Immunotherapy in the Prevention and Treatment of Chronic Fungal Infections

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

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

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-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

training (H3K4me3)

n priming Quintin et al., CHM, 2012

u homeostasis

tolerance (H3K4me3)

a Foster et al., Nature 2007

n i duration (days/weeks?)

b-glucan-induced Trained immunity

IL-23

Th17 STAT1 GOF STAT3

Th17 responses IFN type I and II IL-27

STAT1

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