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Summary module 4 Immunotechnology (CBI-30806)
- Instelling
- Wageningen University (WUR)
Summary of module 4 of the course Immunotechnology (CBI-30806)
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Voorbeeld van de inhoud
Module 4: Immune evasion and modulation by viruses and helminthsIn order to successfully infect a host, pathogens and parasites have to be able to avoid or even
manipulate the immune responses of their targets
Introduction to viruses
Viruses:
Obligate parasites that can only reproduce inside living cells
Move as virus particles from cell to cell
o In extracellular stage can be recognized by antibodies
Is a particle of sub-microscopical size that contains RNA (e.g. influenza, HIV) or DNA (e.g.
herpesvirus) as genetic material
o Genome may be linear or circular, segmented or in one piece, and the RNA or DNA
may be single or double stranded depending on the type of virus
Nucleocapsid: capsid protein that surrounds viral genome and protects it
o If virus only has a nucleocapsid it’s called and naked virus
o Capsid protein binds cell receptor to promote cell entry
Viral envelop: a lipid bilayer on the surface that enwraps the nucleocapsid and contains
transmembrane glycoproteins. Called an enveloped virus
o Surface glycoproteins play crucial roles in the entry into target body cells, as they
may bind to receptors on the cell surface and function as fusion protein that help
with fusion of envelop with cellular membrane releasing nucleocapsid into the cell
Inside cell, the viral genome is transcribed (DNA virus or negative strand RNA virus) or
directly translated (positive strand RNA viruses) and synthesis of the encoded proteins allows
replication of the viral genome and packaging of the newly made genomes in progeny virus
particles, which are then released to infect new cells
High concentration of virus particles mostly found in blood or mucosa
o Upon recovery virus presence can be teste by looking for pathogen-specific
antibodies in serum or mucosa. If found sero-positive
Immune responses to viruses
When a virus enters a cell
Innate immune system is activated
o Cell starts producing type I interferons (IFN-α and IFN-β)
o IFNs activate NK cells that attack and kill infected cells
o IFN production also leads to antiviral state of neighbouring cells
Expression of antiviral enzyme encoding genes
o IFN production also leads to increased MHC-I on surface of
infected cells so they are better recognisable for cytotoxic T cells
Adaptive immune system
o CTLs start to develop which recognize specific viral antigens
presented by MHC-I
o Virus-specific antibodies start to produce
Neutralizing antibodies: prevent progeny virus from
infecting other body cells
Innate and adaptive work together
Virus-specific PAMPs lead to IFN production
IFNs synthesis is triggered by virus specific PAMPs, mainly dsRNA
Especially MDA-5 and RIG-I are important intracellular receptors
dsRNA may also be sensed by specific TLRs in endosomes
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, These molecules signal to interferon regulatory factors (IRFs) which translocate to the
nucleus, where they function as transcription factors for IFN-α and -β genes. These drive the
synthesis of type I IFNs.
o Many viruses interfere with the onset of type I IFN synthesis (Ebola and Marburg
interfere with IRF3/IRF7 interaction and influenza interferes with INF synthesis)
Activation of the JAK-STAT pathway upon IFN sensing
Signal transduction of IFN binding to IFN receptor goes via the JAK-STAT pathway leads to IFN
responsive gene expression
Crucial step in this pathway is the dimerization of the IFN receptor once IFN binds to the
receptor, which activated JAK
JAK recruits STAT and phosphorylates it
Phosphorylated STAT forms dimers and moves to nucleus, where it activates IFN responsive
promoters
Viruses also can inhibit IFN signalling by interfering with the JAK-STAT pathway (Chikungunya
prevents phosphorylation of STAT)
The antiviral state in neighbouring cells
Type I IFN signalling, in cell that are not yet infected, leads to expression of IFN effector genes
These enzymes are able to restrict virus propagation antiviral state
Most important ones:
o Protein kinase R (PKR)
o 2',5' oligoadenylate synthetase (2'-5' OAS)
o RNAse L
o Mx GTPases
Protein kinase R (PKR)
Kinase that phosphorylates other proteins when activated by dsRNA
PKR levels are upregulated as a response to IFN signalling by previously infected cells
In uninfected cells is PKR present in inactive form
dsRNA triggers the phosphorylation of PKR, which subsequently forms dimers
The activated PKR then phosphorylates the alpha-subunit of eukaryotic translation initiation
factor eIF2 (eIF2α)
Phosphorylation of eIF2α leads to a halt in translation initiation, also known as host shut off
PKR blocks the inhibitor of NF-kB and thus stimulates the expression of pro-inflammatory
genes
2'-5' oligo A synthase (OAS) and RNAse L
Activated by dsRNA
Through the formation of oligoA molecules this enzyme activates RNAse L, which
subsequently degrades viral RNA
Vaccinia, encodes the protein E3L that prevents the activation of 2'-5' OAS
Vaccinia and herpes viruses (also DNA viruses) encode proteins to inhibit PKR activation
Mx GTPases
All vertebrates have Mx GTPases
These enzymes restrict virus replication, probably by interfering with the viral
ribonucleoproteins formed by RNA viruses
viral gene expression and virion assembly is inhibited
Mx GTPases are active against negative-strand RNA viruses
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