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Harro Frauendorf. Introduction. Infection: microbes vs. host Viruses try to secure a niche for replication Host must limit pathogen's advance Type 1 interferons are key players many members: IFN- α / β Virus evolved tricks to avoid antiviral effects of IFNs (co evolution).

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Introduction
Introduction

  • Infection: microbes vs. host

  • Viruses try to secure a niche for replication

  • Host must limit pathogen's advance

  • Type 1 interferons are key players

    • many members: IFN-α/β

  • Virus evolved tricks to avoid antiviral effects of IFNs (co evolution)


Induction of type 1 ifns by viruses
Induction of type 1 IFNs by viruses

  • Two functional classes:

    • Extracytoplasmic pathway

    • Cytoplasmic pathway

    • Localization: either cell membrane or cytoplasm consequence: IFN production either in infected cells and/or before viral contact


Extracytoplasmic pathway

TLR-dependent

Extracytoplasmic pathway

general sensor

constitutively expressed in a subset of cells, the plasmacytoid dendritic cells (PDCs),

(TLR2 and TLR4 can also detect viral products such Core, NS3

or F-protein, Env-protein.)


Extracytoplasmic pathway by tlr3
Extracytoplasmic pathway by TLR3

  • TLR3 become activated and transmit signals through their cytoplasmic Toll/ interleukin-1 receptor (TIR) domains

  • TIR domain–containing adaptor inducing IFN-β (TRIF)

  • TRIF mediates the activation of IκB kinase ε (IKK ε) and tankbinding kinase 1 (TBK1)

  • which phosphorylate IFN regulatory factor 3 (IRF3), resulting in its dimerization and nuclear translocation´where it promotes gene transcription

  • activation of neural factor κB (NF-κB) and activating protein 1 (AP1) through the kinase complex IKKα/β/γ and the mitogen-activated protein kinase (MAPK) cascade

     Interferon


Extracytoplasmic pathway by tlr7 8 9
Extracytoplasmic pathway by TLR7/8/9

  • myeloid differentiation primary response protein 88 (MyD88)

  • interleukin-1 receptor–associated kinases IRAK1 and IRAK4, and the tumor necrosis factor receptor–associated factor 6 (TRAF6)

  • IRF7 initiates the general induction of the IFN-a genes

  • TLR7/8/9 and IRF7 appear to be constitutively expressed in only a subset of cells, the plasmacytoid dendritic cells (PDCs), which are characterized by high IFN production

     Interferon


Cytoplasmic pathway
Cytoplasmic pathway

  • TLR-independent

  • DExD/H box RNA helicase that contain caspase-recruiting domains (CARDs)

  • Intracellular recognition of viruses by:

    • Retinoic acid-inducible gene I (RIG-I)

    • melanoma differentiation associated gene 5 (mda5).


Cytoplasmic pathway1
Cytoplasmic pathway

  • RNA helicases, upon binding to dsRNA, interact with a downstream molecule

    (named independently by four different groups as mitochondrial antiviral signaling protein (MAVS), IFN-b promoter stimulator 1 (IPS-1), virus-induced signaling adaptor (VISA), and CARD adaptor–inducing IFN-β (CARDIF))

  • next steps are not well define  Interferon



Ifn mediated effects on defense1

type 1 IFNs regulate a range of immune responses through the type 1 IFN receptor

IFN-a receptor 1 (IFNAR1) and IFNAR2

subunit dimerization and activation of kinases that associate with their cytoplasmic tails: the Janus-activated kinase 1 (JAK1) and tyrosine kinase 2 (TYK2)

tyrosine phosphorylation activates the signal transducers and activators of transcription 1 and 2 (STAT1 and STAT2), to form a trimeric STAT1-STAT2-IRF9 complex, also known as IFN-stimulated gene factor 3 (ISGF3)

STAT1 homodimer complex, known as the IFN-γ–activated factor (GAF)

Both complexes translocate to the nucleus and bind to DNA regulatory sequences containing IFN-stimulated response elements (ISREs) and IFN-g–activated sites (GAS)

IFN-mediated effects on defense


Ifn mediated effects on defense2
IFN-mediated effects on defense type 1 IFN receptor


Antiviral activities of isgs
Antiviral activities of ISGs type 1 IFN receptor

Protein kinase R

(myxovirus-resistance A)

2′,5′-oligoadenylate synthetase 1


Myxovirus resistance a mxa

The MxA protein accumulates in the cytoplasm on intracellular membranes (such as the endoplasmic reticulum, ER) as oligomers formed by association between the leucine zipper (LZ) domain and central interactive domain of the protein.

