updates on candida immunology - wild apricot...candidiasis mucosal t lymphocytes systemic...
TRANSCRIPT
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Updates on Candida Immunology
2018 MSGERC Biennial MeetingPlenary Lectures on ”Candida”September 26, 2018
Michail S. Lionakis, MD, ScD
Chief, Fungal Pathogenesis SectionLaboratory of Clinical Immunology & MicrobiologyNational Institute of Allergy & Infectious Diseases
0 20 806040 100
COLONIZED HUMANS NON-COLONIZED HUMANS
COMMENSAL STATEINFECTION
MUCOCUTANEOUS CANDIDIASIS SYSTEMICCANDIDIASIS
NOT LIFE-THREATENING
≈ 75% of all women → vaginitis≈ 25% of antibiotic-treated women → vaginitis
≈ 90% of AIDS patients → oral thrush
LIFE-THREATENING
SURVIVAL
The Disease Burden of Candidiasis in Humans
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CANDIDIASIS
MUCOSAL
T lymphocytes
SYSTEMIC
Neutrophils Macrophages
CANDIDIASIS
MUCOSAL
T lymphocytes
SYSTEMIC
Neutrophils Macrophages
IL-17 Signaling is Important for Anti-Candida Mucosal Host Defense
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Chronic Mucocutaneous Candidiasis
in Humans with Inborn Errors of
Interleukin-17 ImmunityAnne Puel,1*‡ Sophie Cypowyj,2* Jacinta Bustamante,1 Jill F. Wright,3 Luyan Liu,1 Hye Kyung Lim,2
Mélanie Migaud,1 Laura Israel,1 Maya Chrabieh,1 Magali Audry,2 Matthew Gumbleton,4 Antoine
Toulon,5 Christine Bodemer,5 Jamila El-Baghdadi,6 Matthew Whitters,3 Theresa Paradis,3 Jonathan
Brooks,3 Mary Collins,3 Neil M. Wolfman,3 Saleh Al-Muhsen,7 Miguel Galicchio,8 Laurent Abel,1,2†
Capucine Picard,1,9,10†Jean-Laurent Casanova1,2,7,10‡
www.sciencemag.org SCIENCE VOL 332 1 APRIL 2011
Inherited IL-17RC deficiency in patients
with chronic mucocutaneous candidiasisYun Ling, Sophie Cypowyj, Caner Aytekin, Miguel Galicchio, Yildiz Camcioglu, Serdar Nepesov,
Aydan Ikinciogullari, Figen Dogu, Aziz Belkadi, Romain Levy, Mélanie Migaud, Bertrand Boisson,
Alexandre Bolze, Yuval Itan, Nicolas Goudin, Julien Cottineau, Capucine Picard, Laurent Abel,
Jacinta Bustamante, Jean-Laurent Casanova, Anne Puel
www.jem.org JEM VO 212 27 APRIL 2015
IL-17 Signaling is Important for Anti-CandidaMucosal Host Defense in Mice and Humans
Conti et al., J Exp Med. 2009
Holland, NEJM, 2009; Lionakis & Levitz. Annu Rev Immunol, 2018
IL-17–Mediated Protection via Generation of Anti-Candida Antimicrobial Peptides
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CANDIDIASIS
MUCOSAL
T lymphocytes
SYSTEMIC
Neutrophils Macrophages
The Clinical Observations
Although ICU patients share clinical and microbiological risk factors for candidiasis,
only a small minority develops the infection
Among infected patients, the outcome of candidiasis varies greatly
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The Hypothesis
Variation in immune function-related genes modulates the risk of developing candidiasis
and worse outcome after infection
Bench to Bedside Study of Systemic
Candidiasis
Can we identify patients with specific
host genetics that are at higher risk for
the infection?- Sample size, replication, functional analyses,
frequency
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Macrophages
Qian et al., J Immunol. 1994
Phagocytes but not Lymphocytes are Critical in Host Defense against Systemic Candidiasis
Per
cen
t su
rviv
al
Neutrophils
0 2 4 6 8 10 12 140
20
40
60
80
100
Days post-infection
Perc
en
t su
rviv
al
Neutropenic
Non-neutropenic
Unpublished data
MONOCYTESMACROPHAGES
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Lionakis & Levitz. Annu Rev Immunol. 2018
Candida Yeasts Are Effectively Picked up by Macrophages Early After Infection in the Kidney
Macrophages (CX3CR1)dTomato-Candida
2 hrs post-infection
Lionakis et al., J Clin Invest. 2013
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Macrophages Wrap Around Candida Hyphae Early After Infection in the Kidney
Macrophages (CX3CR1)dTomato-Candida
2 hrs post-infectionLionakis et al., J Clin Invest. 2013
CX3CR1 is Protectiveagainst Systemic Candidiasis
Lionakis et al., J Clin Invest, 2013
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Targeted Immunogenetic Approaches:
CX3CR1-M280
Cx3cr1 is important for macrophage survival and protects from death after systemic candidiasis (MICE)
The CX3CR1-M280 mutation impairs human monocyte survival and is a risk factor for systemic candidiasis
(HUMANS)
Lionakis et al., J Clin Invest, 2013; Collar et al, JCI Insight, 2018
NEUTROPHILS
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Red: dTomato-C. albicans
Green: Cx3cr1(macrophages)
Grey: Ly6G(neutrophils)
unpublished
47 67
Phagosome
Cytoplasm
1o
granule
2o
granule
GECG
MPOPR3Defensins
LactoferrinCD11b
40
Candida
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4767
e- O2-
HOCl
H2O2
Phagosome
NADPH
NADP+
Cytoplasm
GECGGECG
40
Candida
4767
e- O2-
HOCl
H2O2
Phagosome
NADPH
NADP+
Cytoplasm
40
~5% of CGD Patients Develop Invasive
Candidiasis
Winkelstein et al., Medicine. 2000
Candida
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4767
e- O2-
HOCl
H2O2
Phagosome
NADPH
NADP+
40
~5% of Patients with Complete MPO
