TY - JOUR
T1 - CARD9-dependent neutrophil recruitment protects against fungal invasion of the central nervous system
AU - Drummond, Rebecca A.
AU - Collar, Amanda L.
AU - Swamydas, Muthulekha
AU - Rodriguez, Carlos A.
AU - Lim, Jean K.
AU - Mendez, Laura M.
AU - Fink, Danielle L.
AU - Hsu, Amy P.
AU - Zhai, Bing
AU - Karauzum, Hatice
AU - Mikelis, Constantinos M.
AU - Rose, Stacey R.
AU - Ferre, Elise M.N.
AU - Yockey, Lynne
AU - Lemberg, Kimberly
AU - Kuehn, Hye Sun
AU - Rosenzweig, Sergio D.
AU - Lin, Xin
AU - Chittiboina, Prashant
AU - Datta, Sandip K.
AU - Belhorn, Thomas H.
AU - Weimer, Eric T.
AU - Hernandez, Michelle L.
AU - Hohl, Tobias M.
AU - Kuhns, Douglas B.
AU - Lionakis, Michail S.
PY - 2015/12/17
Y1 - 2015/12/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84953220467&partnerID=8YFLogxK
U2 - 10.1371/journal.ppat.1005293
DO - 10.1371/journal.ppat.1005293
M3 - Article
C2 - 26679537
AN - SCOPUS:84953220467
SN - 1553-7366
VL - 11
JO - PLoS pathogens
JF - PLoS pathogens
IS - 12
M1 - e1005293
ER -
