Trained immunity - MolMed. Moorlach.pdf · 2018. 6. 7. · Pathway analysis of H3K27ac changes Arts...
Transcript of Trained immunity - MolMed. Moorlach.pdf · 2018. 6. 7. · Pathway analysis of H3K27ac changes Arts...
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Trained immunity
A memory for innate host defense
Simone J.C.F.M. Moorlag, MSc, MD
PhD candidate Radboudumc Promotor: Mihai G. Netea Virology course Rotterdam 30 May 2018
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Innate versus specific immunity
Dranoff, 2004
Innate immunity: - rapid - not-specific, indiscriminate
- lacks immunological memory
Adaptive immunity: - needs 10-14 days - a specific activation against a particular microorganism, enhancing the effectivity of the response - builds immunological memory
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Holometa-bolous
Annelids
Molluscs
Insects
Heterometa-bolous
Urochordates Echinoderms
-800 My
-450 My
Gnathostomes
Fishes Amphi- bians
Reptiles Birds
95% Innate
5% Innate and Adaptive
Plants
-1 By
Memory: the ability of a system to store and recall information on previously encountered characteristics
Agnathans
Mammals
Placoderms
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Systemic acquired resistance
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Do insects have immunological memory?
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Increased response to secondary infection
Netea et al: Cell Host and Microbe 2011
Innate immune memory also present in vertebrates?
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Low dose of C. albicans
PBS
Priming 7 days Secondary exposure
Lethal dose C. albicans
Outcome?
Innate memory in mice: model
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Innate immunity-dependent protection in mice
Quintin et al, Cell H&M, 2012
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Trained immunity
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In-vitro preincubation model
PBMCs/Monocytes 1st stimuli
Day 0
Wash-out 1st stimuli
Day 1 Cytokine analysis
2nd stimuli
Day 6
37°C
Resting time
ELISA
Quintin et al, Cell H&M, 2012
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membrane phospholipid bilayer, with intercalated ergosterol molecules and enzyme proteins
mannan
protein
1:6 glucan
1:3 glucan
chitin
cell w
all
Fungal cell envelope: target for polyenes, echinocandins, nikkomycins
The Candida albicans cell wall
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NF-B
Raf-1
Dectin-1
Syk
CARD9
P
1st challenge =
priming C. albicans
cytokines
-glucans 2nd challenge
Enhanced secondary response to Candida
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0
2
4
6
8
10
12
Total TB deaths
% m
ort
alit
y
BCG-
BCG +
Introduction of BCG in Sweden, 1927-31: Mortality at 0-4 years- 20,000 children
BCG → 50% reduction in mortality
Naeslund, Rev de la Tuberculose, 1931
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Non-specific effects of BCG: reduced mortality
3 RCT’s: 38%↓
Shann, Arch. Dis. Child, 2010
32-53%↓
34-40%↓ 12-48%↓
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BCG-Induced Trained Immunity
Kleinnijenhuis et al. PNAS, 2012 Netea et al. Science, 2016
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BCG enhances monocyte-derived cytokines
Kleinnijenhuis et al, PNAS, 2012
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BCG effect on epigenetics and transcription
Kleinnijenhuis et al, PNAS, 2012
Low gene expression Increased gene expression
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Tolerance
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Saeed, Quintin et al, Science, 2014
What are the pathways distinguishing Training vs Tolerance ?
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metabolism
signaling
Saeed, Quintin et al, Science, 2014
What are the pathways distinguishing Training vs Tolerance ?
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Warburg effect:
A metabolic switch
- Switch from oxidative phosphorylation -> glycolysis - Results in more lactate and faster production of ATP
Trained immunity:
Arts et al, 2016, Seminars in Immunology
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Model of metabolic activation in TRIM
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Innate memory responses
Netea et al. Science, 2016 Quintin J et al. Cell Host & Microbe, 2012
Histone modifications
Altered cellular metabolism
Initial stimulus (infection/vaccination)
Training programs
1st infection 2nd infection
time
2nd infection
Tolerance programs
1st infection
time
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1) Does BCG induce epigenetic changes at a genome wide level? 2) Can we demonstrate the impact of BCG in a model of human infection?
BCG-Induced Trained Immunity
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0.5
1
BCG induced genome wide histone modifications
• ChIP-sequencing • H3K27ac changes in monocytes of 7 volunteers
Arts and Moorlag et al. Cell host and Microbe, 2018
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Several important signaling and inflammatory related pathways upregulated
- EGFR, VEGF, FGF, cytokines and chemokines
- PI3K-Akt
Pathway analysis of H3K27ac changes
Arts and Moorlag et al. Cell host and Microbe, 2018
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BCG induces enhanced cytokine responses
Arts and Moorlag et al. Cell host and Microbe, 2018
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Impact of BCG in a model of human infection
Arts and Moorlag et al. Cell host and Microbe, 2018
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Induction of IL-1β correlates with YF viremia
Arts and Moorlag et al. Cell host and Microbe, 2018
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• BCG vaccine induces genome wide epigenetic changes
→ functional changes in signaling and inflammatory pathways
• BCG protects against a viral human experimental infection
→ induction of IL-1β is the most reliable correlate of this protection
• IL-1β is a crucial mediator of trained immunity
Conclusions
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Trained immunity induces Functional Reprogramming of Myeloid Precursor Cells
Christ et al. Cell, 2018
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Innate memory in health & disease
Training programs
Tolerance programs
• Innate immunity maturation • Nonspecific protection by vaccines - e.g. BCG vaccine
• Mucosal tolerance • Limitation of tissue damage in infection
• Contributes to hyperinflammation: - atherosclerosis - reumatoid artritis - diabetes
Training programs
Tolerance programs
• Immune paralysis in sepsis
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Siroon Bekkering et al. Arterioscler Thromb Vasc Biol.
2014;34:1731-1738
Trained immunity and atherosclerosis
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Applications
• Trained immunity as a new strategy to modulate levels of IL-1:
1) enhance IL-1 responses to improve bone marrow recovery
• Boost the immune system of young children and elderly people
2) inhibition of trained immunity in IL-1 driven autoinflammatory diseases
• Improve vaccination responses
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Effect of BCG on influenza vaccination (1)
• Influenza-related morbidity and mortality remain high
• Seasonal vaccination is the backbone of influenza management but does
not always result in protective antibody titers
• Nonspecific effects of BCG vaccination
• Could BCG vaccination could also enhance immune responses to influenza vaccination?
Leentjens et al., J Infect Dis. 2015
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Methods
Healthy volunteers received: - live attenuated BCG vaccine (n = 20) or placebo (n = 20) in a randomized fashion - trivalent influenza vaccine 14 days later
Outcome: - Hemagglutination-inhibiting (HI) antibodies - ex vivo leukocyte responses
Leentjens et al., J Infect Dis. 2015
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BCG enhances HI antibody responses
In BCG-vaccinated subjects: enhanced HI antibody responses against the 2009 pandemic influenza A(H1N1) vaccine strain
Trend toward more-rapid seroconversion
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Nonspecific effects of influenza vaccination
Before vs after influenza vaccination Before vs after BCG vaccination
• Modulation of cytokine responses against unrelated pathogens
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Acknowledgements
University of Groningen Vinod Kumar Yang Li Cisca Wijmenga
Radboudumc Rob Arts Boris Novakovic Chantal Reusken Marion Koopmans Marije Doppenberg Leo Joosten Hendrik Stunnenberg Reinout van Crevel Mihai Netea