A mooc of the Institut Pasteur

Fungal Diseases
Can Have A Genetic Cause

Anne PUEL
PhD

Lab of Human Genetics of Infectious Diseases

INSERM U1163, Institut Imagine, Université de Paris, Paris, France
Rockefeller University, NYC, USA

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 Fungal Diseases

May be life-threatening, major public health problem

• Rapidly growing at-risk population of patients
• Emergence of resistant strains
• Considerable morbidity and mortality worldwide

Frequent in patients with acquired immunodeficiencies A. fumigatus P. jirovecii

• Pathogenesis largely unknown

Can occur in otherwise healthy individuals (idiopathic)

Hypothesis: a genetic origin for at least a part of the idiopathic fungal infections
C. neoformans C. albicans

Identification of the disease-causing gene

• Gain insights into fungal disease pathogenesis
• Crucial mechanisms in anti-fungal immunity
• Patients’ care
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 Chronic Mucocutaneous Candidiasis (CMC)

IL-17 IMMUNITY IS CRUCIAL AGAINST C. ALBICANS MUCOCUTANEOUS INFECTIONS

Isolated CMC
Syndromic CMC
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 Invasive Fungal Diseases and autosomal
recessive CARD9 deficiency

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Glocker et al. NEJM 2009; Lanternier et al. NEJM 2013
 Invasive Fungal Diseases and autosomal recessive CARD9
deficiency

Over 60 patients from 41 kindreds (15 countries, 4 continents) mainly vulnerable to

Ascomycete but not to common viral, bacterial, parasitic diseases

Puel A, Hum Genet 2020, Perez L et al. J Clin Immunol. 2020; Corvilain E et al. Clin Immunol 2018; Arango-
MEDICAL Franco CA et al. J Clin Immunol. 2018; Li J et al. Curr Opin Microbiol 2017; Grumach AS et al J Clin
6MYCOLOGY Immunol. 2015; Lanternier F et al. J Allergy Clin Immunol. 2015; Lanternier F et al. J Infect Dis. 2015;
Lanternier F et al. N Engl J Med. 2013
 Primary immunodeficiencies and Fungal Diseases
Lymphocyte Cell Numbers/Function (SCID, CID, CD4 lymphopenia)
• Pneumocystis jirovecii pneumonia (SCID, HIGM, idiopathic CD4 lymphopenia, MHC Class II deficiency, AR IL-21R deficiency, NF-kB
disorders, AD IKAROS deficiency)
• Cryptococcosis (idiopathic CD4 lymphopenia, HIGM)

Phagocytic Cell Deficiency (CGD, SCN, LAD deficiency, AR complete MPO deficiency)
• Aspergillosis

AD GATA2 Deficiency
• Aspergillosis (XL-WAS), histoplasmosis, cryptococcosis

AD STAT1 Gain-of-Function
• CMC, candidiasis, aspergillosis, dimorphic fungi (histoplasmosis, coccidioidomycosis), PJP, cryptococcosis, fusariosis, mucormycosis

IL-12/IFN-γ axis Deficiency

• Dimorphic fungi (histoplasmosis, coccidioidomycosis, paracoccidioidomycosis)

AR CARD9 Deficiency
• CMC, invasive candidiasis, deep dermtophytosis, phaeohyphomycosis, mucor…

Auto-antibodies against GM-CSF or IFN-

• Cryptococcosis

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 TAKE HOME MESAGES

Fungal Diseases (FD) can have a genetic determinism (even in adults)

Deciphering of:
• PID/IEI with an increased susceptibility to fungal diseases
• Fungal diseases in otherwise healthy individuals
• Gain insights into disease pathogenesis
• Crucial pathways involved in anti-fungal immunity in human

Medical implications:

• Diagnostic and genetic counseling

• Development of adapted immuno-therapeutical strategies (e.g. GM-CSF, JAK inhibitors)

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 The patients and their families
Laboratory of Human Genetics of Infectious Diseases

Laurent Abel Jean-Laurent Casanova

All our clinicians and scientific collaborators worldwide

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