Transcript Immune Responses to Viral Infections

Immune Responses to Viral
Infections
Interferons
• Proteins synthesized and secreted by cells in response to
virus infection.
• A strong trigger for interferon production is dsRNA, which is
produced, not only by dsRNA viruses, but also by ssRNA
viruses as they replicate.
• The roles of interferons are to protect adjacent cells from
infection and to activate T cell-mediated immunity.
• There are a number of types of interferon.
• Alpha- and beta- (α- and β-) interferons are produced by
most cell types when they become infected with viruses.
• After secretion, the interferon molecules diffuse to nearby
cells, where they can trigger various anti-viral activities by
binding to interferon receptors.
Action of IFNs
• Activation of genes that encode antiviral proteins,
such as dsRNA-dependent protein kinase R and
RNase L.
• Stimulation of production of major
histocompatibility (MHC) class I molecules and
proteasome proteins; these molecules enhance
the presentation of viral peptides on the infected
cell surface to T cells.
• Activation of NK cells
• Induction of apoptosis
Immune Response to Virus
The induction of Interferon (IFN)- and 
virus
Receptor-mediated entry into host cells
Pathogen-associated molecular patterns
Viral replication
Viral PAMP
dsRNA
TLR-3
Unmethylated CpG
Intracellular TLR-9
TLRs
Induction of IFN-/ synthesis
IFN-/ are type I interferons (many infected cells)
IFN- is type II interferon (NK cells, TH1, CTL)
Class switching to IgG2a is induced by IFN-
during immune response to viral infection.
V(D)J
I
Mouse IgH
 
S
LPS
3
IL-4
1
C
IFN- IL-4
LPS
2a
2b

I2a S2a
C2a
IFN-
Induced by B cell
activation and IFN-
Active in B cell
V(D)J 2a


2a (IgG2a)
IgG2a facilitates ADCC by NK cells during viral infection.
Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
TGF-

