Encyclopedia of Medical Immunology

Living Edition
| Editors: Ian MacKay, Noel R. Rose

CARD9 Deficiency

  • Christina Gavino
  • Marija Landekic
  • Donald C. VinhEmail author
Living reference work entry

Latest version View entry history

DOI: https://doi.org/10.1007/978-1-4614-9209-2_59-2


Despite an estimated 1.5 million species of fungi, ubiquitous in distribution resulting in constant exposure, few cause human disease. Those that do reflect a defect of immunity, either inherent or acquired. Although the taxonomy of fungi and the field of medical mycology are relatively young compared to other fields of microbiology, historical reports of fungi causing nail, hair, and superficial skin infections, as well as invasive disease, can be traced back to the mid-nineteenth century, prior to the advent of advanced therapeutics accounting for modern-day iatrogenic mycoses. Further, rather than causing true epidemics like bacteria and parasites, fungi were recognized to typically cause “sporadic” disease, that is, affecting select individuals, families, or races. The study of primary immunodeficiencies (PID) has led to the identification of critical genes that account, at least in part, for this inherent basis for susceptibility.

Spontaneously occurring fungal...

This is a preview of subscription content, log in to check access.


  1. Alanio A, Vernel-Pauillac F, Sturny-Leclere A, Dromer F (2015) Cryptococcus neoformans host adaptation: toward biological evidence of dormancy. mBio 6(2)Google Scholar
  2. Alves de Medeiros AK, Lodewick E, Bogaert DJ, Haerynck F, Van Daele S, Lambrecht B, et al. Chronic and invasive fungal infections in a family with CARD9 deficiency. J Clin Immunol. 2016;36(3):204–9.CrossRefPubMedGoogle Scholar
  3. Belisle G, Lachance W, Leblanc G. Meningitis caused by Candida albicans. Report of a case and discussion. L’union Med Can. 1968;97(6):710–5.Google Scholar
  4. Bertin J, Guo Y, Wang L, Srinivasula SM, Jacobson MD, Poyet JL, et al. CARD9 is a novel caspase recruitment domain-containing protein that interacts with BCL10/CLAP and activates NF-kappa B. J Biol Chem. 2000;275(52):41082–6.CrossRefPubMedGoogle Scholar
  5. Black JT. Cerebral candidiasis: case report of brain abscess secondary to Candida albicans, and review of literature. J Neurol Neurosurg Psychiatry. 1970;33(6):864–70.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bow EJ, Evans G, Fuller J, Laverdiere M, Rotstein C, Rennie R, et al. Canadian clinical practice guidelines for invasive candidiasis in adults. Can J Infect Dis Med Microbiol = J Can Mal Infect Microbiol Med. 2010;21(4):e122–50.Google Scholar
  7. Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-gamma immunity. Semin Immunol. 2014;26(6):454–70.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Celmeli F, Oztoprak N, Turkkahraman D, Seyman D, Mutlu E, Frede N, et al. Successful granulocyte colony-stimulating factor treatment of relapsing Candida albicans meningoencephalitis caused by CARD9 deficiency. Pediatr Infect Dis J. 2016;35(4):428–31.CrossRefPubMedGoogle Scholar
  9. Cohen MS, Isturiz RE, Malech HL, Root RK, Wilfert CM, Gutman L, et al. Fungal infection in chronic granulomatous disease. The importance of the phagocyte in defense against fungi. Am J Med. 1981;71(1):59–66.CrossRefPubMedGoogle Scholar
  10. de Groot RP, Coffer PJ, Koenderman L. Regulation of proliferation, differentiation and survival by the IL-3/IL-5/GM-CSF receptor family. Cell Signal. 1998;10(9):619–28.CrossRefPubMedGoogle Scholar
  11. Drewniak A, Gazendam RP, Tool AT, van Houdt M, Jansen MH, van Hamme JL, et al. Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency. Blood. 2013;121(13):2385–92.CrossRefPubMedGoogle Scholar
  12. Drummond RA, Collar AL, Swamydas M, Rodriguez CA, Lim JK, Mendez LM, et al. CARD9-dependent neutrophil recruitment protects against fungal invasion of the central nervous system. PLoS Pathog. 2015;11(12):e1005293.CrossRefPubMedPubMedCentralGoogle Scholar
  13. Gavino C, Cotter A, Lichtenstein D, Lejtenyi D, Fortin C, Legault C, et al. CARD9 deficiency and spontaneous central nervous system candidiasis: complete clinical remission with GM-CSF therapy. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2014;59(1):81–4.CrossRefGoogle Scholar
  14. Gavino C, Hamel N, Zeng JB, Legault C, Guiot MC, Chankowsky J, et al. Impaired RASGRF1/ERK-mediated GM-CSF response characterizes CARD9 deficiency in French-Canadians. J Allergy Clin Immunol. 2016;137(4):1178–88.e1-7.CrossRefPubMedGoogle Scholar
  15. Gazendam RP, van Hamme JL, Tool AT, van Houdt M, Verkuijlen PJ, Herbst M, et al. Two independent killing mechanisms of Candida albicans by human neutrophils: evidence from innate immunity defects. Blood. 2014;124(4):590–7.CrossRefPubMedGoogle Scholar
  16. Germain M, Gourdeau M, Hebert J. Case report: familial chronic mucocutaneous candidiasis complicated by deep candida infection. Am J Med Sci. 1994;307(4):282–3.CrossRefPubMedGoogle Scholar
  17. Glocker EO, Hennigs A, Nabavi M, Schaffer AA, Woellner C, Salzer U, et al. A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med. 2009;361(18):1727–35.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Graser Y, Scott J, Summerbell R. The new species concept in dermatophytes-a polyphasic approach. Mycopathologia. 2008;166(5–6):239–56.CrossRefPubMedGoogle Scholar
  19. Gross O, Gewies A, Finger K, Schafer M, Sparwasser T, Peschel C, et al. Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature. 2006;442(7103):651–6.CrossRefPubMedGoogle Scholar
  20. Grumach AS, de Queiroz-Telles F, Migaud M, Lanternier F, Filho NR, Palma SM, et al. A homozygous CARD9 mutation in a Brazilian patient with deep dermatophytosis. J Clin Immunol. 2015;35(5):486–90.CrossRefPubMedGoogle Scholar
  21. Hara H, Saito T. CARD9 versus CARMA1 in innate and adaptive immunity. Trends Immunol. 2009;30(5):234–42.CrossRefPubMedGoogle Scholar
  22. Hara H, Ishihara C, Takeuchi A, Imanishi T, Xue L, Morris SW, et al. The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and toll-like receptors. Nat Immunol. 2007;8(6):619–29.CrossRefPubMedGoogle Scholar
  23. Herbst M, Gazendam R, Reimnitz D, Sawalle-Belohradsky J, Groll A, Schlegel PG, et al. Chronic Candida albicans meningitis in a 4-year-old girl with a homozygous mutation in the CARD9 gene (Q295X). Pediatr Infect Dis J. 2015;34(9):999–1002.CrossRefPubMedGoogle Scholar
  24. Huang HK, Liu CE, Liou JH, Hsiue HC, Hsiao CH, Hsueh PR. Subcutaneous infection caused by Corynespora cassiicola, a plant pathogen. J Infect. 2010;60(2):188–90.CrossRefPubMedGoogle Scholar
  25. Iles KE, Forman HJ. Macrophage signaling and respiratory burst. Immunol Res. 2002;26(1–3):95–105.CrossRefPubMedGoogle Scholar
  26. Jabado N, Casanova JL, Haddad E, Dulieu F, Fournet JC, Dupont B, et al. Invasive pulmonary infection due to Scedosporium apiospermum in two children with chronic granulomatous disease. Clin Infect Dis: Off Publ Infect Dis Soc Am. 1998;27(6):1437–41.CrossRefGoogle Scholar
  27. Jabara HH, Ohsumi T, Chou J, Massaad MJ, Benson H, Megarbane A, et al. A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency. J Allergy Clin Immunol. 2013;132(1):151–8.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Jachiet M, Lanternier F, Rybojad M, Bagot M, Ibrahim L, Casanova JL, et al. Posaconazole treatment of extensive skin and nail dermatophytosis due to autosomal recessive deficiency of CARD9. JAMA Dermatol. 2015;151(2):192–4.CrossRefPubMedGoogle Scholar
  29. Jia XM, Tang B, Zhu LL, Liu YH, Zhao XQ, Gorjestani S, et al. CARD9 mediates Dectin-1-induced ERK activation by linking Ras-GRF1 to H-Ras for antifungal immunity. J Exp Med. 2014;211(11):2307–21.CrossRefPubMedPubMedCentralGoogle Scholar
