A chance for treatment - immunotherapy in the prevention and treatment of chronic fungal infections Frank L. van de Veerdonk Radboud Center for Infectious diseases (RCI) ESCMID eLibrary © by author Candida infections Mucocutaneous infections Invasive candidiasis Th ESCMIDT helper cells eLibraryPhagocytes © by author Chronic Candida infection 30% to 50% of individuals are colonized with Candida at any given moment, but only rarely causing mucosal infections Even more rarely are these infections chronic However, several clinical syndromes have been described with chronic CandidaESCMIDinfections eLibrary © by author Mucosal host defence against Candida ESCMID eLibrary Nature Microbiol. Reviews 2012 © by author Mucosal host defence against Candida ESCMID eLibrary Nature Microbiol. Reviews 2012 © by author Chronic Candida infections Hyper IgE syndrome (HIES) Dectin-1/CARD9 deficiency Chronic mucocutaneous candidiasis (STAT1 GOF, APECED, IL-17F, IL-17R) ESCMID eLibrary © by author Characteristics of Hyper IgE syndrome ESCMID eLibrary © by author Loss of function STAT3 mutation Heterozygous mutation in STAT3 ESCMIDDominant negative eLibrary © by author Cytokine signalling INTERLEUKIN-6/23 IL-6/IL-23 RECEPTOR STAT3 phosphorylation IL-17 ESCMID eLibrary PMN Levy and Loomis et al, NEJM 2007 © by author Th17 deficiency in HIES IL-17 ESCMID eLibrary IFNg van de Veerdonk et al, Clin Exp Immunol© 2010by author Chronic Candida infections Hyper IgE syndrome (HIES) Dectin-1/CARD9 deficiency Chronic mucocutaneous candidiasis ESCMID eLibrary © by author Dectin-1/CARD9 recognition pathway Candida Cell wall Mannans ESCMIDb-glucans eLibrary © by author Dectin-1 deficiency - Recurrent vulvovaginal infections - Onychomycosis ESCMID eLibrary Ferwerda et al. NEJM 2009 © by author Decreased Th17 response ESCMID eLibrary © by author Dectin-1 deficiency dectin-1 con Loss of a Glutamic acid that binds calcium dectin-1 pat Folding/transport is disturbed no expression of dectin-1 at ESCMID eLibrarythe cell membrane © by author CARD9 deficiency - Increased susceptibility to both mucocutaneous and systemic Candida infections (brain) - Deficient Th17 response ESCMID eLibrary Glocker et al. NEJM 2009 © by author CLR-CARD9 pathway ESCMID eLibrary © by author Chronic Candida infections Hyper IgE syndrome (HIES) Dectin-1/CARD9 deficiency Chronic mucocutaneous candidiasis ESCMID eLibrary © by author APECED AIRE gene: autoimmune regulator on chr. 21 Expression in thymus: ESCMID eLibraryimportant for depletion of autoreactive cells Nature Genetics 1997 © by author Auto-antibodies against IL-17 ESCMID eLibrary © by author Th17 deficiency: How important is IL-17 for controlling mucosal candidiasis? ESCMID eLibrary © by author ESCMID eLibrary Autosomal recessive IL-17RA deficiency Autosomal dominant IL-17F deficiency © by author IL-17 signalling pathway ESCMID eLibrary © by author IL-17 signalling pathway ESCMID eLibrary © by author Family with autosomal dominant CMC ESCMID eLibrary van de Veerdonk et al, NEJM 2011 © by author Chronic mucocutaneous candidiasis (CMC) ESCMID CharleseLibrary Kirkpatrick © by author First documented CMC? ESCMID eLibrary Ferdinand Bol, Vier regenten van het© Leprozenhuis, 1649by author First documented CMC? ESCMID eLibrary Ferdinand Bol, Vier regenten van het© Leprozenhuis, 1649by author T helper cytokines ESCMID eLibrary © by author Systematical approach Neutrophil Interleukin(IL) ESCMID-1 eLibrary TNF © by author Th1: defective IL-12 response IL-12 Th1 ESCMID eLibraryIFN g © by author Th17: defective IL-23 response IL-23 