Transcript cytokine storm

The 3rd International Medical Congress of Prof. Alireza Yalda
Foundation in Medical Sciences
17-20th November 2012
Tehran
The Role of Cytokine Storm in Influenza
Pathogenesis
Presented by:
Talat Mokhtari-Azad
Director of National Influenza Center
WHO Collaborating Center
School of Public Health, Tehran
University of Medical Sciences
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Some people get horribly sick from the flu, and even
die. Others just rest for a few days.
What’s behind this fateful variation?
How is it that the flu virus can have such a variable impact on people?
Nature 2011; 480 (8) S14
Influenza A virus tropism
NATURE REVIEWS MICROBIOLOGY 2011; 595 (9)
Influenza A virus tropism
NATURE REVIEWS MICROBIOLOGY 2011; 595 (9)
Influenza A virus tropism
NATURE REVIEWS MICROBIOLOGY 2011; 595 (9)
Influenza A virus tropism
NATURE REVIEWS MICROBIOLOGY 2011; 595 (9)
Viral and host factors influencing the pathogenesis of influenza A virus
NA promotes efficient
release of viral progeny
from infected cells
Viral factors
PB1-F2 induces
apoptosis, promotes
bacterial growth and
acts as interferon
antagonist
HA determines receptor binding, and
antigenicity and tropism depending on the
presence or absence of a polybasic clavage
site:
H5N1: PQRERRRKKR↓G
H7N1: PEIPKR-RRR↓G
H1N1: PSIQ-------SR↓G
H3N3: PEKQ-----TR↓G
H2N2: PQIE------ SR↓G
The genotype of PB1, PB2,
PA and NP determine viral
replication competence
NS1 is a
multifunctional
interferon
antagonist
NATURE REVIEWS MICROBIOLOGY 2011; 595 (9)
Viral and host factors influencing the pathogenesis of influenza A virus
Host factors
Understanding health conditions
that increase suseptibility:
Elderly (>65 years of age)
Children (< 2 years of age)
Pregnant women
Immunocompromised individuals
Understanding health conditions
that increase suseptibility:
Asthma and COPD
Cardiovascular disease
Obesity
Diabetes
Increased and sustained inflammatory •
responses contribute to disease severity
Host factors influence viral infection by direct or indirect interactions with
viral proteins during different stages of replication:
Required factors include ATP6V0D1, CAMK2B, CLK1 and p27
restriction or regulatory factors
NATURE REVIEWS MICROBIOLOGY 2011; 595 (9)
NOVEL CONCEPT ABOUT INFLUENZA
PATHOGENESIS
-The sequence of HA cleavage site is a major determinant of
disease severity ( local versus systemic)
- PB1-F2 protein , which leading to apoptosis( e.g.1918/
H1N1 and in various isolates of H5N1), promotes and
increases pathogenesis of secondary pneumonia infection
- PB1-F2 cooperate with NS1 to inhibit INF response
- NS1protein , which is an antagonist of INF-mediated
antiviral host response and a modulator of adaptive
immune responses , and can inhibit global host gene
expression through its interaction with the nuclear
cleavage and polyadenylation factors (cpsf4 or CPSF 30)
- NS1 contributes to the cytokine dysregulation that is seen
in human that succumb to HPAI H5N1 virus infection.
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TISSUE TROPISM IN THE INFLUENZA
PATHOGENESIS
- Influenza has different disease phenotypes most commonly URT,
conjunctives, pneumonia, and encephalitis
- Seasonal flu has strong tropism to URT ( rhinitis, pharynitis,
laryngitis), tracheo bronchitis
- HPAIV H5N1 weak tropism to URT and strong tropism to LRT
which may explain in part its failure to transmit efficiently
among human
- URT is lined by olfactory mucosa and HPAIV H5N1 replicate in
olfactory mucosa of URL and virus spreads directly from OM to
the olfactory bulb and rest of the CNS and causing severe
meningitis, encephalitis
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TISSUE TROPISM IN THE INFLUENZA
PATHOGENESIS
- H7N7 associated predominantly to conjunctivitis. And probably is
mediated by a signal transduction pathway in corneal epithelial
cells related to NF –kB
- HpH5N1 and Hp AIV H7N1 have strong tropism to LRT and
attaches abundantly to Clara cells lining bronchioles, type II
pneumocyte lining alveoli, and alveolar
- Macrophage in alveoli and this tissue tropism fit with the primary
diagnosis in the acute stage by alveolar epithelial necrosis,
flooding of alveolar lumina by edema fluid mixed with fibrin,
erythrocytes, macrophages , and neutrophil and lining alveolar
ducts by hyaline membranes
-H5N1 induced significantly higher production of the cytokine( TNF
(in macrophages and may explain in part the severity of LTR
disease and high fatality rate of H5N1 infection infection
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THE ROLE OF CYTOKINES IN THE IMMUNE SYSTEM
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Pro-inflammatory cytokines, such as interleukin (IL)-1, IL-6,
tumor necrosis factor (TNF)-α, and interferon (IFN) -γ, serve
to recruit cells to the site of infection and mediate direct
antiviral effects.