Deficiency Develop Invasive Candidiasis
Parry et al., Ann Intern Med. 1981
Candida
Non-oxidative Cytotoxic anti-CandidaMechanisms of Neutrophils are Largely Unknown
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Targeted Immunogenetic Approaches:
CXCR1-T276
Cxcr1 is important for neutrophil killing and protects from death after systemic candidiasis (MICE)
The CXCR1-T276 mutation impairs human neutrophil killing and is a risk factor for systemic candidiasis
(HUMANS)
Swamydas et al., Science Transl Med, 2016
TAGAP, CD58, LCE4A-C1orf68
Unbiased Approaches:
GWAS
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Other important examples:
The Clinical Observations
A surge of small molecule inhibitors for treatment of autoimmune and neoplastic
conditions
Predictable and non-predictable effects on anti-Candida immunity
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The Hypothesis
Novel iatrogenic risk factors for candidiasis
The Hypothesis
Novel iatrogenic risk factors for candidiasis- Fostamatinib (SYK inhibitor)- Avacopan (C5AR1 inhibitor)- Danirixin (CXCR2 inhibitor)
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CARD9 is centrally positioned in antifungal immune pathways
Lionakis & Netea, PLoS Pathog, 2013; Lionakis & Levitz, Annu Rev Immunol, 2018
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CARD9 deficiency results in decreased neutrophil accumulation in the CSF
Drummond et al, PLoS Pathog, 2015
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The CARD9-/- Infected CSF is not Chemotactic to Neutrophils ex vivo
Card9-/- Mice Develop Uncontrolled Fungal Brain Infection
Card9-/-
Card9+/+
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CARD9+/+
200x
CARD9-/-
200x
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Card9 is Required for Neutrophil Accumulation in the Fungal-Infected Brain
0 24 720
20000
40000
60000
hours post-infection
# n
eu
tro
ph
ils/b
rain
********
Card9-/-
Card9+/+No defect in neutrophil:- Production in bone
marrow- Egress in blood- Survival- Cell-intrinsic
chemotaxis
No defect in the kidney, no defect in staphylococcal brain infection
Drummond et al, PLoS Pathog, 2015
A Model of Microglial Engagement for CNS Protective Antifungal Immunity
Drummond et al, under revision
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Microglia-Mediated Production of IL-1 and CXCL1 is CARD9-Dependent
ng
/g tis
sue
Frequency of pro-IL-1/CXCL1 positive microglia determined by intracellular flow cytometry after 4 hour incubation with Brefeldin A +/- additional stimulation
CXCL1 is not induced in the CARD9-/- infected CSF
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SYK-CARD9 are centrally positioned in antifungal immune pathways
Lionakis & Netea, PLoS Pathog, 2013; Lionakis & Levitz, Annu Rev Immunol, 2018
39 trials in ClinicalTrials.gov- RA- Lymphomas- Solid tumors- Autoimmune
cytopenias
CXCR2 is Critical for Neutrophil Recruitment and Function During Systemic Candidiasis
Swamydas et al, in preparation
0 2 4 6 8 100
20
40
60
80
100
Day post infection
Perc
en
t su
rviv
al
Cxcr2+/+
Cxcr2 -/-
P=0.0033
Opsonized Unopsonized0
50
100
150
Killin
g c
ap
acit
y (
co
mp
are
d t
o W
T)
Cxcr2+/+
***P=0.0001
Cxcr2-/-
*** ***
HYPHAE
10 trials in ClinicalTrials.gov (COPD, severe lung viral infections)
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C5AR1 is Critical for Macrophage Killing During Systemic Candidiasis
Desai et al, in preparation
0 10 20 300
50
100
days post infection
Perc
en
t su
rviv
al C5ar1
+/+
C5ar1-/-
P < 0.0001
C5a
r1+/
+
C5a
r1-/-
0
50
100
150
no
rmalized
Can
did
a
killin
g (
%)
**
6 trials in ClinicalTrials.gov (ANCA vasculitis, HUS, Glomerulonephritis)66 trials of eculizumab in ClinicalTrials.gov (HUS, Glomerulonephritis, kidney transplantation, PNH, HSCT)
Take Home MessagesPhagocytes are crucial for immunity during systemic candidiasis
- Early neutrophil recruitment- Early monocyte/macrophage-Candida contact - Non-oxidative killing mechanisms
Individualized host genetics affect the risk of systemic candidiasis and may provide the platform for personalized risk stratification and prognostication strategies in humans
- Chemokine/cytokine signaling, PRRs, type I interferon genes
Basic immunology studies may uncover novel iatrogenic risk factors for candidiasis in patients treated with small molecule inhibitors for autoimmunity/malignancies.
Future needs: tissue-specific responses, non-albicans Candida
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Acknowledgements
• FPS– Rebecca
Drummond
– Timothy Break
– Mandy Collar
– Lekha Swamydas
– Jigar Desai
– Vas Oikonomou
– Elise Ferre
– Monica Schmitt
– Mike Abers
– Greg Constantine
– Ahnika Kline
• iPSCs– Colleen Sweeney
– Harry Malech
Thank you!
• Candidalysin mutants
– Julian Naglik
– Bernie Hube
• Collaborators– Yasmine Belkaid
– Kat Mayer-Barber
– Phil Murphy
– Brian Kelsall
– Warren Strober
– Tobias Hohl
– Gordon Brown
– Yoichiro Iwakura
– Sergio Lira
– Brian Schaefer
• Candidemia cohorts
– John Perfect
– Melissa Johnson
– Mihai Netea