Th17 IL-17 ESCMID eLibraryIL-22 Van de Veerdonk et al, NEJM 2011 © by author Molecules shared by IL-12 and IL-23 pathways Upstream Downstream ESCMID eLibrary © by author Next generation sequencing All exons from 100 selected genes Mutation in STAT1 ESCMID eLibraryArg274Trp © by author Many more STAT1 mutations ESCMID eLibrary © by author What is the mechanism leading to susceptibility to mucocutaneous candidiasis? ESCMID eLibrary © by author STAT molecules INTERLEUKINS RECEPTOR STAT phosphorylation IL-17 ESCMID eLibrary Levy and Loomis, NEJM 2007 © by author STAT1 hyperphosphorylation ESCMID eLibrary © by author Gain of function mutation STAT1 hyperphosphorylation ESCMID eLibrary Liu et al., JEM 2011 © by author Hypothesis Hypothesis Th17 responses IFN type I and II IL-27 STAT1 GOF ESCMID eLibrary © by author Immunomodulatory options? ESCMID eLibrary © by author Hypothesis IL-23 Th17 STAT3 IL-17 ESCMID eLibrary © by author Hypothesis IL-23 STAT1 GOF Th17 STAT3 IL-17 ESCMID eLibrary © by author HypothesisSTAT1 inhibitor (fludarabine) IL-23 STAT1 GOF Th17 STAT3 IL-17 ESCMID eLibrary © by author HypothesisSTAT1 inhibitor (fludarabine) IL-23 STAT1 GOF Th17 STAT3 IL-17 IL-22 ESCMID eLibrary © by author STAT1 GOF clinical phenotype - Chronic candida/trichophyton infection skin and mucosa (long known) - Severe disseminated cutaneous fusariosis - Disseminated endemic mycosis (Coccidioidomycosis and histoplasmosis) - Disseminated aspergillosis - Viral infections (herpes) - IPEX like syndrome - PD-L1 overexpression and decreased B cell survival - Progression to full SCID - Cerebral and pulmonary arterial aneurysms - Esophageal and oropharyngeal carcinomas - ESCMIDAutoimmune diseases (AHIA, autoimmune eLibrary hepatitis) © by author Hypothesis Hypothesis Th17 responses IFN type I and II IL-27 STAT1 GOF ? ESCMIDWhat else….. eLibrary © by author Trained immunity training (H3K4me3) e s n priming Quintin et al., CHM, 2012 o p s e r e n u homeostasis m m i tolerance (H3K4me3) e t a Foster et al., Nature 2007 n n i duration (days/weeks?) primary secondary infESCMIDection infection eLibrary Saeed, Quintin et al, Science, 2014 © by author Hypothesis b-glucan-induced Trained immunity ESCMID eLibrary © by author Epigenetic modification by STAT1? ESCMID eLibrary © by author Epigenetic modification by STAT1? ESCMID eLibrary © by author Epigenetic modification by STAT1? IL-23 Th17 STAT1 GOF STAT3 IL-17 ILESCMID-22 eLibrary © by author Hypothesis Another approach Th17 responses IFN type I and II IL-27 STAT1 GOF ESCMID eLibrary © by author Ruxolitinib (JAK1/JAK2 inhibitor) ESCMID eLibrary © by author ESCMID eLibrary © by author Ruxolitinib STAT1 ESCMID eLibrary © by author Ruxolitinib STAT1 ESCMID eLibrary © by author Take home messages Dysregulated Th17 responses play a major role in chronic Candida infections Restoring dysregulated STAT1-STAT3 activation in CMC: - Direct inhibition of STAT1 - Epigenetic modulation - Indirect via JAK inhibitors or anti-cytokine antibodies Future:ESCMID gene surgery? eLibrary © by author University of Colorado Mark Gresnigt Tania Azam Katharina Becker Charles Dinarello Berenice Rosler Xiaowen Wang East Tennessee State University James Cheng David Williams Ralph Maas Sanne Smeekens Newcastle University UK Bart Ferwerda Desa Lilic Marije Oosting Gerben Ferwerda NIH Liesbeth Jacobs Ofer Zimmerman Alexander Hoischen Steven Holland Joris Veltman Jos van der Meer INSERM Leo Joosten Anne Puel Bart Jan Kullberg Mihai Netea Freiburg University ESCMIDBodo Grimbacher eLibrary © by author ESCMID eLibrary © by author.