Blood Journal
Leading the way in experimental and clinical research in hematology

Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency

  1. Agata A. Drewniak1,
  2. Roel P. Gazendam1,*,
  3. Anton T.J. Tool1,
  4. Michel van Houdt1,
  5. Machiel H. Jansen2,
  6. John L. van Hamme1,
  7. Ester M.M. van Leeuwen2,
  8. Dirk Roos1,
  9. Emmanuel Scalais3,
  10. Carine de Beaufort4,
  11. Hans Janssen5,
  12. Timo K. van den Berg1, and
  13. Taco W. Kuijpers6
  1. 1 Sanquin Research, and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Netherlands;
  2. 2 Department of Experimental Immunology, Academic Medical Center, Amsterdam, Netherlands;
  3. 3 Division of Pediatric Neurology, Centre Hospitalier de Luxembourg, Luxembourg;
  4. 4 Division of Pediatric Endocrinology, Centre Hospitalier de Luxembourg, Luxembourg;
  5. 5 Division of Cell Biology, Dutch Cancer Institute, Amsterdam, Netherlands;
  6. 6 Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
  1. * Corresponding author; email: r.gazendam{at}

Key points

  • Human CARD9-deficiency is characterized by a selective neutrophil killing defect, resulting in invasive candidiasis


Caspase recruitment domain-containing protein 9 (CARD9) is an adaptor molecule in the cytosol of myeloid cells, required for induction of T-helper cells producing IL-17 (Th17 cells) and important in anti-fungal immunity. In a patient suffering from Candida dubliniensis meningoencephalitis mutations in the CARD9 gene were found to result in the loss of protein expression. Apart from the reduced numbers of CD4+ Th17 lymphocytes, we identified a lack of monocyte-derived cytokines in response to Candida strains. Importantly, CARD9-deficient neutrophils showed a selective Candida albicans killing defect with abnormal ultrastructural phagolysosomes and outgrowth of hyphae. The neutrophil killing defect was independent of the generation of reactive oxygen species (ROS) by the NADPH oxidase system. Taken together, this demonstrates that human CARD9 deficiency results in selective defect in the host defense against invasive fungal infection, caused by an impaired phagocyte killing.

  • Submitted August 16, 2012.
  • Accepted December 30, 2012.