The up-regulation of anti inflammatory cytokines, such as IL10 and transforming growth factor (TGF)-β, also occurs
during infection with the purpose of regulating the extent of
inflammation.
This forms of regulation are critical to contain excessive
inflammation that can cause more harm than good.
However, during some infections and pathological conditions,
regulation fails, and an unbalanced cytokine response called a
cytokine “storm” can develops, leading to uncontrolled
inflammation and increased morbidity and/or mortality for
the host.
Non-cytopathic virus
Neutrophil
pDC
TH1,TH2 &
TH17 cells
NK cell
CTL
DAMPs
PAMPs
iDC
Immunity
Non-cytopathic virus
Cytopathic virus
Tissue cell
Type 1 IFNs
MQ
RNS
IL-17
ROS
IL-1β
IL-6
IL-10
TGF-β
IL-1β
Treg cell
TH1,TH2, TH17 cells
IFN-γ
TNF-α
Perforin Immunopathology
Granzymes
Infected tissue
Mature DC
CTL
MHC-II
TCR
IL-6 IL-21
B cell
IFN-γ
IL-12
TH1
IL-4
IL-5
CD4 T cell
TGF-β
IL-6 TGF-β
TFH
TH17
Virus inducers
Vasulitis glomerulonephritis
Immune complex formation
& complement activation
Lymph node
T cell cytokines
Treg cell
IFN-γ
TNF-α
IL-10
Almost
all
Viruses
TH2
Treg
IL-17
IL-22
IL-21
TNF-α
HSV
HCV
HIV
TGF-β
IL-10
IL-35
IL-4
IL-5
IL-13
HSV
HCV
HIV
Friend virus
Dengue virus
RSV
IL-21
?
THE IMMUNE RESPONSE TO INFLUENZA
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Production of proinflammatory cytokines by epithelial and
immune cells increases vascular permeability, allowing the
additional cells of the immune system to pass through the
endothelial barrier and reach the infected tissue.
Continuous viral replication leads to a constant influx of immune
cells into the site of infection and increased production of
cytokines.
Without control mechanisms, this positive feedback loop between
cytokines and immune cells results in hypercytokinemia,
ultimately causing severe damage to the host.
HOST DETERMINANT
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PATHOGENESIS
-Highly PI viruses can induce the high plasma level of:
INF gama- induced protein(IP10; also known asCXCL10)
-Monocyte chemoattractant protein 1( also known CCL2)
-Interleukin 8(IL-8), IL-6, IL-10 and other pro-inflammatory cytokines that correlate with
an elevated pharyngeal viral load and increased frequency of death caused by viral
pneumonia
-Increased and prolonged of transcription of type 1 IFN , inflammation and innate
immune induction are seen during infection with HPH5N1 virus, resulting apoptosis of
DC and severe pathology
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-TNF and IL-1 increase infiltration level of leukocyte, neutrophil and macrophages
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-CD8 effector T- cell, by producing IL-10 could control the lung inflammation and injury
that is induced during acute influenza infection
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-NK cell, B cell and antigen presenting cell are susceptible to influenza virus
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Balance between pro- and anti-inflammatory mechanisms may decide the
outcome of viral infection!
