Download Viral mechanisms for subversion of immune responses

Viral mechanisms for subversion
of specific immune responses
How viruses think?
• Many viruses subvert particular parts of the immune system
– synthesis of complement-regulatory molecules
• capture of cellular genes for cytokines or chemokines and their
receptors
• the production of decoy proteins that mimic the host proteins involved
in inflammation and immunosuppression
•
– E.g. Decoy proteins for TIR domains that are part of the TLR/IL-1 receptor
signaling pathway
– The human cytomegalovirus (CMV ), another herpesvirus, produces a
protein called UL18, which is homologous to an HLA class I molecule
– CMV also impairs antiviral responses by producing a homolog of the
cytokine IL-10, called cmviL-10, which down regulates the production of
several pro-inflammatory cytokines by immune cells, including IFN, IL-12
and IL-23, IL-l, IL-6, and TNF-a, to promote tolerogenic rather than
immunogenic adaptive responses to viral antigens
Several viruses also produce molecules that interfere with chemokine
responses, either by producing decoy chemokine receptors or chemokine
homologs that interfere with natural ligand-induced signaling through
chemokine receptors
Mechanisms used by viruses of the herpes and pox
families to subvert the host immune system
Mechanisms used by viruses of the herpes and pox
families to subvert the host immune system
Immune escape in
HBV and HCV
HBV- Virus that sneak in the immune system
• HBV (DNA virus) uses three strategies to gently
sneak in the immune system (innate immunity)
– Viruses may remain undetectable for long periods of
time i.e. can be two months elapse until a significant
number of viruses are detectable
– Mainly because HBV are not cytolytic, as death of
infected cells is an important danger signal detected
by the innate immune system
– It does not activate the interferon defense system
despite being an enveloped virus
• Antibodies against HBsAg are detected until rather later during the infection
• They are usually soaked up by the empty viral envelopes
• The antibodies titre is an indication that the virus is cleared by immune
system
• Due to the lack of neutralizing antibodies the viral clearance is largely
dependent on the killer T cells
• In 70% of people infected the virus gets cleared by the immune system
• For the rest of 30% of infected individuals liver damage occurs as a result of
the attack of CTL to hepatocytes resulting in symptoms such as
– Elevated serum aminotransferases
– Nausea
– Vomiting
– Liver pain
– Jaundice
– Dark urine
• These symptoms may continue for months until the virus gets cleared in 90%
of infected people
• HBV subverts the adaptive immune response by interfering with
dendritic cell activation and maturation possibly myeloid DCs
• Consequently leading to the inadequate activation of CD4 T cells and
a lack of TH1 cell differentiation
• The RNA polymerase that the virus uses to replicate its genome lacks
proofreading capacity
• This contributes to a high viral mutation rate and thus a change in its
antigenicity, which allows it to evade adaptive immunity
Damage due to the HBV- genotoxins
• Usually hepatocytes are in resting phase,
therefore the damage caused by genotoxins is
fixed before the damaged cells are replaced,
• p53 gene gaurds against any proliferation of
any unchecked mutation
• However CTL-mediated killing of hepatocytes
may lead to extra proliferation burden on liver
cells due to which they may proliferate with
mutated DNA
• In the presence of genotoxins and
proliferation burden the liver cells may get
exposed to cancer causing mutations
• Hep B associated liver cancers were found to
contain cells having parts of HBV genomes
• HBV encoded protein i.e. X protein is known to
play an important role in the pathogenesis
towards liver diseases
• May disrupt the function of p53(tumor
suppressor gene)- guardian of the genome
Hepatocyte
repair
Hepatocyte
regeneration
HCV- an escape artist
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RNA virus, identified in 1989
Infects both liver cells and macrophages
Binds to low density lipoproteins (CD81)
and infects the target cell
200 billion liver cells in adult human,
infected hepatocytes may vary from 5100%
Immune response takes place through
CTLs and antibodies
As an envelped virus it is expected that
interferon response will take place and
eradicate it
However two virally encoded proteins i.e
NS5A and E2 seems to help virus escape
the interferon response through
inhibiting PKR
Pathogenesis varies from genotype to
genotype
• Regulatory T cells play an important role in the
pathogenesis of HBV and HCV infections
Regulatory T cells
• Play an important role in the outcome of infectious
disease
• Some pathogens promote adaptive immune responses
dominated by regulatory Treg cells rather than effector
T cells
• Two kinds of regulatory T cells are present:
– 'Natural' FoxP3+ Treg cells arise in the thymus and migrate
to the periphery, where they help to maintain tolerance by
suppressing the differentiation of lymphocytes recognizing
autoantigens
– 'induced' or 'adaptive' Treg cells- FoxP3+/- CD25+ CD4
regulatory T cells that differentiate from naive CD4+ T cells
in the periphery
Common chronic infection caused due to
regulatory T cells
• In most of the cases the induction of Treg cells is promoted by the pathogen,
– which thus avoids clearance and can set up a chronic infection
 This mechanism seems to contribute to chronic liver infections caused by HBV and
HCV
 Patients infected with HBV and HCV have elevated numbers of FoxP3+ Treg cells in the circulation
and in the liver,
 and in vitro depletion of Treg cells enhances cytotoxic lymphocyte responses against the virus
 During infections with the protozoan parasite Leishmania major, Treg cells
accumulate in the dermis, where they impair the ability of effector T cells to
eliminate pathogens from this site
• However there are some studies that indicate the positive effects of Treg cells i.e.
in restraining inflammation
– studies in both humans and mice have shown that the inflammation occurring during ocular
infections with HSV is limited by the presence of Treg cells
– If Treg cells are depleted from mice before HSV infection, a more severe disease results, even when
smaller doses of virus are used to cause infection
– In the pulmonary disease that occurs in immunodeficient mice infected with the opportunistic
yeast-like fungal pathogen Pneumocystis jirovecii (formerly known as Pneumocystis carinii), which
is a common pathogen in immunodeficient humans