Download Immunopathology of viral infections

Immunopathology of viral infections
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Characteristics of a virus-induced immune pathology
• disease is based on the immune reaction against a viral infection
• disease is induced by chronic persistent viral infections
• immune response induces symptoms
• immunocompromised patients will not develop symptoms
Effectors of a virus-induced immune pathology
• activated B-cells/plasma cells > auto reactive antibodies
• fulminant innate immune response > e.g. cytokine expression
• activated T-cells > CD8+ CTL (destruction of chronic infected cells, autoimmune
reactions)
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Immunopathology of viral infections: examples
Viral infection
Immune response
Antibody-dependent
enhancement of virus infection
(dengue virus)
Overreaction of the immune
system „cytokine storm“
(influenza virus)
Induction of autoimmune
reactions
„molecular mimicry“
(coxsackievirus)
Tissue destruction via the
immune response against
virus-infected cells
(hepatitis B virus)
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Immunopathology of viral infections
Antibody-dependent enhancement
(ADE) of viral infections occurs when
non-neutralizing antiviral proteins
facilitate virus entry into host cells,
leading to increased infectivity and
fulminant immune responses.
http://www.the-scientist.com/images/March2013/dengue_virus.pdf
- Disease:
- Pathogen:
Dengue fever (DF)
Dengue hemorrhagic fever (DHF)
Dengue hemorrhagic shock syndrome (DHSS)
Dengue virus (4 types: DENV1-4)
Flaviviridae, single-stranded (+)RNA (ca. 11 kb)
enveloped capsid, 40-50 nm in size
http://www.stanford.edu/group/virus/flavi/2000/dengue.htm
www.guatezona.org
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Immunopathology of viral infections
- Distribution:
ca. 2.5 billion people live in endemic areas
next to Malaria, DF is the most important tropical disease
DF:
ca. 50-100 (300) million cases/year
DHF/DHSS:
ca. 0.5 million cases/year
world-wide increase of diseases and fatal casualties due to
an increase of distribution of viral strains (multiple infections), endemic in > 110 countries
most frequently imported tropical disease
in Germany: 656 cases in 2014
„Epidemiologisches Jahrbuch“ of the RKI 2013:
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http://www.rki.de/DE/Content/Infekt/Jahrbuch/Jahrbuch_2013.pdf?__blob=publicationFile
Immunopathology of viral infections
Outbreak:
Starting October 2012, the most
important DENV1 outbreak has been
observed in Europe since 1927.
Until 18.2.2013:
- 2164 cases with 122 hospitalizations
- no fatal casualties
- Germany: 19 imported cases
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Immunopathology of viral infections
- Transmission:
man > mosquitoes > man
vector: yellow fever mosquito Stegomyia aegypti
(also: blood or organ donations)
- Incubation period:
3-14 days
- Symptoms:
DF: fever, headache, characteristic skin rash (similar to
measles), muscle and joint pain (“break bone fever”),
vomiting, diarrhea
DHF/DHSS: bleeding, fever, low levels of blood platelets,
blood plasma leakage, low blood pressure, death
- Treatment:
supportive, oral and/or intravenous rehydration
- Prevention:
no approved vaccination, control and prevention from
mosquito bites, control of mosquito habitats
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Immunopathology of viral infections
Antibody-dependent enhancement (ADE) of viral infection
Induction of virus-specific antibodies
Rothman, Nature Review Immunol., 2011, 11, 532-43.
Glycoprotein E von DENV
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Immunopathology of viral infections
Antibody-dependent enhancement (ADE) of viral infection
Induction of virus-specific antibodies
DENV1 infection
DENV2 infection
Fc receptor
> Generation of neutralizing (Y) as well as binding/
non-neutralizing (Y) antibodies against DENV1
> cross reaction
Y
Y
Y
Y Y
> enhanced viral uptake of DENV2 via viral and
Fc receptors of monocytes and macrophages
> increased release of inflammatory cytokines
> endothelial damage
> hemorrhagic fever, shock, death (1-15 % )
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Immunopathology of viral infections: examples
Viral infection
Immune response
Antibody-dependent
enhancement of virus infection
(dengue virus)
Overreaction of the immune
system „cytokine storm“
(influenza virus)
Induction of autoimmune
reactions
„molecular mimicry“
(coxsackievirus)
Tissue destruction via the
immune response against
virus-infected cells
(hepatitis B virus)
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Immunopathology of viral infections
Overreaction of the innate immune system „cytokine storm“
(influenza virus)
„cytokine storm“:
- over boarding reaction of the immune system based on enhanced production
and release of inflammatory mediators (>150 cytokines, chemokines etc. etc.)
