CARD9-dependent neutrophil recruitment protects against fungal invasion of the central nervous system

Rebecca A. Drummond, Amanda L. Collar, Muthulekha Swamydas, Carlos A. Rodriguez, Jean K. Lim, Laura M. Mendez, Danielle L. Fink, Amy P. Hsu, Bing Zhai, Hatice Karauzum, Constantinos M. Mikelis, Stacey R. Rose, Elise M.N. Ferre, Lynne Yockey, Kimberly Lemberg, Hye Sun Kuehn, Sergio D. Rosenzweig, Xin Lin, Prashant Chittiboina, Sandip K. DattaThomas H. Belhorn, Eric T. Weimer, Michelle L. Hernandez, Tobias M. Hohl, Douglas B. Kuhns, Michail S. Lionakis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

100 Citations (Scopus)


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.

Original languageEnglish
Article numbere1005293
Number of pages32
JournalPLoS pathogens
Issue number12
Publication statusPublished - 17 Dec 2015

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology


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