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HOST DEFENSE AGAINST VIRAL INFECTIONHOST DEFENSE AGAINST VIRAL INFECTION--
ANIMALSANIMALS
Primary defenses- physical and chemical barriers
-skin
-mucous secretions
-tears
-acid pH
-surface cleansing mechanisms (swallowing,
blinking)
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IMMUNE DEFENSESIMMUNE DEFENSES
Three critical processes in the immune defense:
-recognition
-amplification
-control
The immune response to viral infection consists of:Innate (nonspecific) defense: first line of immune
defense, responds to any infection, recognizes
characteristics common to microbial invaders,consists
of interferons, complement, natural killer cells, dictatesthe adaptive response
Adaptive (specific) defense: antibody response and the
lymphocyte-mediated response also called the humoral
and cell-mediated responses
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Innate and adaptive
immune responses:
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The innate immune response:The innate immune response:
Can be activated rapidly and functions within hours
of a viral infection.
Continued activity is damaging to the host.
Considerable interplay occurs between the adaptive
and innate immune defenses.
Important components are:
-cytokines
-complement
-collectins
-natural killer (NK) cells
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Differentiates self from nonself, tailored to the
particular invader
Has memory; subsequent infection by the same
agent are met with a robust and highly specific
response that stops the infection
Consists of the:
antibody response - humoral response
lymphocyte mediated response- cell-mediated
response
The adaptive immune response:The adaptive immune response:
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ONeill, Scientific American, Jan 2005 pp. 38-45
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The inflammatory response:The inflammatory response:
Essential in initiating immune defenses
Cell and tissue damage caused by infection
induces the inflammatory response
Provides communication with the components of
the immune system
Characterized by redness, heat, swelling and pain
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The inflammatory assault is initiated by TollThe inflammatory assault is initiated by Toll--like receptorslike receptors
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Inflammation can be initiated in
several ways:
By interferon released by
immature dendritic cells
Locally produced cytokines,
such as interleukin-1, tumor
necrosis factor- Eand
interferon-K control the
reactions that occur during
inflammation
Inflammatory cytokines also
activate B and T cells that are
needed for the adaptive
response
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Cytokines:Cytokines:
Regulatory proteins that mediate intercellular
communication during an antiviral defense.
Their presence is one of the first indicators that the
host has been infected.
They act locally, near the cells that make them.
They control inflammation, induce and antiviral state
in cells and regulate the adaptive immune response.
They exert their activities by binding to specific
receptors and activating gene expression. Three types of interferons are the most important
cytokines in the innate response to viral infection.
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Ifn-Kis induced only when certain lymphocytes are
stimulated to replicate and divide after binding a foreign
antigen
Ifn-E and Ifn-F are induced by viral infection of any cell
type
InterferonsInterferons
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Ifn is induced by accumulation of double stranded
RNA (dsRNA).
Ifn induces gene expression at the transcriptional
level after binding to specific cell surface receptors.
A cell that is bound to interferon and responds to it
is in an antiviral state. Ifn induces expression of more that 100 genes,
products of many of these genes possess broad
spectrum antiviral activity.
They lead to cell death by apoptosis or programmedcells death, limiting cell to cell spread of virus.
Production of large amounts if Ifn causes common
symptoms such as fever, chills, nausea, etc.
InterferonsInterferons
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Interferon induced antiviral responses:Interferon induced antiviral responses:
Both viral and cellular protein synthesis stops in Ifn
treated cells.
This is dues to two cellular proteins, ds-RNA activated
protein kinase (Pkr) and ribonuclease L (RNase L).
Pkr is a serine/threonine kinase that has antiviralproperties, as well as antiproliferative and antitumor
functions.
Activated Pkr phosphorylates the alpha subunit of the
translation initiation factor eIF2, inhibiting translation. RNase L is a nuclease that can degrade cellular and viral
RNA; its concentration increases after Ifn treatment.
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RNase L concentration increases 10-1,000 fold after
Ifn treatment, but is inactive unless 2-5-oligo(A)synthetase is produced.
2-5-oligo(A) synthetase produces 2, 5 oligomers of
adenylic acid, only when activated by dsRNA.
These poly(A) oligomers then activate RNase L,
which degrades all host and viral mRNA in the cell.
RNase L participates not only in Ifn-mediated
antiviral defense, but also in apoptosis.
Ifn is a broad spectrum, highly effective antiviral
agent. However, viruses have developed numerous
mechanisms for inhibiting interferon action.
Interferon induced antiviral responses:Interferon induced antiviral responses:
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Humoral response
Consists of lymphocytes of the B-cell lineage
Interaction of a specific receptor on precursor B
lymphocytes with antigens promotes differentiation
into antibody secreting cells (plasma cells). Cell-mediated response
Consists of lymphocytes of the T-cell lineage
Cytotoxic T cells (Tc cells) and T-helper cells (Thcells) are the key effectors of this response.
The adaptive immune response:The adaptive immune response:
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T lymphocytes recognize antigens on the surface of
self cells.
The antigens on self cells can be recognized only by a
receptor on the surface of T cells when they are bound
to the MHC family of membrane proteins.
The Th cells recognize antigens bound to MHC class II
molecules and produce powerful cytokines that affect
other lymphocytes (B and T cells) by promoting or
inhibiting cell division and gene expression.
Once activated by Th cells, Tc cells differentiate into
CTLs that can kill virus infected cells.
Cell-mediated response cont.
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The antigen receptors on the surface of B and T cellsThe antigen receptors on the surface of B and T cells
B cells have about 100,000 molecules
of a single antibody receptor per cell,which has specificity for one antigen
epitope.
T cells bearing the surface membraneprotein CD4 always recognize
peptides bound to MHC class II
proteins and function as Th cells.
T cells bearing the surface membraneprotein CD8 always recognize peptide
antigens bound to MHC class I
proteins and function as cytotoxic T
cells.
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Endogenous antigen processing: MHC class I peptideEndogenous antigen processing: MHC class I peptide
presentationpresentation
Intracellular proteins of host and virus are marked for
degradation by ubiquitination and are degraded by theProteasome.
The resulting viral peptides are transported into the ER
lumen by the Tap1-Tap2 heterodimeric transporter.
In the ER lumen, viral peptides associate with newly
synthesized MHC class I molecules.
MHC class I-peptide complex is transported to the cellsurface via the golgi compartments.
On the cell surface, the MHC class I-peptide complex
interacts with the T- cell receptor of a Tc cell carrying the
CD8 coreceptor.
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Endogenous antigen processing: MHC class I peptide presentationEndogenous antigen processing: MHC class I peptide presentation
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Exogenous antigen processing: MHC class II peptideExogenous antigen processing: MHC class II peptide
presentationpresentation
MHC class II complex is prevented form binding to viral
peptides in the ER by association with the invariant chain.
The complex is transported through golgi where the
invariant chain is removed, activating the MHC class II
complex.
The peptides are derived from extracellular proteins
that enter the cell by endocytosis.
Viral proteins are degraded in the lysosomes by
proteases that are activated by low pH.
Endosomes fuse with vesicles containing MHC class II.
On the surface of the cell the MHC class II complex
interacts with the T cell receptor of a Th cell carrying the
CD4 coreceptor.
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Exogenous antigen processing: MHC class II peptideExogenous antigen processing: MHC class II peptide
presentationpresentation