- positive feedback increases reaction
- live-threatening shock conditions including massive inflammations
- observed by influenza, smallpox, Ebola, sepsis etc.
Osterholm. New England Journal of Medicine,
352 (18): 1839, 2005
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Immunopathology of viral infections
Overreaction of the innate immune system „cytokine storm“
(influenza virus)
Influenza pandemia 1918
•
March-June 1918 (1th wave):
–
•
August-December 1918 (2.nd wave):
–
–
–
–
–
–
–
•
extreme contagious and extreme lethal esp. among young adults
maximum: September-November 1918
up to 70 % mortality induced by secondary bacterial pneumonia
decreased average life span in the US more than 10 years
probably contributed to the end of WW I
in the US: one third of the population was infected
in Germany: ca. 10 mill. people were infected
1919-1920 (3. rd wave)
–
•
extreme contagious but less lethal
global situation: 10-20 mill. fatalities (?)
Analysis:
–
tissue material of victims, 2005: complete sequence
> virus reconstruction (H1N1)
–
only a few sequence differences
–
Host transmission: bird > man/pig or pig only > man (?)
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Immunopathology of viral infections
Overreaction of the innate immune system „cytokine storm“
(influenza virus)
death
Emerging Infectious Diseases, 18, 2012
disease
High fatality rate by:
- new virus variant
- changes in the HA, NA and polymerase
- overreaction of the immune system of young
immunocompetend adults
- damage of the lung epithelium
- secondary bacterial infections with
Haemophilus influenzae, Streptococcus
pneumonia, Streptococcus pyogenes,
Staphylococcus aureus
- social aspects (war, hunger etc.)
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Immunopathology of viral infections
Overreaction of the innate immune system „cytokine storm“
(influenza virus)
Aim: Is it possible to reduce the severity of influenza virus infection via the application
of immune modulators?
„Player“:
PNAS, 2011, 108(29), 12018-12023
Virus:
FLUAV H1N1 2009 pandemic
Drugs:
modulation via sphingosine-1-phosphate-(S1P) agonists
AAL-R (synthetic sphingosine analogue)
sphingosine (C18H37NO2)
(R-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol)
part of sphingomyeline
in cell membranes
phosphorylation via sphingosine kinase 2
AFD-R (R-2-amino-4-(4-heptyloxyphenyl)-2methylbutyldihydrogenphosphate)
Finglimod/Fingolimod
(Gilenya®, FTY720, Novartis)
drug against multiple sclerosis
S1P receptor binding:
> lymphocytes remain in lymph nodes
> suppression of the immune response
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Immunopathology of viral infections
Overreaction of the innate immune system „cytokine storm“
(influenza virus)
Sphingosine-1-phosphate: synthesis and function
- cell proliferation
- cell migration
- angiogenesis
- apoptosis
www.caymanchem.com/images/currents/017/Sphingosine.jpg
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Immunopathology of viral infections
Overreaction of the innate immune system „cytokine storm“
(influenza virus)
Function: sphingosine-1-phosphate/sphingosine-1-phosphate receptor
Involvement of S1P receptors in the regulation of physiological
and pathophysiological phenomena.
S1P receptor agonists:
> endothelial barrier
> release of pro-inflammatory cytokines/chemokines
> cellular viability
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Nature Reviews Drug Discovery, 8, 2009, 297-307
Immunopathology of viral infections
Overreaction of the innate immune system „cytokine storm“
(influenza virus)
AAL-R administration leads to significant increase of the survival rate.
AAL-R administration decreases inflammatory reactions.
AAL-R and/or oseltamivir administrations do not influence the
formation of neutralizing antibodies.
