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

PLoS Pathogens

Sandip K. Datta¹  Hatice Karauzum¹  Michelle L. Hernandez²  Constantinos M. Mikelis³  Kimberly Lemberg⁴  Hye Sun Kuehn⁴  Sergio D. Rosenzweig⁴  Carlos A. Rodriguez⁵  Jean K. Lim⁵  Xin Lin⁶  Eric T. Weimer⁷  Thomas H. Belhorn⁸  Michail S. Lionakis⁹  Stacey R. Rose⁹  Lynne Yockey⁹  Muthulekha Swamydas⁹  Elise M. N. Ferre⁹  Amanda L. Collar⁹  Rebecca A. Drummond⁹  Amy P. Hsu^1,10  Tobias M. Hohl^1,11  Bing Zhai^1,11  Laura M. Mendez^1,12  Douglas B. Kuhns^1,12  Danielle L. Fink^1,12  Prashant Chittiboina^1,13 

[1] Bacterial Pathogenesis Unit, LCID, NIAID, NIH, Bethesda, Maryland, United States of America;Center for Environmental Medicine, Asthma, and Lung Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America;Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America;Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, Maryland, United States of America;Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America;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;Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America;Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America;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;Immunopathogenesis Section, LCID, NIAID, NIH, Bethesda, Maryland, United States of America;Infectious Disease Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America;Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland, United States of America;Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland, United States of America

关键词: Neutrophils;    C;    ida albicans;    Central nervous system;    Fungal diseases;    Chemokines;    Monocytes;    Cerebrospinal fluid;    Yeast infections;   

DOI  :  10.1371/journal.ppat.1005293

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY