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

Research output: Contribution to journalArticle

Authors

  • 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. Datta
  • Thomas H. Belhorn
  • Eric T. Weimer
  • Michelle L. Hernandez
  • Tobias M. Hohl
  • Douglas B. Kuhns
  • Michail S. Lionakis

Colleges, School and Institutes

External organisations

  • National Institute of Allergy and Infectious Diseases
  • Icahn School of Medicine at Mount Sinai
  • Inc.,
  • Memorial Sloan Kettering Cancer Center
  • Texas Tech University Health Sciences Center at Permian Basin
  • NIH Clinical Center
  • The University of Texas MD Anderson Cancer Center
  • National Institute of Neurological Disorders and Stroke
  • Univ. of North Carolina Chapel Hill

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.

Details

Original languageEnglish
Article numbere1005293
Number of pages32
JournalPLoS pathogens
Volume11
Issue number12
Publication statusPublished - 17 Dec 2015