Innate immunity - Paul-Ehrlich

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Innate immunity
[email protected]
Paul-Ehrlich-Institut
Paul-Ehrlich-Institut
Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel
Wettrüsten zwischen Wirt und Virus
Evolution
Anti-virales
Wirtsmolekül
Virales
Molekül
Virus
//
lution
Evolution
Slide adapted from Carsten Münk
„Hierzulande musst du so schnell rennen, wie du kannst, wenn
du am gleichen Fleck bleiben willst. Um woandershin zu
kommen, musst du mindestens doppelt so schnell laufen!“
The Red Queen to Alice in Alice in Wonderland
SM. Hedrick 2004
Slide adapted from Carsten Münk
Das Immunsystem als Hürde
für die Virus-Ausbreitung
Intrinsische
Immunität
Angeborene
Immunität
Erworbene
Immunität
Flint, Principles of Virology, 2009
Das Immunsystem als Hürde
für die Virus-Ausbreitung
Intrinsische
Immunität
Angeborene
Immunität
Erworbene
Immunität
Flint, Principles of Virology, 2009
Intrinsic defenses
• Barriers (e.g. skin, normal flora, …)
• Apoptosis (“altruistic suicide”)
• Autophagy (“eating in to avoid infection”)
• Epigenetic silencing (defense against DNA viruses replicating in the nucleus)
• RNA silencing (sequence-specific degradation of virus RNA)
• Cytosin deamination (Apobec affecting RT of retroviruses)
• Trim Proteins (protection against endemic retroviruses)
Intrinsic barriers to infection
Skin
Gut
Lungs
Eyes/Nose
Apoptosis upon viral infections
At the cell surface:
• Induction of apoptosis-inducing cytokines
• Alteration of membrane integrity
In the cytoplasm:
• Production of metabolic inhibitors
• Modification of cytoskeleton
Infection of human epithelial cells with HSV-1 results in membrane
blebbing and apoptotic body formation
In the nucleus:
• Damage to DNA
• Alteration of gene expression
• Disruption of cell cycle
Adapted from Flint, Principles of Virology, 2009
Autophagy
disposing invaders without disposing the whole cell
Levine et al., 2007 Nature Reviews
Das Immunsystem als Hürde
für die Virus-Ausbreitung
Intrinsische
Immunität
Angeborene
Immunität
Erworbene
Immunität
Flint, Principles of Virology, 2009
Innate immune responses
C
• Complement (classical pathway, lectin pathway, alternative pathway)
• Innate immune cells (e.g. dendritic cells, NK cells, …)
IFN
• Cytokines (e.g. type I interferons)
Innate immune responses
C
• Complement (classical pathway, lectin pathway, alternative pathway)
• Innate immune cells (e.g. dendritic cells, NK cells, …)
IFN
• Cytokines (e.g. type I interferons)
Cells of the innate immunity
Macrophage
• Phagocytosis and
activation of bactericidal
mechanisms
• Antigen presentation
Neutrophil
• Phagocytosis and
activation of bactericidal
mechanisms
Dendritic cell
• Phagocytosis
• Antigen presentation
Eosinophil
• Killing of antibody-coated
parasites
NK cell
• Release of lytic granules
that kill virus-infected cells
Basophil
• Unknown
Mast cell
• Release of granules
containing histamine
and other active agents
Dendritic cells detect „foreign“
• Detect PAMPs (pathogen associated molecular patterns) via PRRs (pattern recognition receptors)
• Sentinel cells “show” the pathogen on MHC II to cells of the adaptive immunity
• Get activated in periphery and mature (MHC II upregulation, upregulation of costimmulatory molecules, cytokine release)
• Migrate to secondary lymphatic organs
• Initiate adaptive immune response
Flint, Principles of Virology, 2009
Natural killer cells detect „missing self“
• “Dynamic equilibrium concept”
• Inhibition of NK cells by detecting MHC I molecules
• Activation of NK cells by “alert molecules” (self and non-self)
• Release perforins and granzymes perforating membranes and trigger caspase-mediated cell-death
• Produce IFN-
• Antibody-dependent cell cytotoxicity (ADCC) via Fc receptor CD16
Vivier et al., 2008 Nature Reviews
Viral mechanisms for modulation of NK cell activity
1.
