CARD9-Dependent Neutrophil Recruitment Protects against Fungal Invasion of the Central Nervous System

PLoS Pathog. 2015 Dec 17;11(12):e1005293. doi: 10.1371/journal.ppat.1005293.

Rebecca A Drummond ¹, Amanda L Collar ¹, Muthulekha Swamydas ¹, Carlos A Rodriguez ², Jean K Lim ², Laura M Mendez ³, Danielle L Fink ³, Amy P Hsu ⁴, Bing Zhai ⁵, Hatice Karauzum ⁶, Constantinos M Mikelis ⁷, Stacey R Rose ¹, Elise M N Ferre ¹, Lynne Yockey ¹, Kimberly Lemberg ⁸, Hye Sun Kuehn ⁸, Sergio D Rosenzweig ⁸, Xin Lin ⁹, Prashant Chittiboina ¹⁰, Sandip K Datta ⁶, Thomas H Belhorn ¹¹, Eric T Weimer ¹², Michelle L Hernandez ¹³, Tobias M Hohl ⁵, Douglas B Kuhns ³, Michail S Lionakis ¹

Affiliations

1 Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases (LCID), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
2 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
3 Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, United States of America.
4 Immunopathogenesis Section, LCID, NIAID, NIH, Bethesda, Maryland, United States of America.
5 Infectious Disease Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
6 Bacterial Pathogenesis Unit, LCID, NIAID, NIH, Bethesda, Maryland, United States of America.
7 Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America.
8 Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, Maryland, United States of America.
9 Department of Molecular and Cellular Oncology, Division of Basic Science Research, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
10 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, United States of America.
11 Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
12 Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
13 Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

PMID: 26679537 DOI: 10.1371/journal.ppat.1005293

Abstract

Candida is the most common human Fungal pathogen and causes systemic infections that require neutrophils for effective host defense. Humans deficient in the C-type lectin pathway adaptor protein CARD9 develop spontaneous Fungal disease that targets the central nervous system (CNS). However, how CARD9 promotes protective Antifungal immunity in the CNS remains unclear. Here, we show that a patient with CARD9 deficiency had impaired neutrophil accumulation and induction of neutrophil-recruiting CXC Chemokines in the cerebrospinal fluid despite uncontrolled CNS Candida Infection. We phenocopied the human susceptibility in Card9-/- mice, which develop uncontrolled brain candidiasis with diminished neutrophil accumulation. The induction of neutrophil-recruiting CXC Chemokines is significantly impaired in infected Card9-/- brains, from both myeloid and resident glial cellular sources, whereas cell-intrinsic neutrophil chemotaxis is Card9-independent. Taken together, our data highlight the critical role of CARD9-dependent neutrophil trafficking into the CNS and provide novel insight into the CNS Fungal susceptibility of CARD9-deficient humans.

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