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Research ArticleGeneticsImmunology
Open Access | 
10.1172/jci.insight.176676
1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
2Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada.
3Infectious Disease and Immunity in Global Health, Research Institute of the McGill University Health Center, Montréal, Québec, Canada.
4Department of Pathology, McGill University Health Center, Montréal, Québec, Canada.
5Department of Human Genetics, McGill University, Montréal, Québec, Canada.
6Fungal Pathogenesis Section, Laboratory of Clinical Immunology & Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
7Department of Molecular & Biomedical Sciences, University of Maine, Orono, Maine, USA.
8Department of Medicine, Division of Infectious Diseases, McGill University Health Centre, Montréal, Québec, Canada.
Address correspondence to: Donald C. Vinh, RI-MUHC, 1001 Décarie Blvd., EM3-3211, Montréal, Quebéc, Canada H4A 3J1. Phone: 514.934.1934 ext. 42419; Email: donald.vinh@mcgill.ca.
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Published May 27, 2025 - More info
Published in Volume 10, Issue 13 on July 8, 2025
AbstractHuman Caspase Recruitment Domain Containing Protein 9 (CARD9) deficiency predisposes to invasive fungal disease, particularly by Candida spp. CARD9 deficiency causes chronic central nervous system (CNS) candidiasis. Currently, no animal model recapitulates the chronicity of disease, precluding a better understanding of immunopathogenesis. We established a knock-in mouse homozygous for the recurring p.Y91H mutation (Y91HKI) and, in parallel to Card9-/– mice, titrated the intravenous fungal inoculum to the CARD9 genotype to develop a model of chronic invasive candidiasis. Strikingly, CARD9-deficient mice had predominantly CNS involvement, with neurological symptoms appearing late during infection and progressive brain fungal burden in the absence of fulminant sepsis, reflecting the human syndrome. Mononuclear cell aggregation at fungal lesions in the brain correlated with increased MHCII+Ly6C+ monocyte numbers at day 1 after infection in WT and Y91HKI mice, but not in Card9-/– mice. At day 4 after infection, neutrophils and additional Ly6C+ monocytes were recruited to the CARD9-deficient brain. As in humans, Y91HKI mutant mice demonstrated cerebral multinucleated giant cells and granulomata. Subtle immunologic differences between the hypomorphic (p.Y91H) and null mice were noted, perhaps explaining some of the variability seen in humans. Our work established a disease-recapitulating animal model to specifically decipher chronic CNS candidiasis due to CARD9 deficiency.
IntroductionInborn errors of immunity in Caspase Recruitment Domain Containing Protein 9 (CARD9) lead to spontaneous development of invasive fungal disease in humans, particularly of the central nervous system (CNS), with Candida albicans (1). CARD9 deficiency is caused by loss-of-function mutations, ranging from complete loss of protein expression to hypomorphic missense mutations, and it is inherited in an autosomal recessive pattern. The recurring c.T271C (p.Y91H) mutation has been reported in 6.7% of patients deficient in CARD9 (2, 3), but how this missense substitution leads to invasive candidiasis is still poorly understood (2, 4).
Commonly used models of candidiasis in mice rely on pharmacologically induced fungal colonization and dissemination, by antibiotic or corticosteroid treatment, use of anticancer agents that suppress the immune system, or a combination of these strategies (5, 6). These preclinical models reflect the human form of iatrogenic invasive candidiasis, providing great insight into acute fungal disease associated with malignancy (7). However, invasive fungal disease in CARD9 deficiency is spontaneous (i.e., in the absence of exogenous immunosuppression) and indolent; thus, the conventionally used experimental approaches do not accurately model this specific human condition. Consequently, these aforementioned mouse models preclude our understanding of CARD9-dependent mechanisms underlying host antifungal defenses, particularly in the CNS. A model of candidiasis that accurately recapitulates human CARD9 deficiency is invaluable to decipher its immunopathogenesis.
CNS involvement has been studied as an extension of multi-organ disease (disseminated candidiasis) in mice with candidemia (8, 9). This latter approach typically uses an inoculum ranging 1 × 104 to 1 × 106 CFU of C. albicans yeast cells in C57BL/6 mice delivered by i.v. injection. WT mice that succumb to infection at these doses die of progressive sepsis and kidney failure (10, 11); on necropsy, neutrophil-mediated kidney immunopathology is apparent, as is damage to other organs, including the brain (10, 12, 13). These studies have shown that myeloid cells, namely neutrophils, monocytes, and tissue-resident macrophages, are essential for tissue protection, since ablation or inhibition of any of these cells increases mortality in mice (10, 14, 15). Using this model, Card9–/– mice show that the early neutrophil infiltration into the brain (24 hours postinfection [p.i.]) is essential to control fungal growth, as impaired neutrophil trafficking enhances disease (9). However, since invasive candidiasis associated with human CARD9 deficiency is often chronic in nature, with a median age at onset of 17.5 years (range, 3.5–58 years) (1, 16), and is not typically accompanied by fulminant sepsis, the relevance of these mouse models to understanding the chronic features of the human disease remains unclear. By using WT mice, but infected with a lower fungal inoculum, a recent study has also demonstrated that mononuclear phagocytes, including brain-resident macrophages (microglia) and monocytes, play a key role in limiting tissue fungal burden by forming “fungus-induced glial granuloma” in the absence of neutrophil infiltration (17). Importantly, the immune response of CARD9-deficient mice at lower doses may also diverge from the response reported using the acute sepsis model of candidemia. Therefore, a preclinical system that more closely models the clinical presentation of CARD9 deficiency in humans would provide an experimental platform to better understand the mechanisms by which CARD9 mediates anti-Candida immunity, and it could be used for development of therapeutic strategies.
In this study, we used CRISPR/Cas9 technology to generate a knock-in mouse homozygous for the c.T271C (p.Y91H) mutation (Y91HKI mice). By titrating the C. albicans inoculum to the CARD9 genotype, we established a clinically pertinent CARD9-deficient model of chronic invasive candidiasis that recapitulates distinct clinical and histopathological features of the human CNS disease, including primarily neurological symptoms, occasional skull destruction, and granulomatous-like inflammation during late-stage infection. At a systemic level, the Y91HKI mice phenocopy Card9–/– mice in terms of survival, dissemination, and tissue fungal burden, confirming that the homozygous p.Y91H mutation is sufficient for fungal disease. At the level of host defense, Y91HKI neutrophil anticandidal functions parallel those of Card9–/– neutrophils. By tracing the kinetics of both tissue fungal growth and the myeloid response in the brain, we identify the critical role of mononuclear phagocyte responses to fungal infection in the brain. Specifically, our data implicate MHCII+Ly6C+ monocyte-derived cells (moDC) as early responders to CNS fungal invasion. The development of a CARD9-dependent chronic invasive candidiasis murine model that better emulates human CARD9 deficiency provides a framework to decipher the disease’s immunopathology and potentially direct the development of mechanism-based intervention strategies.
ResultsKnock-in of the human p.Y91H mutation in mice. To understand how the p.Y91H mutation in CARD9 predisposes to invasive candidiasis, we used CRISPR/Cas9 to knock in the c.T271C mutation into C57BL/6N (B6N) mice (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.176676DS1). Mice were bred to homozygosity to generate a CARD9c.T271C/c.T271C homozygous knock-in mouse (Y91HKI). All genotyping was confirmed by Sanger sequencing (Figure 1A). We initially evaluated Card9 expression in Card9–/– (C57BL/6J background; B6J) and Y91HKI BM-derived macrophages (BMDM) by reverse transcription PCR (RT-PCR) (Figure 1B) and Western blot (Figure 1B). B6J and B6N were used as controls for the genetic background of each mutant mouse throughout our investigations. Card9–/– BMDM show a loss of expression at both the mRNA and protein level. Y91HKI BMDM retained expression of CARD9 at both the transcript and protein levels, consistent with monocytes from patients with CARD9p.Y91H (4, 18). Using flow cytometry, we first performed immunophenotyping of the myeloid compartment of the bone marrow, blood, spleen, brain, and kidney at steady state (Supplemental Figure 1, B–D) and found no differences between the KO, knock-in, or WT mice. These data support the absence of overt myeloid cell deficiencies in patients with CARD9 deficiency (1, 16, 20), indicating CARD9 is redundant for myeloid cell development and homeostasis in mice at steady state (19). Thus, the Y91HKI mouse is a newly developed tool to potentially understand the immunological mechanisms by which CARD9 regulates susceptibility to candidiasis.
