Immunopathology Of Viral Infections: Dept. Of Microbiology Fk Undip

Immunopathology of viral infections Dept. of Microbiology FK Undip

Semarang, Oktober 2017

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Objectives • Mengulas kembali respon imun terhadap infeksi virus (refreshment class!) • Imunopatologi pada infeksi virus: o Antibody-dependent enhancement pada infeksi virus o Kerusakan jaringan yang disebabkan respon imun terhadap sel yang terinfeksi virus o Over reaksi sistem imun “cytokine storm” o Induksi reaksi autoimun yang disebabkan “molecular mimicry”

I. Overview of immune response to viral infection (refreshment class)

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Line of defense 1. Lini pertama

 mencegah patogen menginvasi tubuh o Nonspesifik o Pasif

2. Lini kedua

 mencegah penyebaran patogen o Respon peradangan o Nonspesifik o Aktif o Komponen: seluler (fagosit), humoral (komplemen, interferon, protein fase akut, dll.)

3. Lini ketiga o o o o

Spesifik Aktif Komponen: humoral (antibodi), seluler (limfosit) Memori

INNATE IMMUNITY

ADAPTIVE IMMUNITY

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PAMPs of virus dan their respective PRRs

PAMP: pathogen-associated molecular patterns PRR: pattern recognition receptor

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Innate Immunity against Virus Infection

Humoral: interferon

Seluler : NK cell

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Effects of interferon

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Anti-viral activities triggered by α- and β-interferons (type I interferons) • 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 in the antigen-presenting cells (APCs) • Enhance the antiviral function of NK cells and adaptive immune cells (B cells, T cells)  the production of antibody (B cells) and cytotoxic responses (T cells and NK cells) • Induction of apoptosis

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Adaptive Immunity against Virus Infection

Humoral : Antibodi

Seluler : CD8 CTL

II. Immunopathology of viral infection

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Immunopathology • In many viral infections, clinical symptoms such as fever, tissue damage, pain, and nausea are a consequence of the immune response • Damage caused by the immune system is known as immunopathology • For some viruses that do not directly kill cells (non-cytolytic viruses) the immune response is the main cause of disease

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Effectors of a virus-induced immune pathology • fulminant innate immune response > e.g. cytokine expression • activated T-cells > CD8+ CTL (destruction of chronic infected cells, autoimmune reactions) • activated B-cells/plasma cells > auto reactive antibodies

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Immunopathology of viral infections: examples

• Antibody-dependent enhancement of virus infection • Overreaction of the immune system “cytokine storm“ • Tissue destruction via the immune response against virusinfected cells • Induction of autoimmune reaction molecular mimicry“

dengue virus influenza virus hepatitis B virus coxsackievirus

III. “Antibody-dependent enhancement“ of virus infection Example: Dengue infection

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Dengue infection • Caused by dengue virus, Flaviviridae, enveloped, single-stranded (+) RNA virus: DEN-1, DEN-2, DEN-3, DEN-4, (DEN-5) • Can result in a range of symptoms : - No symptoms - Mild to moderate signs of the disease - severe complications Depends on : - Immune response (secondary heterologue infection) - Virus virulence

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Multiple theories of dengue immune pathogenesis

St John. Plos Pathogens. 2013

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Antibody to Dengue virus

Nature Reviews Immunology 11, 532-543 (August 2011)

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Antibody dependent enhacement

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Antibody dependent enhacement

High levels of epitope occupancy  antibodies can block the binding of virions to the cellular receptor or can block fusion at a post-binding stage Lower epitope occupancy levels  antibodies can enhance the uptake of virions into cells by interacting with immunoglobulin (Fc) receptors.

IV. Overreaction of the immune system “cytokine storm“ (influenza virus)

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Influenza virus • Orthomyxoviridae • enveloped virus • negative strand RNA genome • three types, A, B and C • Type A: o 16 subtypes of HA o 9 subtypes of NA • 5-120 nm, spiked particles • Eight genome segments in A and B

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Antigenic drift Genom: o RNA genome o eight separate segments

Natural mutation

antigenic drift

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Antigenic shift/ genetic reassortment Human Inf Virus

antigenic shift Avian Inf Virus

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Antigenic drift

Y

Antigenic drift vs Antigenic shift

Y

Y

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Antigenic shift

H2N2 Asian flu

Zoonoses

1977

H1N1 H5N1 H7N2 H7N3 H7N7 H9N2

Epidemic H3N2 Hong Kong flu

2009

H1N1 Spanish flu

Epidemic 1957

1918

Epidemic

Pandemic

?

1968

Pandemic

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Pandemic

Influenza A virus pandemics of the last century - and recent pandemic threats -

H1N1 Mexican flu

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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.

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Cytokine storm in the lung following severe influenza infection

Viruses infect lung epithelial cells and alveolar macrophages  produce progeny viruses and release cytokines/chemokines (mainly contains interferons) Cytokine/chemokine-activated macrophages and virally infected dendritic cells  extensive immune response  cytokine storm

Released chemokines  attract more inflammatory cells to migrate from blood vessels into the site of inflammation, and these cells release additional chemokines/cytokines to amplify cytokine storm.

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• In an ARDS condition, will oxigenation via intubation help?

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Research: Is it possible to reduce the severity of influenza virus infection via the application of immune modulators?

Immune modulator: sphingosine analog (AAL-R)

V. Tissue destruction via the immune response against virus-infected cells (Hepatitis B)

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Hepatitis B • Hepadnaviridae, enveloped, 40-42 nm in size, partially dsDNA circular genome • Transmission: parenteral via blood transfusion, needle stick injury, iv. drug abuse, sex, perinatal, asymptomatic HBsAg carrier often with more than 108 HBV- particle/ml blood, but also via shaver, toothbrush, tattooing, body piercing etc. • 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 80% of all liver cancers) • Therapy: interferon, nucleoside/tide analogs (e.g. Lamivudin) • Prevention: vaccination, aseptic conditions, control of blood donors, education

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HBV infects the liver but does not cause direct cytopathology Cell-mediated immune lysis of infected cells produces the symptoms and resolves the infection Insufficient immunity can lead to chronic disease

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VI. Induction of autoimmune reaction due to “molecular mimicry“ (example: coxsackievirus) Molecular mimicry: where a foreign antigen shares sequence or structural similarities with self-antigens

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Diabetes mellitus

Type 1 diabetes = Juvenile diabetes • destruction of the insulinproducing beta cell of the islets of Langerhans  complete insulin deficiency. • Genetic predisposition (HLA variants) > MHC molecules on cells • environmental factors like viral infections > 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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Environmental factors and type 1 diabetes

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How enterovirus causes type 1 diabetes mellitus

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