which are conserved, germ line-encoded receptors able to sense and signal the presence of conserved microbial characteristics called pathogen-associated molecular patterns (PAMPs). Signaling pathways activated by PRRs trigger direct cell-autonomous responses and instruct adaptive immune mechanisms via soluble mediators and induction of surface-expressed factors. Among PRRs, toll-like receptors (TLRs) constitute a group of membrane-spanning factors differentially associated with biological membranes. In contrast with TLR1/2/4/5/6/10 members expressed on the plasma membrane, TLR3/7/8/9 factors are positioned within compartments of the endocytic pathway. TLR2/3/4/7/8/9 are able to sense nucleic acids or proteins of viral origin [19]. Except TLR3 that signals by recruiting an adaptor called TRIF, TLRs engagement leads to recruitment of the MyD88 adaptor and to activation of the transcription factor nuclear factor-kappa B (NF-κB). This pathway is essential to induce inflammatory cytokine gene expression. In some instances, TRIF can be recruited by TLR4 to activate type I interferon (IFN-I) regulatory transcription factors (IRFs) such as IRF3 and IRF7, that are involved in the synthesis of antiviral type-I interferon (IFN-α/β). IFN-I synthesis is a hallmark of the sensing of viral constituents by TLRs. This illustrates how important IFNα/β are in the resistance to invading viruses [20]. Immediately after virus sensing, a large amount of the IFNα/β produced originates from the so-called plasmacytoid dendritic Ellipticine mg (pDCs). Such a property relies on the preexisting expression of IRF3/7 transcription factors. This makes pDCs clearly apart from other cell types where IRF3 is the sole IRF that can be constitutively expressed. IFNβ interacts with the IFN-I receptor (IFNAR) to initiate an autocrine/paracrine-positive feedback loop that in turn ensures an abundant secretion of IFNα. As to the IFNα–IFNAR interaction, it activates the expression of a large number of genes called IFN-stimulating genes (ISGs) that constitute additional means to resist viral infections, for instance, by reinforcing the capacity of cells to sense pathogens or by interfering with the viral cycle. IFN-I signal through the Janus kinase (JAK)–signal transducers and activators of transcription (STAT) pathway. Many ISGs can be induced through the JAK–STAT pathway but others are induced directly via IRFs independently of JAK–STAT factors. The cytosolic protein kinase regulated by RNA (PKR) is an example of ISGs induced through the JAK–STAT pathway associated to IFNAR engagement. PKR is a factor capable of sensing double-stranded (ds) viral RNA. Its engagement induces its auto-phosphorylation that leads to phosphorylation of the eukaryotic translation initiation factor-2 subunit-1 (eIF2α) that can inhibit protein translation. Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) constitute another group of factors able to sense the presence of viruses within the cytosol. The viral RNA sensors RIG-I and MDA5 are well known examples of RLRs. RIG-I engagement leads to its interaction with mitochondria-associated adaptor IFN-β promoter stimulator 1 (IPS-1; also named MAVS, CARDIF or VISA), which auto-assemble in aggregates to trigger the activation of TRAFs, NF-κB and IRF3/7 leading to the secretion of IFN-I and pro-inflammatory cytokines [21]. In turn, both IFN-I stimulation and viral infection can up-regulate the expression level of RLRs such as RIG-I and MDA5. IPS1 can also be recruited upon engagement of NOD2, a prototypical member of the nod-like receptor (NLR) family of PRRs, which is specialized in the cytosolic sensing of single-stranded (ss) viral RNAs [22]. Cells possess additional means to detect viral nucleic acids within the cytosol. The DNA-dependent activator of IRFs (DAI) initiates inflammatory cytokines and/or IFN-I production in response to viral DNA sensing. Upon dsRNA binding, the 2′–5′-oligoadenylate synthase (OAS) activates latent ribonuclease (RNAseL) to degrade viral RNA and interfere with replication. The OAS homolog cyclic GMP-AMP (cGAMP) synthase (cGAS) binds DNA leading to production of the 2′–5′-linked intermediate cGAMP that activates antiviral genes, including IFN-I, through STimulator of INterferon Genes (STING), a component expressed on the ER [23], [24]. During viral infection, large complexes of cytosolic proteins called inflammasomes can be assembled. NLRP3 and Absent in melanoma 2 (AIM2) are NLR factors capable of mediating inflammasome activation in response to PAMPs. This activation induces the caspase 1-mediated cleavage of precursors of pro-inflammatory cytokines that are induced by the NF-κB pathway in response to PAMPs. Prototypical pro-inflammatory cytokines produced by this activation [e.g., interleukin (IL)-1β, IL-18 and IL-33] underlie various forms of cellular responses such as the recruitment and activation of macrophages, dendritic cell (DC) maturation or differentiation of inflammatory T cells. Thus, several pathways contribute to anti-viral defense through the detection of viral nucleic acids in the cytosol or in endosomes. While some receptors trigger the activation of transcription factors that induce anti-viral factors and cytokines, other receptors mount antiviral activity via direct targeting. As we will see, the autophagic process itself, and the autophagy machinery at large, can contribute to, intersect with and regulate the engagement of Ellipticine mg these pathways during viral infection.