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Summary Modules 4-6 - Immunotechnology (CBI30806)
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Summary Modules 4-6 - Immunotechnology (CBI30806), useful for the second multiple choice exam
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Immunotechnology summaryModule 4-6
,Immune evasion
Viruses are obligate parasites that can only reproduce inside living cells. Viruses move as virus
particles from cell to cell and in that extracellular stage, viruses can be recognized by antibodies. A
virus is a particle of sub-microscopical size that contains RNA (influenza, HIV) or DNA (herpesvirus) as
genetic material. This genome may be linear or circular,
segmented or in one piece, and the RNA or DNA may be single or
double stranded. The viral genome is surrounded by capsid
proteins that protect the viral genome in the environment
(genome + capsid = nucleocapsid). Viruses may have a lipid
bilayer on the surface, also called a viral envelope. This envelope
enwraps the nucleocapsid and contains transmembrane
glycoproteins that point out from the surface. These surface
glycoproteins play crucial roles in the entry of the virus into
target body cells, as they may bind to receptors on the cell surface. Alternatively, glycoproteins may
function as viral fusion proteins that assist in the fusion of the viral envelope with cellular
membranes. This may happen directly at the surface of the cell or in endosomes, thereby releasing
the nucleocapsid into the cells. For naked viruses that lack an envelope, the capsid proteins bind to
receptors to promote cell entry. Once inside the 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 titres of virus particles are often found in blood or mucosa samples
during an acute infection, but upon recovery of the patient, these levels
decline. An infection can then be traced better by testing for pathogen-
specific antibodies in serum or mucosa. If antibodies are found in the serum
sample someone is called sero-positive.
When a virus enters a cell, the first response is activation of innate immune
mechanisms. A mammalian cell responses by producing type I interferon
(IFN-α and IFN-β), leading to activation of natural killer cells that can attack
and kill the infected cell. The secretion of interferons also leads to the
induction of an antiviral state in neighbouring cells, making these cells more
resistant to virus infections. Another response is the increased synthesis of
class I MHC molecules on the surface of infected cells, which leads to better
recognition by cytotoxic T cells. Also, virus-specific antibodies will start to be
produced that can bind to progeny virus to limit the spread of infection.
Antibodies that prevent progeny virus from infecting other body cells are
called neutralizing antibodies.
The synthesis of IFNs by virus-infected cells is triggered by the recognition of
virus-specific PAMPs, mainly dsRNA in the case of virus infections. Especially
MDA-5 and RIG-I are important intracellular receptors of these molecules,
but dsRNA may also be sensed by specific TLRs in endosomes. These
molecules signal to interferon regulatory factors (IRFs) that then translocate to the nucleus of the cell,
where they function as transcription factors for IFNα and -β genes. Many viruses interfere with the
onset of type I IFN synthesis. Ebola and Marburg virus, for instance, encode proteins that interfere
, with IRF3/IRF7 activation (last step before IFNα and -β gene transcription). Influenza encodes a non-
structural protein (NS1) that interferes with interferon synthesis.
IFN produced by virus-infected cells binds to IFN receptors on the cell
surface of infected and neighbouring cells. The signal is transduced
via the JAK-STAT pathway and finally leads to gene expression of a set
of IFN responsive genes. Crucial steps in this pathway is the
dimerization of the IFN receptor, which activates JAK. JAK then
recruits STAT to the receptor and phosphorylates STAT.
Phosphorylated STAT forms dimers and translocates to the nucleus,
where it activates IFN responsive promoters.
Viruses may also inhibit IFN signalling by interfering with the JAK-
STAT pathway. The Chikungunya virus nsp2 protein, for instance, is
known to interfere with JAK-STAT signalling by preventing
phosphorylation of STAT.
Type I IFN signalling to not yet infected cells, leads to the expression
of a set of IFN effector genes. The encoded enzymes have the
ability to restrict virus propagation, hence the name antiviral
state. The most important ones are:
Protein kinase R (PKR): a kinase that phosphorylates
other proteins when activated by dsRNA. PKR levels are
upregulated as a response to IFN signalling. After
infection, dsRNA triggers the phosphorylation of PKR,
which subsequently forms dimers. The activated PKR
then phosphorylates the α-subunit of eukaryotic
translation initiation factor eIF2 (eIF2α), leading to a
halt in translation initiation, also known as host shut off.
In addition, PKR blocks the inhibitor of NF-kB and as
such stimulates the expression of pro-inflammatory
genes.
2',5' oligoadenylate synthetase (2'-5' OAS): also
activated by dsRNA. Through the formation of oligoA
molecules, this enzyme activates RNAse L, which
degrades viral RNA. Cells infected with DNA viruses may
also contain dsRNA. The DNA virus vaccinia, belonging to the family Poxviridae, encodes the
protein E3L that prevents the activation of 2'-5' OAS. Vaccinia and herpes viruses (also DNA
viruses) also encode proteins that inhibit PKR activation.
Mx GTPases: all vertebrates have Mx GTPases and these enzymes restrict virus replication,
probably by interfering with the viral ribonucleoproteins formed by RNA viruses. As a
consequence, viral gene expression and virion assembly is inhibited. Most Mx GTPases are
active against negative-strand RNA viruses. Human Mx GTPases also provides resistance
against a few positive-strand RNA viruses and some DNA viruses.
There are three different species of influenza, A, B and C. Influenza A and B viruses infect the human
population. Every year, you can receive an Influenza vaccination. This yearly flu vaccination is not
because of the loss of immunity against influenza, but because the influenza virus constantly changes.
Influenza viruses have negative-sense ssRNA genomes, which are segmented into eight pieces, each
encoding a viral protein. The viral envelope contains two types of glycoproteins that extrude from the
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