Pro-inflammatory mechanisms
Cytokines and chemokines:
IL-2, IFNs, TNF, IL-1β, IL-6, IL-8
IL-12, IL-17, CCL2, CCL3 and CXCL2
Chemical mediators:
Prostaglandins, histamines and
cyclooxygenases
Reactive species:
Reactive oxygen species
Reactive nitrogen species
Proteinases:
Matrix metalloproteinases
Anti-inflammatory mechanisms
Treg cells
Cytokines: IL-10, TGF-β and IL-23
Chemical mediators:
Resolvins, protectins, galectin 1 and galectin
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Inhibitory receptors:
PD-1, LAG3, TIM3 and CTLA4
Innate immune regulatory proteins:
TLR signal inhibitors: A20, SOCS1 and
SOCS3
RLR regulators: ubiquitin ligase
NLR inhibitors: p202
Pro-inflammatory mechanisms
Anti-inflammatory mechanisms
Tissue damage
Homeostasis
Viral persistence
Nature Reviews Immunology 2010; 10
THE GOOD, THE BAD AND THE UGLY
PATHOGENESIS IN INFLUENZA
The good : protection afforded by innate and adaptive
immunity
- To activate rapid response recognition of RNA by toll
like receptors and retinoic inducible gene I(RIG-1) is
key
-These receptor leads to the production of
proinfammatory cytokines and type I IFN-α and β
- These cytokines exert antiviral activity by inhibiting
viral replication and jump stars the adaptive immune
response (virus specific B and T responses) and result
in clearance of the infection)
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THE GOOD
-Individual
that have experienced an influenza
infection in the past are more resistant to
subsequent infection with influenza viruses of the
same type (p2009 H1N1)
-Infection with influenza viruses also induce protective
immunity to influenza A viruses of other subtypes (
heterotypic Immunity)
-Immune response to conserved proteins (NP, M) are at
the basis of heterotypic immunity specially cross
reactive T-cell response are involved.
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THE BAD
Increased virulence is often correlated
with:
 Increased virus replication
 Tropism
 Regulation of immune response
The best known determinants of virulence
are the multibasic cleavage site of HA,
receptor binding preference of HA, NA
activity, PB2, PB1, NP, NS1
NS1 through it antagonise the innate
response specially INF.
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THE UGLY
The excessive or dysbalanced immune response, especially in the LTR, may
be determined
- Overproduction of cytokines such as TNF-α, IL-6, IL-8, IFN type I or
II as well as chemokines can result in severe inflammation, including
excessive recruitment of neutrophils and mononuclear cells at the site
of infection. This may damage lung tissue , reduce respiratory
capacity and cause severe disease and mortality (e.g. H5N1, 1918
H1N1)
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UGLY
-In sufficient expression anti-inflammatory molecule such as
HLA-G, interleukin 10, transforming growth factor-beta
could influence extent of inflammation and pathogenesis of
infection.
-Importantly , alveolar macrophages expressing high level of
CD200R are critical immune-suppressive cells that upon
activation prevent elevated cytokine environment.
-In contrast to monocyte-derived macrophages that infiltrate
the lung after infection starts, resident alveolar
macrophages may be important in suppressing
inflammation of the lung.
-Recently it was shown that activation of endothelial cells
plays a central role in the initiation of excessive cytokine
production and inflammatory cell recruitment.
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POSSIBLE THERAPEUTIC AVENUES
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Antiviral therapies that directly target the virus (including NA
inhibitors: oseltamivir and zanamivir, and M2 inhibitors:
amantadine and rimantadine) are currently the main form of
influenza treatment.
Viral resistance to M2 inhibitors is widespread among seasonal
and pandemic influenza strains, while oseltamivir resistance is
mainly observed in seasonal influenza and is not very common in
pandemic influenza strains.
The success of oseltamivir and zanamivir lies in the fact that most
influenza viruses have difficulty altering the NA site that they
target, making viral escape difficult.
However, a low number of oseltamivir-resistant pandemic (H1N1)
2009 as well as H5N1 viruses have been reported in several
countries.
POSSIBLE THERAPEUTIC AVENUES
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high rates of viral resistance to currently available drugs and
points to the need for strengthening available treatment options,
including therapy that targets the host immune response.
Anti-inflammatory agents that dampen the cytokine responses
during influenza infection have been shown to decrease morbidity
and mortality .
There are a number of anti-inflammatory treatments used to
treat autoimmunity, including TNF blockers, which may be of use
in a cytokine storm situation during acute influenza infection.
Clearly, more research is required before many of these
immunomodulatory concepts can move into the clinic.
CONCLUSION
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Despite an increase in influenza literature over the last two years,
it is still unclear what causes the severe morbidity and mortality
associated with pandemic influenza strains.
One potential mechanism is the induction of a cytokine storm and
an imbalance of protective versus pathogenic immune responses.
Since cytokine storms are likely to arise through various
mechanisms, treatment options should focus on the overall
cytokine imbalance and associated immunopathology rather than
targeting specific components of the storm.
It is clear that more work is needed to fully understand the
pathogenicity of pandemic influenza viruses and correlations of
cytokine storms to disease severity, ongoing efforts in this area
could lead to better therapeutic approaches to combat the next
influenza pandemic.