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Published on: February 18, 2015
A CARD9 deficiency mouse model recapitulates human chronic CNS candidiasis identifying defective monocytic cell
Marija Landekic1, Isabelle Angers2,3, Yongbiao Li3
1Department of Microbiology & Immunology, McGill University, Montréal, Québec, Canada.
Insights
Human CARD9 deficiency leads to chronic fungal brain infections. A new mouse model mimics this human disease, aiding research into its immunopathogenesis and potential treatments.
Area of Science:
- Immunology
- Mycology
- Neuroscience
Background:
- Caspase Recruitment Domain Containing Protein 9 (CARD9) deficiency increases susceptibility to invasive fungal infections, particularly Candida species.
- CARD9 deficiency is linked to chronic central nervous system (CNS) candidiasis in humans.
- Existing animal models do not accurately replicate the chronic nature of CARD9-deficient CNS candidiasis, hindering immunopathogenesis studies.
Purpose of the Study:
- To develop and characterize a novel animal model that recapitulates chronic CNS candidiasis in CARD9-deficient individuals.
- To investigate the immunopathogenesis of chronic CNS candidiasis in a relevant genetic context.
Main Methods:
- Establishment of a knock-in mouse model (Y91HKI) homozygous for the CARD9 p.Y91H mutation.
- Titration of intravenous fungal (Candida spp.) inoculum based on CARD9 genotype in wild-type, Y91HKI, and Card9-/- mice.
- Comparative analysis of fungal burden, immune cell infiltration (monocytes, neutrophils), and neuropathology (granuloma, giant cells) in the CNS.
Main Results:
- CARD9-deficient mice exhibited predominantly CNS involvement with late-onset neurological symptoms and progressive brain fungal burden, mirroring human disease.
- Early mononuclear cell aggregation at fungal lesions was observed in wild-type and Y91HKI mice but not in Card9-/- mice.
- Later stages showed increased neutrophil and monocyte recruitment to the brains of CARD9-deficient mice, with Y91HKI mice developing cerebral multinucleated giant cells and granulomata.
Conclusions:
- The developed Y91HKI mouse model accurately recapitulates chronic CNS candidiasis observed in human CARD9 deficiency.
- This model provides a valuable platform for dissecting the immunopathogenesis of this specific fungal disease.
- Subtle differences between hypomorphic and null CARD9 mutations in the model may explain human disease variability.
Abstract:
Human 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.