Following viral infection, MxA monomers are released and bind viral nucleocapsids or other viral components, to trap and then degrade them.

myxovirus-resistance A (MxA)


Protein kinase r pkr

Protein kinase R is constitutively expressed, and is also induced by type I interferons (IFNs).

The kinase accumulates in the nucleus and cytoplasm as an inactive monomer, which is activated directly by viral RNAs (and by several other ligands

Following activation, PKR monomers are phosphorylated and dimerize to form the active enzyme.

a crucial function of PKR in viral defence is the inhibition of translation by phosphorylation of eukaryotic translation initiation factor 2α (EIF2α).

Protein kinase R (PKR)


2 5 oligoadenylate synthetase 1 oas1

OAS1 is expressed at low constitutive levels and is upregulated by type I interferons (IFNs).

OAS1 protein accumulates in the cell cytoplasm as an inactive monomer.

activation by viral double-stranded RNA (dsRNA), the enzyme oligomerizes to form a tetramer

Synthesize of 2′,5′-oligoadenylates activate constitutivelyexpressed inactive ribonuclease L (RNaseL).

The binding of 2′,5′-oligoadenylates to RNaseL triggers the dimerization of enzyme monomers, through their kinase-like domains, and this then enables RNAseL to cleave cellular (and viral) RNAs.

2′,5′-oligoadenylate synthetase 1 (OAS1)


Regulation of immune responses
Regulation of immune responses upregulated by type I interferons (IFNs).

  • They amplify their own expression through two independent mechanisms:

    • the induction of IRF7 to extend IFN gene expression to a broader range of IFN-αs

    • and the accumulationof PDCs, major contributors to IFN-a/b responses

  • Activate natural killer (NK) cells and induce IL-15 to promote NK cell proliferation

  • At high concentrations, type 1 IFNs inhibit IL-12 and NK cell responsiveness for IFN-γ expression

  • IL-15 contributes short-term proliferation of memory CD8 T cells

  • STAT1 acts to limit nonspecific CD8 T cell expansion

  • antigen-specific CD8 T cells with lower relative levels of STAT1 are induced and preferentially undergo proliferation

  • the type 1 IFN receptor helps with long-term maintenance of the CD8 T cell pool


Viral evasion of ifn responses
Viral evasion of IFN responses upregulated by type I interferons (IFNs).

viral IFN antagonists focus inhibition on at least one of three key pathways: the IRF3, the JAKSTAT, and the PKR pathways


Antagonism of type 1 ifn induction
Antagonism of type 1 IFN induction upregulated by type I interferons (IFNs).

  • Viral inhibition of IRF3

  • influenza and poxviruses encode dsRNA binding proteins NS1 and E3L that prevent IRF3 activation

     RIG-I and mda5 can't detect viral ds RNA.

  • direct binding to mda5 of a viral IFN antagonist resulting in mda5 inhibition (V protein of several paramyxoviruses)

  • MAVS/IPS-1/VISA/ CARDIF is the target for cleavage by the NS3/4A protease of hepatitis C virus. This protease also cleaves TRIF.

    blocks both TLR3- and RIG-I–mediated activation of IFN.

  • The human herpesvirus 8 encodes several analogs of IRF, known as viral IRFs, some of which act as dominant negative mutants of IRF3 action.


Antagonism of type i ifn signaling
Antagonism of type I IFN signaling upregulated by type I interferons (IFNs).

  • The JAK/STAT pathway is also targeted at multiple levels by viral IFN antagonists.

  • Poxviruses secrete a soluble form of the IFNAR that sequesters type 1 IFN before it can bind to the natural IFNAR

  • Inhibition of the JAK kinases has been documented for several viruses.

  • STATs appear to be a preferred target for many paramyxoviruses

     accessory V and W proteins bind to these factors and prevent their activation

    • different specificities for STATs, with some of them inhibiting STAT1, STAT2, STAT3, or a combination of these factors.

    • degradation of the STATs is seen with a subset of paramyxoviruses.

  • V proteins of several paramyxoviruses, and the NS1 and NS2 proteins of respiratory syncytial virusof inhibit both IRF3 and STAT activation


Antagonism of type 1 ifn inducible genes and their products
Antagonism of type 1 IFN-inducible genes upregulated by type I interferons (IFNs). and their products

  • PKR product appears to be a common target for many viral IFN antagonists

  • PKR inhibition pathway are very diverse

    • sequestration of the PKR-activating dsRNA

    • expression of dsRNA mimics

    • binding to PKR preventing its dimerization and activation

  • Influenza virus infection activates a cellular inhibitor of PKR(p58IPK)

  • herpesviruses encode a protein, g34.5, that recruits a cellular phosphatase for the dephosphorylation of eIF2a, reverting the PKR-mediated translational block


Happy new year

Happy New Year! upregulated by type I interferons (IFNs).