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PATH 3610 (113)
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Lecture 4

Lecture 4 notes

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Department
Pathology
Course
PATH 3610
Professor
Rob Foster
Semester
Winter

Description
LECTURE 4 – HOST DEFENSE RIG-I and TLRs • Should know superficially these pathways and understand what species of RNA they recognize Toll-like receptors (TLRs) - Type I transmembrane proteins - Pattern recognition receptors that recognize pathogen-associated molecular patterns (PAMPs) Recept Ligand Origen of ligand or TLR3 Double-stranded viruses RNA TLR7 Single-stranded Viruses RNA TLR8 Single stranded RNA Viruses TLR9 CpG-containing DNA Bacteria and viruses TLR4 Fusion protein Respiratory syncytial viruses Envelope protein Mouser mammary-tumour virus - T+LR 3, 7, 8 and 9 are localized on cytoplasmic vesicles and recognize microbial nucleotides. - TLRs are generally not suitable for recognizing viruses that have infected cells and are localized in the cytoplasm or nucleus. TLR3-dependent signaling pathway • TLR3 recognizes dsRNA and poly(I:C) • TLR3 plays important roles in evoking inflammatory responses • TLR signaling can be beneficial or deleterious depending on the type of virus infection o Influenza virus takes advantage of the TLR3-mediated inflammatory response for establishing infection TLR7 and TLR9 signalling • Present on plasmacytoid dendtritic cells, which produce large amounts of IFN-α • TLR7 recognizes ds-RNA and TLR9 CpG-containing DNA • TLR7, 8 and 9 signal through MyD88 (myeloid differentiation factor 88) • TLR3 and 4 signal via TRIF RIG-I like helicases (RLHs) - Expressed in most cell types - RLHs recognize RNA molecules derived from RNA viruses - RIG-I is made up of caspase recruitment domains (CARDs) and a helicase domain - RIG-I and MDA5 interact with dsRNA through their helicase domains and strongly induce interferon (IFN). • RIG-I and MDA5 recognize different RNA viruses • RNAs are also differentially recognized by RIG-I and MDA5 o MDA5 recognizes longer dsRNAs RIG-I activation - After viral infection, RIG-I binds viral RNA through its repressor/regulatory domain (RD) - TRIM24 adds ubiquitin molecules to the CARDS, helping RIG-I bind to MAVS (mitochondrial antiviral signaling protein) - The signaling cascade turns on IFN and antiviral and inflammatory molecules. Function of IFN and general information about the main IFN effector pathways • What it does, pathways, what are the genes and how they interfere in infections Function - IFNs induce an antiviral state - There are 4 main effector pathways of IFN-mediated antiviral response: o ISG15 ubiquitin-like pathway o MxGTPase pathway o 2’,5’-oligoadenylate-synthase-directed ribonuclease L pathway (OAS-RNAseL) o Protein kinase R pathway (PKR) - To control viral replication, these effector pathways: o Block viral transcription o Degrade viral RNA o Inhibit translation o Modify protein function IFN receptor signalling - Binding of IFN triggers the JAK-STAT pathway which leads to activation of STATs - STAT associate with IRF9 forming ISGF3 (IFN-stimulated gene factor 3) - ISGF3 translocate to the nucleus to induce IFN-stimulated genes from IFN-stimulated response elements (ISREs) IFN-regulated ubiquitin-like protein response - A series of ubiquitin enzymes are induced by type I IFNs through IRSEs - E1, E2, E3 proteins catalyze the conjugation of ISG15 to numerous protein substrates to modulate pleiotropic cellular responses to inhibit virus production. Mechanism of action of MxA - Following stimulation with type I IFNs, MXA gene expression is induces through ISRE in the promoter - MxA protein accumulates in the cytoplasm on intracellular membranes as oligomers - MxA bind viral nucleocapsids or other viral components, to trap and degrade them. The OAS1-RNaseLAntiviral pathway - OAS1 is upregulated by type I IFNs - Induced through ISREs, OAS1 oligomerizes to form a tetramer that synthesizes 2’,5’- oligoadenylates - It enables RNaseL to cleave cellular and viral RNAs. Mechanism of action of PKR - PKR expression induced by type I IFNs under the control of ISRE - PKR is activated in response to dsRNA - Phosphorylation of EIF2α leads to inhibition of translation Tetherin - IFN-inducible cellular factor that impairs release of many enveloped viruses e.g. HIV-1 Effectors of the innate and adaptive immune response e.g. dendritic cells, cytokines - Dendritic cells and macrophages  sentinel cells in peripheral compartments - DCs and MO evoke a rapid antiviral response via production of IFN-α and IFN-β which in turn: o Induce cellular resistance to viral infection o Induce apoptosis of virus infected cells o Activate NK and T cells Dendritic c
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