  30. Jones N, Garcez T, Newman W, Denning D (2016) Endogenous Candida endophthalmitis and osteomyelitis associated with CARD9 deficiency. BMJ Case Rep 2016Google Scholar
  31. Lanternier F, Pathan S, Vincent QB, Liu L, Cypowyj S, Prando C, et al. Deep dermatophytosis and inherited CARD9 deficiency. N Engl J Med. 2013;369(18):1704–14.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Lanternier F, Mahdaviani SA, Barbati E, Chaussade H, Koumar Y, Levy R, et al. Inherited CARD9 deficiency in otherwise healthy children and adults with Candida species-induced meningoencephalitis, colitis, or both. J Allergy Clin Immunol. 2015a;135(6):1558–68.e2.CrossRefPubMedPubMedCentralGoogle Scholar
  33. Lanternier F, Barbati E, Meinzer U, Liu L, Pedergnana V, Migaud M, et al. Inherited CARD9 deficiency in 2 unrelated patients with invasive Exophiala infection. J Infect Dis. 2015b;211(8):1241–50.CrossRefPubMedGoogle Scholar
  34. LeibundGut-Landmann S, Gross O, Robinson MJ, Osorio F, Slack EC, Tsoni SV, et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol. 2007;8(6):630–8.CrossRefPubMedGoogle Scholar
  35. Liang P, Wang X, Wang R, Wan Z, Han W, Li R. CARD9 deficiencies linked to impaired neutrophil functions against Phialophora verrucosa. Mycopathologia. 2015;179(5–6):347–57.CrossRefPubMedGoogle Scholar
  36. Lv GX, Ge YP, Shen YN, Li M, Zhang X, Chen H, et al. Phaeohyphomycosis caused by a plant pathogen. Corynespora cassiicola. Med Mycol. 2011;49(6):657–61.PubMedGoogle Scholar
  37. Mahgoub E. Corynespora cassiicola, a new agent of maduromycetoma. J Trop Med Hyg. 1969;72(9):218–21.PubMedGoogle Scholar
  38. Marks MI, Marks S, Brazeau M. Yeast colonization in hospitalized and nonhospitalized children. J Pediatr. 1975;87(4):524–7.CrossRefPubMedGoogle Scholar
  39. Moraes-Vasconcelos D, Grumach AS, Yamaguti A, Andrade ME, Fieschi C, de Beaucoudrey L, et al. Paracoccidioides brasiliensis disseminated disease in a patient with inherited deficiency in the beta1 subunit of the interleukin (IL)-12/IL-23 receptor. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2005;41(4):e31–7.CrossRefGoogle Scholar
  40. Morris AA, Kalz GG, Lotspeich ES. Ependymitis and meningitis due to Candida (Monilia) albicans. Arch Neurol Psychiatr. 1945;54:361–6.CrossRefGoogle Scholar
  41. Punwani D, Wang H, Chan AY, Cowan MJ, Mallott J, Sunderam U, et al. Combined immunodeficiency due to MALT1 mutations, treated by hematopoietic cell transplantation. J Clin Immunol. 2015;35(2):135–46.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Richardson ET, Shukla S, Nagy N, Boom WH, Beck RC, Zhou L, et al. ERK signaling is essential for macrophage development. PLoS One. 2015;10(10):e0140064.CrossRefPubMedPubMedCentralGoogle Scholar
  43. Rieber N, Gazendam RP, Freeman AF, Hsu AP, Collar AL, Sugui JA, et al. Extrapulmonary Aspergillus infection in patients with CARD9 deficiency. JCI Insight. 2016;1(17):e89890.CrossRefPubMedPubMedCentralGoogle Scholar
  44. Roilides E, Sigler L, Bibashi E, Katsifa H, Flaris N, Panteliadis C. Disseminated infection due to Chrysosporium zonatum in a patient with chronic granulomatous disease and review of non-aspergillus fungal infections in patients with this disease. J Clin Microbiol. 1999;37(1):18–25.PubMedPubMedCentralGoogle Scholar
  45. Rosentul DC, Plantinga TS, Oosting M, Scott WK, Velez Edwards DR, Smith PB, et al. Genetic variation in the dectin-1/CARD9 recognition pathway and susceptibility to candidemia. J Infect Dis. 2011;204(7):1138–45.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Roth S, Ruland J. Caspase recruitment domain-containing protein 9 signaling in innate immunity and inflammation. Trends Immunol. 2013;34(6):243–50.CrossRefPubMedGoogle Scholar
  47. Ruland J. CARD9 signaling in the innate immune response. Ann N Y Acad Sci. 2008;1143:35–44.CrossRefPubMedGoogle Scholar
