Impaired Chemokine Production and Neutrophil Recruitment in CARD9-Deficient Mice and Humans with Brain Fungal Infection

FARE Award Winner

Authors

• RA Drummond
• AL Collar
• M Swamydas
• JK Lim
• AP Hsu
• CM Mikelis
• SR Rose
• EMN Ferre
• L Yockey
• K Lemberg
• HS Kuehn
• SD Rosenzweig
• X Lin
• P Chittiboina
• TH Belhorn
• ET Weiner
• ML Hernandez
• TM Hohl
• DB Kuhns
• MS Lionakis

Abstract

Candida albicans is the most common human fungal pathogen and the cause of systemic infections that are associated with neutropenia and result in significant mortality. C-type lectin receptors are crucial for innate fungal recognition and induction of antifungal immune responses via the adaptor protein CARD9. Humans with autosomal recessive CARD9 deficiency are susceptible to fungal infections that have a unique tropism for the central nervous system (CNS) for reasons that remain poorly understood. Here, we report a novel CARD9 c.170G>A missense mutation in a child with Candida meningoencephalitis. Strikingly, the patient had a distinct absence of neutrophils in the cerebrospinal fluid (CSF) despite uncontrolled fungal disease. Lack of neutrophils in the CSF was not due to peripheral neutropenia, impaired neutrophil survival or a neutrophil-intrinsic chemotaxis defect. Instead, neutrophil-recruiting chemokines were absent in the patient CSF, which was not chemotactic for neutrophils ex vivo. We phenocopied the patient susceptibility in Card9-/- mice, which developed uncontrolled brain candidiasis with profound tissue invasion, and had severely impaired neutrophil accumulation in the infected brain. Card9 was dispensable for neutrophil production in the bone marrow, egress into the blood, survival and induction of neutrophil-targeted adhesion molecules in the Card9-/- brain. While Card9-/- neutrophils showed no cell-intrinsic chemotaxis defect in mixed bone marrow chimera experiments, the induction of neutrophil-recruiting chemokines was significantly impaired in infected Card9-/- brains, from myeloid and non-myeloid cellular sources. Thus, CARD9 is critical for control of fungal invasion in the CNS, acting to promote neutrophil trafficking via production of neutrophil-targeted chemokines.

Scientific Focus Area: Immunology

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