Trained immunity: impact for non-specific effects of vaccination. Mihai G. Netea

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1 Trained immunity: impact for non-specific effects of vaccination Mihai G. Netea

Innate versus specific immunity Innate immunity: - rapid - effective - not-specific, indiscriminate - lacks immunological memory Adaptive immunity:

2 Innate versus specific immunity Innate immunity: - rapid - effective - not-specific, indiscriminate - lacks immunological memory Adaptive immunity: - needs days - a specific activation against a particular microorganism, enhancing the effectivity of the response - builds immunological memory

3 Memory: the ability of a system to store and recall information on previously encountered characteristics Fishes Holometabolous Heterometabolous Amphibians Reptiles Birds Mammals Molluscs Insects 95% Innate 5% Innate and Adaptive Gnathostomes -450 My Placoderms Agnathans Annelids Echinoderms Urochordates Plants -800 My -1 By 3

4 Systemic acquired resistance

5 5

6 Netea et al: Cell Host and Microbe 2011 Increased response to secondary infection

7 Quintin et al, Cell H&M, 2012 Innate immunity-dependent protection in mice

8 Methylation status of H Quintin et al, Cell H&M, 2012

9 MTA: Histone methyltransferase inhibitor Less Methylation Quintin et al, Cell H&M, 2012

10 Trained immunity versus tolerance innate immune response priming duration (days/weeks?) training tolerance (H3K4me3) Quintin et al., CHM, 2012 homeostasis (H3K4me3) Foster et al., Nature 2007 primary infection secondary infection

11 What are the pathways distinguishing Training vs Tolerance? signaling Saeed, Quintin et al, Science, 2014

12 What are the pathways distinguishing Training vs Tolerance? metabolism signaling Saeed, Quintin et al, Science, 2014

13 What are the pathways distinguishing Training vs Tolerance? metabolism signaling Saeed, Quintin et al, Science, 2014

2 present Oxidative phosphorylation Krebs cycle Electron transport 36 ATP

14 Immune cell glucose TLR stimulation glucose autophagy glucose HIF-1α mtor Akt glycolysis 2ATP O 2 not present pyruvate Lactic acid Active cells NAD + PDH O 2 present Oxidative phosphorylation Krebs cycle Electron transport 36 ATP Naïve cells ACC NADH Lipid synthesis AcetylCoA Histone acetyl transferase HIF-1α

15 Model of metabolic activation of trained monocytes glucose b-glucan dectin-1 glucose Increased glycolysis HIF-1α mtor Akt High NAD + pyruvate High Lactic acid PDH Metabolic activation of trained monocyte Cheng et al, Science, 2014 Low TCA cycle Low oxidative phosphorylation Low NADH

Metabolic status and epigenetic programming decides the long-term activation fate of the monocyte Tolerance vs Training Training stimuli camp

16 Metabolic status and epigenetic programming decides the long-term activation fate of the monocyte Tolerance vs Training Training stimuli camp Sustained induction of glycolysis (Warburg) PKA Metabolic activation high H3K4me Latent enhancers Induction of Trained Immunity Maintains Trained status

17 New Scientist Aug Trained immunity in humans

18 Kleinnijenhuis et al, PNAS, 2012 Does this happen in vivo in humans?

19 Kleinnijenhuis et al, PNAS, 2012 BCG enhances monocyte-derived cytokines

20 Kleinnijenhuis et al, Clin Immunol 2014 BCG increases NK cell function

21 Kleinnijenhuis et al, PNAS, 2012 BCG effects on epigenetics and transcription

22 BCG protects against candidiasis in a T/B-independent fasion n=25 n=15 Kleinnijenhuis et al, PNAS, 2012

23 Is autophagy involved in Trained Immunity induced by BCG?

24 SNP in ATG2B (rs ) Buffen et al, PLoS Pathogens, in press

BCG study in vivo ATG2B (rs3759601) Buffen et

25 BCG study in vivo ATG2B (rs ) Buffen et al, PLoS Pathogens, in press ATG2B (rs )

26 Effect on epigenetic level Buffen et al, PLoS Pathogens, in press

27 Buffen et al, PLoS Pathogens, in press Bladder cancer study

28 Fold change % subjects reaching seroconversion Fold change % subjects reaching seroconversion seroconversion Fold change seroconversion % subjects reaching seroconversion A/California/7/ Placebo BCG BCG increases 40 immunogenicity 60 of influenza vaccine A/California/7/ H3N2 serotype Pandemic H1N1 serotype A/Texas/50/2012 B serotype Fold change Fold change Fold change Fold change Fold change Fold change 20 0 A/California/7/ P= A/Texas/50/ P=0.047 A/Texas/50/2012 A/Texas/50/ B/Massachusetts/2/ Influenza 28 vaccination 10 Fold change Leentjens et al, submitted Antibody titer P=0.76 Placebo BCG % subjects reaching seroconversion % subjects reaching seroconversion % subjects reaching seroconversion subjects reaching seroconversion D A/Texas/50/ Placebo BCG 20 P= A/Texas/50/ Placebo BCG E 60 Placebo BCG % subjects reaching seroconversion % subjects reaching seroconversion 30 Placebo 10 BCG A B P=0.56 Fold change C B/Massachusetts/2/ Placebo 20BCG Fold change 10 % subjects reaching seroconversion A/California/7/2009 Seroconversion P=0.72 A/Texas/50/ B/Massachusetts/2/ A/Texas/50/ F B/Massachusetts/2/2012 P= Influenza vaccination Placebo BCG Placebo BCG

29 BCG increases immunogenicity of influenza vaccine C. Albicans ***IL-10 **IFN-ɣ A LPS * TNF-α * IL-6* * IL-1β IFN-ɣ IL-10 C. Albicans ***IL-10 IFN-ɣ B TNF-α *** IL-6** LPS IL-1β* IFN-ɣ IL-10 **IL-1β IL-1β IL-6 TNF-α ***IL-6 TNF-α* *TNF-α * IL-6 TNF-α IL-6 *IL-10 * **IFN-ɣ ** ****IL-1β S. Aureus IL-6 TNF-α IFN-ɣ IL-10*** IL-1β** ** MTB +200% +150% +100% *IL-10 * **IFN-ɣ S. Aureus IL-1β **IL-6 TNF-α IFN-ɣ IL-10** IL-1β MTB +50% 0 * p<0.05 ** p< % *** p< % Leentjens et al, submitted

30 Classical view

32 Thank you! Our lab Jessica Quintin James Cheng Siroon Bekkering Johanneke Kleinnijenhuis Jos W.M. van der Meer Leo Joosten Reinout van Crevel Dept. Molecular Biology - Radboud Sadia Saeed Joost Martens Colin Logie Henk Stunnenberg Dept. Intensive Care - Radboud Matthijs Kox Peter Pickkers AMC - Amsterdam Brendon Scicluna Tom van der Poll Harvard University Aylwin Ng Ramnik Xavier Trinity College Luke O Neill Athens University Evangelos Giamarellos East Tennessee State University David Williams

mtor- and HIF-1α mediated aerobic glycolysis as metabolic basis for trained immunity

RESEARCH RESEARCH ARTICLE SUMMARY IMMUNOGENETICS mtor- and HIF-1α mediated aerobic glycolysis as metabolic basis for trained immunity Shih-Chin Cheng, Jessica Quintin, Robert A. Cramer, Kelly M. Shepardson,