Viral countermeasures against
interferons
• Many viruses produce proteins that inhibit
either the production of interferons or their
activities.
• The NS1 protein of influenza A virus and the
NS3-4A protein of hepatitis C virus block
pathways involved in interferon production.
• Some viruses, such as poliovirus, prevent the
synthesis of interferons as a result of a general
inhibition of cell gene expression.
Cytokines activates NK cells.
DCs, macrophage
IL12, IL18
NK cells
dsRNA
Many cells
IFN-
IL15
Bone marrow
stromal cells
NK cell activation
Natural killer (NK) cells
• NK cells are present throughout the body, but mainly in the
blood.
• They recognize changes in the surface molecules of virusinfected cells as a result of infection, though they do not
recognize specific antigens.
• After recognizing virus-infected cells as target cells, NK cells
are able to bind to them and kill them.
• NK cells kill their target cells either by releasing perforins,
which are proteins that are inserted into the plasma
membrane of the virus-infected cell, or by inducing
apoptosis.
• Also, on binding to infected cells, NK cells release γinterferon
NK cell activity is regulated by stimulatory and
Inhibitory receptors.
NK cell inactive
Stimulatory
receptor
Stimulatory
ligand
NK cell activated
+
NK cell activated
+
Inhibitory
receptor
Self MHC I
killing
Normal cell
Viral infection
Downregulates
MHC I
The missing-self
hypothesis
killing
Viral infection
Upregulates
Stimulatory ligands
Inhibitory receptors
Inhibitory receptors contain ITIM (immunoreceptor tyrosine-based inhibitory motif)
in their cytoplasmic domains.
[I/V]XYXXL: Y is the substrate of tyrosine kinases.
Phosphorylated ITIM recruits phosphatases (SHP-1) that counteract the
ITIM
Phosphorylation cascade of signal transduction.
Stimulatory receptors
Stimulatory receptors contain short cytoplasmic domain without ITIM.
The transmembrane domain associates with signal transduction molecules
that contain ITAM (immunoreceptor
Tyrosine-based activating motif) in the cytoplasmic domain.
YXX[L/I]X6-9YXX[L/I]: Y is the substrate of typrosine kinases.
Phosphorylated ITAM recruits and activates additional kinases for signal ITAM
transduction.
NK cells control viral infection in the first few days of
immune response.
Complete elimination of the infection requires adaptive
immunity.
Viral countermeasures against NK
cells
• The presence of HIV particles in the blood
alters the expression of a number of
molecules on the surface of NK cells.
• This reduces the efficiency of NK cell activities,
including the ability to kill virus-infected cells
and to secrete γ-interferon.
APOBEC3 proteins
• There are enzymes in the cells of humans and animals
that can interfere with the replication of retroviruses.
• Induce lethal mutations by deaminating deoxycytidine
to deoxyuridine during reverse transcription.
• Apolipoprotein B mRNA-editing enzyme, catalytic
polypeptide-like 3 proteins APOBEC3
• Several of these proteins in human cells can interfere
with the replication of HIV.
• Two of them (APOBEC3F and APOBEC3G) can be
incorporated into HIV virions and taken into the next
cell, where they can interrupt reverse transcription.
Inactivating retrovirus by cytidine deamination
Apobec-3 (A-H): homologous to AID.
The seven apobec-3 genes are located in one cluster.
Apobec-3B, F, G deaminates cytidines in reverse transcript during retroviral replication.
RNA genome
5’
C C
C
3’
cDNA reverse transcript
Apobec-3
5’
3’
5’
HIV produces Vif protein to
degrade apobec-3G.
3’
5’
U U
U
3’
cDNA mutated and nonfunctional
Viral countermeasures against APOBEC3
proteins
• In the cytoplasm of an HIV-infected cell the
virus protein Vif can bind APOBEC3G,
triggering its degradation and hence
preventing its incorporation into virions.
Antibody Response to Viruses
Antibody Responses
• Virus-specific antibody can coat both virions and virusinfected cells, and this may lead to their destruction by a
variety of mechanisms.
• A number of cell types in the immune system have
receptors for the Fc region of IgG , allowing these cells to
attach to antibody-coated virions and cells.
• Cell types that have IgG Fc receptors include neutrophils
and macrophages (these cell types are phagocytes and may
phagocytose the antibody-coated materials; they may also
kill cells without phagocytosing them)
• NK cells (these cells may kill virus-infected cells by insertion
of perforins into their membranes).
• Activation of complement
The effector functions of antibodies
Antibodies to viruses can inhibit the infection of viruses to other cells and prevent the
spread of infection.
Antibodies can activate complement to lyse enveloped viruses.
Opsonization can facilitate phagocytosis.
Complement activation
C3b and antibodies serve as opsonins for
Phagocytosis.
Crosslinking of antigens
(agglutination)
to form a aggregate
IgM most effective
Neutralization of infectivity
• Which may occur by a variety of mechanisms.
• Release of nucleic acid from virions.
• In studies with several viruses, including poliovirus, it was found
that antibodies can attach to virions, and then detach leaving empty
capsids devoid of their genomes.
• Prevention of virion attachment to cell receptors - Antibody bound
to a virion may mask virus attachment sites. Not all virus
attachment sites, however, are accessible to antibodies; those of
most picornaviruses are in deep canyons
• Release of virions that have attached to cell receptors.
• Inhibition of entry into the cell. Antibody coating fusion proteins on
an enveloped virion may inhibit fusion of the envelope with a cell
membrane.
• Inhibition of genome uncoating.
T cell activation
DCs can be directly infected by virus.
If DCs are not infected by virus, DCs can still internalize viral antigens from the suroundings
through phagocytosis, endocytosis and macropinocytosis.
The antigens can be presented in the context of both class II and class I MHC through cross-prim
Lysis of infected
cells
DCs are activated by recognition of
Viral PAMPs through TLRs.
DC
virus
Secondary lymphoid tissues
Ag-MHC I
CD8 T cell
CTL
Ag-MHC II
CD4 T cell
TH1
infection
Viral antigen Endocytosis
Pinocytosis
phagocytosis
IL12
IFN-