  48. Sampaio EP, Hsu AP, Pechacek J, Bax HI, Dias DL, Paulson ML, et al. Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol. 2013;131(6):1624–34.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Segal BH, DeCarlo ES, Kwon-Chung KJ, Malech HL, Gallin JI, Holland SM. Aspergillus nidulans infection in chronic granulomatous disease. Medicine. 1998;77(5):345–54.CrossRefPubMedGoogle Scholar
  50. Sudhadham M, Prakitsin S, Sivichai S, Chaiyarat R, Dorrestein GM, Menken SB, et al. The neurotropic black yeast Exophiala dermatitidis has a possible origin in the tropical rain forest. Stud Mycol. 2008;61:145–55.CrossRefPubMedPubMedCentralGoogle Scholar
  51. Sudhadham M, van den Gerrits EAH, Sihanonth P, Sivichai S, Chaiyarat R, Menken SB, et al. Elucidation of distribution patterns and possible infection routes of the neurotropic black yeast Exophiala dermatitidis using AFLP. Fungal Biol. 2011;115(10):1051–65.CrossRefPubMedGoogle Scholar
  52. Torres JM, Martinez-Barricarte R, Garcia-Gomez S, Mazariegos MS, Itan Y, Boisson B, et al. Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity. J Clin Invest. 2014;124(12):5239–48.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Valledor AF, Comalada M, Xaus J, Celada A. The differential time-course of extracellular-regulated kinase activity correlates with the macrophage response toward proliferation or activation. J Biol Chem. 2000;275(10):7403–9.CrossRefPubMedGoogle Scholar
  54. Vinh DC. Insights into human antifungal immunity from primary immunodeficiencies. Lancet Infect Dis. 2011;11(10):780–92.CrossRefPubMedGoogle Scholar
  55. Vinh DC, Masannat F, Dzioba RB, Galgiani JN, Holland SM. Refractory disseminated coccidioidomycosis and mycobacteriosis in interferon-gamma receptor 1 deficiency. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2009;49(6):e62–5.CrossRefGoogle Scholar
  56. Vinh DC, Schwartz B, Hsu AP, Miranda DJ, Valdez PA, Fink D, et al. Interleukin-12 receptor beta1 deficiency predisposing to disseminated coccidioidomycosis. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2011;52(4):e99–e102.CrossRefGoogle Scholar
  57. Wang X, Wang W, Lin Z, Wang X, Li T, Yu J, et al. CARD9 mutations linked to subcutaneous phaeohyphomycosis and TH17 cell deficiencies. J Allergy Clin Immunol. 2014;133(3):905–8.e3.CrossRefPubMedGoogle Scholar
  58. Winkelstein JA, Marino MC, Johnston RB Jr, Boyle J, Curnutte J, Gallin JI, et al. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine. 2000;79(3):155–69.CrossRefPubMedGoogle Scholar
  59. Woods JP. Revisiting old friends: developments in understanding Histoplasma capsulatum pathogenesis. J Microbiol (Seoul, Korea). 2016;54(3):265–76.Google Scholar
  60. Yamada H, Takahashi N, Hori N, Asano Y, Mochizuki K, Ohkusu K, et al. Rare case of fungal keratitis caused by Corynespora cassiicola. J Infect Chemother: Off J Jpn Soc Chemother. 2013;19(6):1167–9.CrossRefGoogle Scholar
  61. Yan XX, Yu CP, Fu XA, Bao FF, Du DH, Wang C, et al. CARD9 mutation linked to Corynespora cassiicola infection in a Chinese patient. Br J Dermatol. 2016;174(1):176–9.CrossRefPubMedGoogle Scholar
  62. Zerbe CS, Holland SM. Disseminated histoplasmosis in persons with interferon-gamma receptor 1 deficiency. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2005;41(4):e38–41.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Christina Gavino
    • 1
  • Marija Landekic
    • 1
  • Donald C. Vinh
    • 2
    • 3
    • 4
    Email author
  1. 1.Research Institute-MUHC (RI-MUHC)MontréalCanada
  2. 2.Infectious Disease Susceptibility ProgramMcGill University Health Centre (MUHC) and Research Institute-MUHC (RI-MUHC)MontréalCanada
  3. 3.Department of Medicine, Division of Infectious Diseases & Medical MicrobiologyMcGill University Health CentreMontréalCanada
  4. 4.Department of Human GeneticsMcGill UniversityMontréalCanada

Section editors and affiliations

  • Stuart Turvey
    • 1
  1. 1.Child & Family Research InstituteVancouverCanada