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Immunopathology of viral infections
Overreaction of the innate immune system „cytokine storm“
(influenza virus)
Ergebnis:
A : IAV infection of lung epithelial tissue > tissue destruction, oseltamivir reduces virus distribution
B : IAV infection activates the innate immune response (cytokines, chemokines, inflammation) > inhibition via AAL-R
C : activation of DC during IAV infection > inhibition via AAL-R
D : DC in lymph nodes: activation and expansion of CD4+ and CD8+ lymphocytes > inhibition via AAL-R
E : normally, activated T lymphocytes control IAV infection efficiently
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Immunopathology of viral infections: examples
Viral infection
Immune response
Antibody-dependent
enhancement of virus infection
(dengue virus)
Overreaction of the immune
system „cytokine storm“
(influenza virus)
Induction of autoimmune
reactions
„molecular mimicry“
(coxsackievirus)
Tissue destruction via the
immune response against
virus-infected cells
(hepatitis B virus)
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Immunopathology of viral infections
Evidence of a viral involvement during autoimmune diseases
• autoimmune diseases occur or increase after viral infections
• autoimmune diseases can be induced by viral infection under experimental conditions
• e.g. „molecular mimicry“: vial and host cell antigens are similar > cross reaction > immune response
directed against own tissue
Induction of autoimmune reactions „molecular mimicry“
(type 1 diabetes and viral infections – coxsackieviruses)
diabetes mellitus
type 1 diabetes
Juvenile diabetes: destruction of the insulinproducing beta cell of the islets of
Langerhans in the endocrine pancreatic
tissue leading to complete insulin deficiency.
Genetic predisposition (HLA variants) >
MHC molecules on cells and environmental
factors like viral infections are important >
autoimmune reaction
type 2 diabetes
„adult-onset diabetes“: multiple factors like
e.g. a genetic insulin resistance (insulin is
produced but cannot bind to receptors >
increased insulin production accompanied
by reduced efficacy > increased blood
sugar levels > obesity), but obesity itself
induces type 2 diabetes as well (metabolic
syndrome)
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Immunopathology of viral infections
Induction of autoimmune reactions „molecular mimicry“
(type 1 diabetes and viral infections – coxsackieviruses)
Coxsackievirus-induced destruction of murine pancreatic tissue
control
log TCID50/0.1 g tissue
8
viral load in pancreas
6
4
2
0
2
4
6
8
days p. i.
10
12
14
2 d p. i.
28 d p. i.
CVB3
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Immunopathology of viral infections
Induction of autoimmune reactions „molecular mimicry“
(type 1 diabetes and viral infections – coxsackieviruses)
type 1 diabetes and detection of viral
infections: clinical analyses:
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Immunopathology of viral infections
Induction of autoimmune reactions „molecular mimicry“
(type 1 diabetes and viral infections – coxsackieviruses)
Detection of viruses in human
insulin-producing cells.
Virus
insulin
glucagon
somatostatine
beta cells
alpha cells
delta cells
double staining
yellow=positive
Jaidane et al., Rev. Med. Virol., 2010, 265-280
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Immunopathology of viral infections
Induction of autoimmune reactions „molecular mimicry“
(type 1 diabetes and viral infections – coxsackieviruses)
Virus-induced immunopathology:
„Molecular mimicry“ between viral proteins and
proteins of the inulin-producing beta-cells:
GAD65:
IAR/IA-2:
HSP60:
glutamic acid decarboxylase
protein tyrosine phosphatases
heat shock protein 60
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Jaidane et al., Rev. Med. Virol., 2010, 265-280
Immunopathology of viral infections
Coxsackieviruses
type 1 diabetes
non-specific viral infection induces a
virus-specific immune response in the
host with genetic predisposition.
