Concurrent central nervous system infection with <i>Candida</i> and <i>Mycobacterium intracellulare</i> in CARD9 deficiency: immunological insights from a single case

INTRODUCTION: Caspase recruitment domain-containing protein 9 (CARD9) deficiency is classically characterized by chronic mucocutaneous candidiasis (CMC) and invasive Candida infections, including central nervous system (CNS) disease. Susceptibility to mycobacterial infection has not been considered a defining feature of CARD9 deficiency. METHODS: We describe a patient with a typical clinical phenotype of CARD9 deficiency associated with compound heterozygous variants in CARD9, initially presenting with CMC and later manifesting CNS candidiasis, complicated by a concurrent CNS infection caused by Mycobacterium intracellulare. This unexpected finding prompted detailed immunological analyses to determine whether the mycobacterial infection represented a coincidental event or reflected an underlying susceptibility. RESULTS: Immunological studies demonstrated preserved neutrophil nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species production, whereas bactericidal/permeability-increasing protein (BPI) was uniquely and markedly reduced among neutrophil antimicrobial proteins. In parallel, monocyte-derived dendritic cells exhibited impaired tumor necrosis factor-α (TNF-α) production in response to mycobacterial stimulation, suggesting impaired cytokine responses downstream of CARD9. CONCLUSION: These findings suggest that impaired dendritic cell cytokine responses to mycobacteria, together with markedly reduced neutrophil BPI content, may have contributed to the development of M. intracellulare infection in this patient. Our study highlights a potential mechanism underlying susceptibility to mycobacterial infection in CARD9 deficiency.