Expression of viral MHC I homolog by infected cell
(HCMV UL18)
2.
Increase of host HLA-E expression
(Nef of HIV1 affects MHC I expression, but not of MHC I E)
3.
Expression of viral activating receptor antagonists
(HCMV E2 envelope protein binding to CD81)
4.
Catch NK cell stimulatory cytokines or produce cytokine
agonists
(Ectromelia encoded IL-18 binding protein inhibits IFN-
production)
5.
Infection of NK cell itself
Adapted from Flint, Principles of Virology, 2009
Innate immune responses
C
• Complement (classical pathway, lectin pathway, alternative pathway)
• Innate immune cells (e.g. dendritic cells, NK cells, …)
IFN
• Cytokines (e.g. type I interferons)
Immunantwort nach Kontakt mit einem Pathogen
- Viren
- Bakterien
- Protozoen
- Parasiten
Interferone
IgM
Killer Zellen
IgG
Tage nach Infektion
4
Angeborene
Immunität
8
Erworbene
Immunität
12
Ausschüttung von Interferon
nach Kontakt mit einem Pathogen
Interferon
Ausschüttung von Interferon
nach Kontakt mit einem Pathogen
Interferon
Interferone sichern das Überleben nach Infektion
Interferon
IgM
Killer
IgG
Überleben
Wild-typ Maus
4
8
12
Überleben
Maus ohne Killer Zellen
4
8
12
Überleben
Maus ohne Antikörper-produzierende Zellen
4
8
12
Überleben
Maus ohne Typ I Interferon System
4
8
12
VSV
Type I, II, and III interferons
Type I interferons
Type II interferon
IFN-
IFN-/
IFNAR
IFNGR
Type III interferons
IFN-1-3
IFNLR
Mechanism of IFN- induction
IFN-
IFNAR
IFN-
IRF-3
STAT
JAK
NF-B
IRF-7
IFN-
Type I IFN-mediated anti-viral effects
Virus-infected host cell
• Induction of 2’-5’ oligoadenylate synthetase
- Activation of an endoribonuclease
- Degradation of viral RNA
• Induction of P1-kinase (serine/threonine kinase)
- Inhibition of translation
- Inhibition of viral replication
IFN- and IFN- expression
>300 target genes
• Induction of Mx
- Mediates resistance against influenza infection
- Targets viral nucleocapsids
- Inhibits RNA sythesis
• Induction of protein kinase R
- dsRNA-dependent
- Inhibits translation initiation
•…
Interferone in klinischen Anwendungen
Zulassungen
Datum
Handelsname
Wirkstoff
Hersteller
Indikation
1983
Fiblaferon®
IFN beta
Rentschler
Schwere Viruserkrankungen / 2003 SARS
04/1987
Roferon A®
IFN alpha-2a
Roche
Krebs
11/1995
Betaferon®
IFN beta-1b
Schering
Multiple Sklerose
03/1997
Avonex®
IFN beta-1a
Biogen
Multiple Sklerose
05/1998
Rebif®
IFN beta-1a
Serono
Multiple Sklerose
02/1999
Inferax®
IFN alphacon 1
Yamanouchi
Hepatitis C
03/2000
Intron A®
IFN alpha-2b
Essex Pharma
Hepatitis B/C
02/2002
PegIntron®
pegyliertes IFN alpha-2b
Essex Pharma
Hepatitis C
06/2002
Pegasys®
pegyliertes IFN alpha-2a
Roche
Hepatitis B/C
10/2007
CinnoVex®
biogeneric IFN beta-1a
CinnaGen
Multiple Sklerose
06/2008
Extavia®
IFN beta-1b
Novartis
Multiple Sklerose (identisch mit Betaferon®)
Ausschüttung von Interferon
nach Kontakt mit einem Pathogen
Interferon
Ausschüttung von Interferon
nach Kontakt mit einem Pathogen
Interferon
Identification of interferon producing cells in the spleen
VSV
Immunohistochemistry: anti IFN- antibody
Barchet et al. (2002), JEM
FACS-sorting of dendritic cell populations
1. VSV infection in vivo
4. FACS analysis and FACS-sorting
VSV
C
2. Suspension of spleen cells
CD11c
A
D
B
E
C/D
GR-1
F
CD11b