Figure 1Mice with knock-in of the human p.Y91H mutation phenocopy Card9–/– mice and are highly susceptible to disseminated candidiasis in vivo. (A) Chromatograms of the Sanger sequencing of B6N and Y91HKI mice showing the knock-in and associated silent PAM site mutation. (B) RT-PCR showing Card9 mRNA expression in BMDM and Western blot for CARD9 protein with GAPDH as a loading control. Representative results of 2 experiments shown. (C) Weight loss of mice injected via lateral tail vein with 1 × 105 CFU of C. albicans. Multiple paired 2-tailed t tests for significance were performed. *P < 0.05, **P < 0.01 in at least 1 time point. Data are shown as mean ± SEM. (D) Kaplan-Meier survival curve of mice injected with 1 × 105C. albicans yeast i.v. *P < 0.05; **P < 0.01 by the log-rank test. (C and D) Three experiments pooled. B6J: C57BL6/J, n = 12 mice; Card9–/–: n = 9 mice; B6N: C57BL6/N, n = 11 mice; Y91HKI: mice homozygous for c.T271C, n = 13 mice; Y91HKI HET: mice heterozygous for c.T271C, n = 17 mice.
Y91HKI mice phenocopy Card9–/– mice during disseminated candidiasis in vivo. To begin investigating the in vivo consequences of the p.Y91H mutation, mice were infected i.v. with 1 × 105 yeast cells, a standard model of disseminated candidiasis (9, 11, 13, 14, 21). Mice were then monitored for morbidity (weight loss) and survival (Figure 1, C and D). In this high-dose model, Y91HKI mice succumbed to infection within 7 days. The survival of Y91HKI mice was slightly longer than Card9–/– mice but did not reach statistical significance. Heterozygous mice displayed an intermediate susceptibility within the 30-day survival experiment. There was no difference in survival between the 2 CARD9 WT mice, showing that any genetic differences between these related strains do not affect survival outcome during infection with high-dose disseminated candidiasis. Thus, Y91HKI mice phenocopied Card9–/– mice during high-dose infection with respect to acuity, morbidity, and mortality, demonstrating that this protein residue was essential for CARD9 function in mice.
The p.Y91H mutation results in enhanced fungal growth and susceptibility to disseminated disease. Since lethality during disseminated candidiasis is correlated to kidney fungal burden in WT mice (21), and Card9–/– mice fail to control fungal growth not only in the kidneys but also in the brain (9, 11), we next compared the kinetics of tissue fungal burden in both kidney and brain (Figure 2). As a control, the fungal burden was also assessed in the spleen, since it is not considered a primary target organ for uncontrolled fungal growth during invasive candidiasis in nonneutropenic hosts (11, 21) (Supplemental Figure 2A). Fungal growth at day 1 p.i. in CARD9-deficient mice is comparable with WT mice, suggesting that initial seeding of C. albicans from the blood into the tissues was similar (Figure 2, A and B). However, the fungal burden was significantly increased in CARD9-deficient mice in the kidney at day 2 p.i. and in the brain after day 3 p.i. (Figure 2, A and B). Together, these data suggest that the initial hematogenous seeding of C. albicans into target organs is subsequently restrained in WT mice, whereas Y91HKI and Card9–/– mice fail to control it, resulting in extensive fungal growth within these tissues.
Figure 2p.Y91H permits enhanced fungal growth in tissue and phenocopies Card9–/– mice in susceptibility to disseminated disease after high-dose C. albicans i.v. infection. (A and B)
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