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Summary module 4 Immunotechnology (CBI-30806)

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Summary of module 4 of the course Immunotechnology (CBI-30806)

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  • March 19, 2021
  • 9
  • 2019/2020
  • Summary
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Module 4: Immune evasion and modulation by viruses and helminths
In 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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