3. MACS pre-sort for CD11c+ cells
A: Lymphoid DC (CD11c+CD11b-); CD8+ DC
B: Myeloid DC (CD11c+CD11b+)
C: GR-1- DC (CD11cintCD11b-GR-1-)
D: GR-1+ DC (CD11cintCD11b-GR-1+)
E: Macrophage-like DC (CD11cintCD11b+)
F: Granulocytes (GR1+)
Barchet et al. (2002), JEM
Identification of plasmacytoid dendritic cells
as IFN- source in the spleen
IFN- RT-PCR
untreated
C
CD11c
A
VSV
D
B
E
C/D
GR-1
F
CD11b
Barchet et al. (2002), JEM
Ausschüttung von Interferon
nach Kontakt mit einem Pathogen
Interferon
Classification of cytokines
Functional group
Selected members
Activity
Pro-inflammatory cytokines
IL-1, TNF-, IL-6, IL-12
Promote leukocyte activation
Anti-inflammatory cytokines
IL-10
Suppress activity of pro-inflammatory
cytokines; return system to basal
“circulate and wait” state
Chemokines
IL-8
Recruit immune cells during early stages
of immune response
Ausschüttung von Interferon
nach Kontakt mit einem Pathogen
Interferon
Ausschüttung von Interferon
nach Kontakt mit einem Pathogen
Interferon
Massive fungal infection in Toll-/- fruit flies
Lemaitre et al. (1996), Cell
How do DC sense pathogens?
1996
Spätzle/Toll/cactus control potent antifungal response in
Drosophila (Lemaitre et al., Cell)
1998
Positional cloning of LPS resistance in C3H/HeJ mice revealed that
LPS is recognized by TLR4 (Poltorak et al., Science)
Toll-like receptors (TLRs)
PRR: pattern recognition receptors
PAMPs: pathogen associated molecular patterns
LRR
extracellular
cytoplasm
TIR domain
MyD88
TRIF
TLR-dependent and -independent pathogen recognition
bacterial
lipoproteins
LPS
PLP
Flagellin
?
TLR2
TLR6/1
TLR4
TLR5
TLR10, 12, 13
TLR11
extracellular
cytoplasm
PPP
TLR3
TLR7/8
dsRNA
ssRNA
dsDNA
RIG-I
MDA5
DAI
TLR9
endosome
?
PKR
TLR signaling
…updated July 2004
updated September 2005
updated October 2005
updated March 2008
updated ……..
Pattern-recognition receptors expressed by human DC subsets
Kadowaki et al. (2001)
PAMPs trigger cytokine production
LTA
(TLR2)
LPS
(TLR2/4)
CpG
(TLR9/DAI?)
poly I:C
(TLR3/RLH)
pDC
imDC
mono.
pDC
imDC
mono.
pDC
imDC
mono.
pDC
imDC
mono.
pDC
imDC
mono.
IL-12
INF-
IL-6
TNF-
PGN
(TLR2)
Kadowaki et al. (2001)
Ausschüttung von Interferon
nach Kontakt mit einem Pathogen
Interferon
Ausschüttung von Interferon
nach Kontakt mit einem Pathogen
Interferon
Type I IFN-mediated effects on adaptive immunity???
IgM
IgG
CTL
response
IFN-I
days post infection
4
Innate
immunity
8
Adaptive
immunity
12
IFNAR-dependent antibody class switch
VSV-VLP
Antibody class switch?
WT or IFNAR-/-
Bach et al. (2005)
Type I IFN-mediated effects on adaptive immunity???
IgM
IgG
CTL
response
IFN-I
days post infection
4
Innate
immunity
8
Adaptive
immunity
12
IFNAR-dependent T cell expansion
WT
IFNAR-/-
T cell expansion?
IFN
% transferred T cells
of CD8+
T cell
30 MVAgp33
WT
IFNAR-/-
Development
-
Activation
-
Proliferation
+
Expansion
+
Survival
+
Function
+
20
10
0
3
4
5
days post infection
6
7
Frenz et al., 2010
Bridging innate and adaptive immunity
IFN-/
4
2
1
3
pDC
6
5
n
mDC
X
CD8+
T cell
B cell
IgM
Clearance of viral infection
IgG
Paul-Ehrlich-Institut
Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel
Literature
ISBN: 1555814794
ISBN: 3-8274-2047-4
ISBN: 978-1-904455-81-3
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