cross reaction with proteins of the insulinproducing beta-cells induces an autoimmunebased tissue destruction > insulin deficiency
onset of type 1
diabetes
pancreatic cancer
non-specific viral infection induces
acute pancreatitis
acute pancreatitis evolves
to chronic pancreatitis >
activation of oncogenes
onset of pancreatic cancer
4 % survival after 5 years
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Immunopathology of viral infections: examples
Viral infection
Immune response
Antibody-dependent
enhancement of virus infection
(dengue virus)
Overreaction of the immune
system „cytokine storm“
(influenza virus)
Induction of autoimmune
reactions
„molecular mimicry“
(coxsackievirus)
Tissue destruction via the
immune response against
virus-infected cells
(hepatitis B virus)
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Immunopathology of viral infections
Tissue destruction via the immune response against virus-infected cells
(hepatitis B virus)
- Characteristics: family: Hepadnaviridae, enveloped, 40-42 nm in size, partially dsDNA circular
genome, reverse transcriptase, genetic stabile (1 serotype, 7 genotypes), highly stable in the
environment
- Distribution: worldwide, one of the most frequent
infection, ca. 370 mill. chronicinfected people
HBV particles
HBsAg filaments
HBsAg particles
binding of virusspecific antibodies
capsid (core protein):
secreted form:
envelop protein:
http://www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2014/Ausgaben/30_14.pdf?__blob=publicationFile
Constant number of infections
HBcAg
HBeAg
HBsAg
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Immunopathology of viral infections
Tissue destruction via the immune response against virus-infected cells
(hepatitis B virus)
- Transmission: parenteral via blood transfusion, needle stick injury,
i.v. drug abuse, sex, perinatal, asymptomatic HBsAg carrier often with more than 108 HBVparticle/ml blood, but also via shaver, toothbrush, tattooing, body piercing etc.
(HBV is 40-100 times more infectious than HIV)
- Time of incubation: 75 (45-160) days
- Symptoms: 2/3 without any symptoms, 1/3 with symptoms of an acute hepatitis with growing
pains, bellyache, nausea, vomiting and diarrhea
cirrhosis of the liver or liver cancer
reason of ca. 80 % of all liver cancers
- Diagnostic: antigen detection via e.g. ELISA, PCR, serology, liver biopsy
- Therapy: interferon, nucleoside/tide analogs (e.g. Lamivudin)
- Prevention: vaccination, aseptic conditions, control of blood donors, education
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Immunopathology of viral infections
Tissue destruction via the immune response against virus-infected cells
(hepatitis B virus)
Course:
infection
marginal replication
immune defense
inapparent
transient
infection
immunity
fulminant replication
delayed, intense
immune defense
acute
healing
fulminant
immune tolerance
inapparent, chronic
incomplete immune defense
HBsAg
carrier
chronic
hepatitis
cirrhosis of liver
liver cancer 29
Immunopathology of viral infections
Tissue destruction via the immune response against virus-infected cells
(hepatitis B virus)
Cirrhosis of liver: pathological final state of disease; chronic, irreversible disease
characterized by replacement of liver tissue by fibrosis (scar tissue)
These changes lead to loss of liver function.
healthy tissue
cirrhotic tissue
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Immunopathology of viral infections
Tissue destruction via the immune response against virus-infected cells
(hepatitis B virus)
Evidence of immunopathology:
- HBV replicates without cytophatic effects
- HBV carrier with active viral replication do not have a liver damage
- chronic HBV-infected newborns reveal no symptoms
- patients with a chronic-active hepatitis B reveal infiltrates of mononuclear cells in
the liver
- HBV-transgenic mice produce huge amounts of HBV without symptoms
- HBV-infected chimpanzees reveal liver damage after the acute phase
sALT: serum alanine aminotransferase
marker of liver damage
experimental infection
of chimpanzees
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Immunopathology of viral infections
Tissue destruction via the immune response against virus-infected cells
(hepatitis B virus)
Hypothesis of the immune-mediated
pathogenesis of hepatitis B:
HBV infection
immune response
virus carrier
missing T-cell reaction
induces conditions of inapparent
virus carriers
chronic hepatitis
healing
intense T-cell reaction
Induces a fast
virus elimination
weak T-cell reaction induces viral
persistence accompanied by an ongoing
destruction of virus-infected cells
Chronic forms of hepatitis B are induced by a weak but ongoing
immune responses against HBV.
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Immunopathology of viral infections
Summary:
Immune responses play a role during pathogenesis of certain viral infections:
- humoral immune reactions may increase the pathogenesis of viral
infections via ADE reactions (DHSS)
- induction of an overwhelming expression of inflammatory
immune mediators induces severe forms of diseases (influenza)
- immunological cross-reactions following viral infections play a role in the
onset of autoimmune reactions (type 1 diabetes)
- cellular immune responses against persistent-infected cells may induce
ongoing chronic tissue destructions followed by cancer (hepatitis B)
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