TH1 failitates CD8 T cell
activation by producing IL2
and activation of DCs
through CD40L-CD40
B cell activation
DC
Viral antigen
TH cells
B cell
Natural
antibody
Seoncdary lymphoid tissues
Antigen-antibody
complex
B1 cells
B cell activation
FDC
antibodies
• The viral antigens are displayed on the surface
of infected cells in association with MHC class
I molecules, flagging infected cells for
destruction by cytotoxic T cells.
• Cytotoxic T cells can kill target cells by
insertion of proteins (perforins) into their
membranes or by inducing apoptosis.
Viral countermeasures against
cytotoxic T cells
• Some viruses, such as herpesviruses, reduce
the level of expression of MHC class I
molecules at the surface of infected cells,
thereby making it more difficult for cytotoxic T
cells to recognize infected cells.
Immunological memory
• The quantity and quality of the adaptive immune response depends
on whether or not the host is encountering the virus for the first
time.
• Some B cells and T cells can survive as memory cells long after the
first or subsequent encounters. Memory cells have returned to a
resting state, from which they can be reactivated if they encounter
the same antigen again.
• These cells are the basis of immunological memory, which can be
formed as a result of a natural infection, but also as a result of
encountering antigens in vaccines.
• The outcome of infection of a vertebrate animal with a virus may
depend on whether or not the host has immunological memory of
the virus antigens.
• If immunological memory is present then signs and symptoms of
disease are likely to be less severe, or totally absent.
Immune Response to Virus
Innate immunity
Virus
Infected cells
IFN-
M, DC
MHC I
Stimulatory ligand
IL12, IL18
IL15
Inhibit protein sythesis
Apoptosis of infected cell
NK cells
Lysis of infected cell
IFN-
Activate antigen presentation
Promote TH1 response
Adaptive Immunity
Virus
DC
B cell
CD4 T cell
IL12
IFN-
antibodies
CTL
TH1
Activated B cells
IFN-
CD8 T cell
IL2
neutralization
complement
Antigen
Presentation
ADCC
IgG2a
T cell
proliferation
Lysis of infected cell
Latent viral infection
Latent viruses do not replicate, do not cause disease, and
are not detected by the immune system.
These laten viruses are activated when immune system is
weakened.
Herpes simplex viruses establish latency in sensory neuron.
environmental stress or decrease in immune function
reactivate the virus to cause cold sores.
Epstein-Barr virus (EBV, herpes virus) establish latency
in B cells. It produces EBNA-1, which is needed for
replication. But EBNA-1 inhibits proteasome processing
and antigen presentation.
Some of these infected cells can be transformed. When
T cell function is compromised, they could develop into
B cell lymphomas (Burkitt’s lymphoma).
Mutation as evasion strategy
Influenza virus
H5N1, H1N1, etc
Evasion by hiding
Neurons produce very low levels of class I MHC.
Viruses (Rabies virus) are not effectively recognized by T cells
Destruction of Immune Cells
HIV destroyes CD4 T cells.
HBV kills CD8 effector T cells that are specific for HBV infected hepatocytes.
Interference with cytokine function
EBV, HCMV produces IL-10 like molecules to inhibit TH1 resposne.
Some viruses express mimetics of IFN, IL2.
Downregulation of class I MHC
Inhibition of transcription, intererence with peptide transport by TAP, targeting of
Newly synthesized class I MHC for degradation, and rapid turnover of surface expressed
MHC.
Superantigen
Viral superantigen: mouse mammary tumor virus, rabies virus, Epstein-Barr virus
Bacteria superantigen: staphylococcal enterotoxins (SEs, foodpoisoning)
toxic shock syndrome toxin-1 (TSST-1, toxic shock syndrome)
Superantigens crosslink class II MHC
with TCR V chain.
The interaction is independent of
Peptide sequence.
Each superantigen can bind 2-20%
of all T cells.
Superantigens are not processed
and presented by MHC.
Superantigens can cause massive activation of CD4 T cells, which release cytokines
(IFN-, TNF-) and activate macrophages to release inflammatory cytokines (IL1, TNF-)
These cytokines cause the toxic shock syndrome (similar to septic shock).
The massive activation of CD4 T cells eventually lead to their death, and cause immunol
suppression, which aid the propagation of pathogens.
RNA silencing
• RNA silencing, also known as posttranscriptional gene silencing or RNA
interference (RNAi), is an intracellular process
that is induced by dsRNA.
• The process results in the destruction of
mRNAs that have the same sequence as the
inducing dsRNA; both cellular and viral mRNAs
can be destroyed.
Protein complex
RISC: RNA-induced silencing complex
siRNA: small interfering RNA
Viral countermeasures against RNA silencing
• Some plant viruses encode proteins that can
suppress RNA silencing, for example the
‘helper component proteinase’ of potyviruses
and the P19 protein of tombusviruses are
strong suppressors of RNA silencing.
Programmed cell death
• Virus infection of a cell may initiate a process that causes the death
of the cell before progeny virus has been produced, hence
preventing the spread of infection to other cells.
• In animal cells this suicide mechanism is known as apoptosis.
• It is triggered, not only by virus infection, but also when the lifespan of cells, such as epithelial cells, is complete.
• Bacteria have developed similar mechanisms to protect the species
from phage infection. The death of a host bacterium before any
progeny phage has been produced protects other susceptible cells
from infection. These mechanisms have been found in Escherichia
coli and in many other species.
• If a virus-infected cell successfully completes the process of
programmed cell death then it altruistically commits suicide for the
benefit of either a multicellular host or a population of unicellular
hosts.
Viral countermeasures against
apoptosis
• Many viruses have evolved mechanisms that
can suppress apoptosis at a variety of points in
the process, for example several DNA viruses
encode proteins related to the cell BCL-2
proteins that control apoptosis.
• These viral proteins block apoptosis, resulting
in the survival of host cells and the completion
of virus replication cycles.