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Mycopathologia

, Volume 179, Issue 5–6, pp 347–357 | Cite as

CARD9 Deficiencies Linked to Impaired Neutrophil Functions Against Phialophora verrucosa

  • Pin Liang
  • Xiaowen Wang
  • Runchao Wang
  • Zhe Wan
  • Wenling HanEmail author
  • Ruoyu LiEmail author
Article

Abstract

Caspase recruitment domain-containing protein 9 (CARD9) is an adaptor molecule that is critical for NF-κB activation and forms a complex with B cell lymphoma 10 and mucosa-associated lymphoid tissue lymphoma translocation gene 1 that mediates C-type lectin receptors (CLRs)-triggered intracellular signaling during antifungal immunity. However, the role of CARD9 in the host defense against Phialophora verrucosa (P. verrucosa) infection remains to be elucidated. In the present study, we investigated the functions of polymorphonuclear neutrophils (PMNs) from patients with CARD9 deficiencies against P. verrucosa. By isolating PMNs from patients and healthy blood donors and subsequently challenging the cells with P. verrucosa, we demonstrated that, compared with healthy donors, CARD9-deficient PMNs exhibited defects in P. verrucosa killing and pro-inflammatory cytokine productions, which can be rescued in the presence of serum; however, the CARD9-deficient PMNs exhibited normal reactive oxygen species generation and phagocytotic ability. In conclusion, our results indicate that CARD9 is indispensable for P. verrucosa killing by PMNs, and serum opsonization acts as a CARD9-independent way, which could be a promising immunotherapy in the future.

Keywords

Phialophora verrucosa CARD9 Neutrophil ROS Phagocytosis Pro-inflammatory cytokines 

Notes

Acknowledgments

The authors are grateful for the participation of the patients and healthy donors and the financial support of National Natural Science Foundation of China (Grant 81171510) and National Natural Science Foundation of China (Grant 81472890).

Conflict of interest

All the co-authors declare that they have no relevant conflicts of interest.

Ethical Standard

Written informed consent was obtained from all subjects, and the study was approved by the ethics committee of the Peking University First Hospital. Peripheral blood PMNs were isolated from venous blood specimens of patients and healthy blood donors, in accordance with the guidelines of the local ethical committee and the Declaration of Helsinki.

References

  1. 1.
    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.CrossRefPubMedGoogle Scholar
  2. 2.
    McGinnis MR. Chromoblastomycosis and phaeohyphomycosis: new concepts, diagnosis, and mycology. J Am Acad Dermatol. 1983;8(1):1–16.CrossRefPubMedGoogle Scholar
  3. 3.
    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
  4. 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. 5.
    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.CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    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
  7. 7.
    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.Google Scholar
  8. 8.
    Lanternier F, Barbati E, Meinzer U, Liu L, Pedergnana V, Migaud M, et al. Inherited CARD9 deficiency in two unrelated patients with invasive Exophiala infection. J Infect Dis. 2014. doi: 10.1093/infdis/jiu412.
  9. 9.
    Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13(3):159–75.CrossRefPubMedGoogle Scholar
  10. 10.
    Peltroche-Llacsahuanga H, Schnitzler N, Jentsch S, Platz A, De Hoog S, Schweizer KG, et al. Analyses of phagocytosis, evoked oxidative burst, and killing of black yeasts by human neutrophils: a tool for estimating their pathogenicity? Med Mycol. 2003;41(1):7–14.CrossRefPubMedGoogle Scholar
  11. 11.
    Drewniak A, Boelens JJ, Vrielink H, Tool AT, Bruin MC, van den Heuvel-Eibrink M, et al. Granulocyte concentrates: prolonged functional capacity during storage in the presence of phenotypic changes. Haematologica. 2008;93(7):1058–67.CrossRefPubMedGoogle Scholar
  12. 12.
    Peltroche-Llacsahuanga H, Schnitzler N, Schmidt S, Tintelnot K, Lutticken R, Haase G. Phagocytosis, oxidative burst, and killing of Candida dubliniensis and Candida albicans by human neutrophils. FEMS Microbiol Lett. 2000;191(1):151–5.CrossRefPubMedGoogle Scholar
  13. 13.
    Yamamoto H, Nakamura Y, Sato K, Takahashi Y, Nomura T, Miyasaka T, et al. Defect of CARD9 leads to impaired accumulation of gamma interferon-producing memory phenotype T cells in lungs and increased susceptibility to pulmonary infection with Cryptococcus neoformans. Infect Immun. 2014;82(4):1606–15.CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Luo S, Skerka C, Kurzai O, Zipfel PF. Complement and innate immune evasion strategies of the human pathogenic fungus Candida albicans. Mol Immunol. 2013;56(3):161–9.CrossRefPubMedGoogle Scholar
  15. 15.
    Rambach G, Speth C. Complement in Candida albicans infections. Front Biosci (Elite Ed). 2009;1:1–12.CrossRefPubMedGoogle Scholar
  16. 16.
    Pereira HA, Hosking CS. The role of complement and antibody in opsonization and intracellular killing of Candida albicans. Clin Exp Immunol. 1984;57(2):307–14.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Parker LC, Whyte MK, Dower SK, Sabroe I. The expression and roles of toll-like receptors in the biology of the human neutrophil. J Leukoc Biol. 2005;77(6):886–92.CrossRefPubMedGoogle Scholar
  18. 18.
    Arnaout MA. Structure and function of the leukocyte adhesion molecules CD11/CD18. Blood. 1990;75(5):1037–50.PubMedGoogle Scholar
  19. 19.
    Frohner IE, Bourgeois C, Yatsyk K, Majer O, Kuchler K. Candida albicans cell surface superoxide dismutases degrade host-derived reactive oxygen species to escape innate immune surveillance. Mol Microbiol. 2009;71(1):240–52.CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Wu W, Hsu YM, Bi L, Songyang Z, Lin X. CARD9 facilitates microbe-elicited production of reactive oxygen species by regulating the LyGDI-Rac1 complex. Nat Immunol. 2009;10(11):1208–14.CrossRefPubMedGoogle Scholar
  21. 21.
    Sorensen OE, Follin P, Johnsen AH, Calafat J, Tjabringa GS, Hiemstra PS, et al. Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood. 2001;97(12):3951–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Futosi K, Fodor S, Mocsai A. Neutrophil cell surface receptors and their intracellular signal transduction pathways. Int Immunopharmacol. 2013;17(3):638–50.CrossRefPubMedCentralPubMedGoogle Scholar
  23. 23.
    Ferrante A. Tumor necrosis factor alpha potentiates neutrophil antimicrobial activity: increased fungicidal activity against Torulopsis glabrata and Candida albicans and associated increases in oxygen radical production and lysosomal enzyme release. Infect Immun. 1989;57(7):2115–22.PubMedCentralPubMedGoogle Scholar
  24. 24.
    Seyedmousavi S, Netea MG, Mouton JW, Melchers WJ, Verweij PE, de Hoog GS. Black yeasts and their filamentous relatives: principles of pathogenesis and host defense. Clin Microbiol Rev. 2014;27(3):527–42.CrossRefPubMedGoogle Scholar
  25. 25.
    Scapini P, Lapinet-Vera JA, Gasperini S, Calzetti F, Bazzoni F, Cassatella MA. The neutrophil as a cellular source of chemokines. Immunol Rev. 2000;177:195–203.CrossRefPubMedGoogle Scholar
  26. 26.
    Baggiolini M. Novel aspects of inflammation: interleukin-8 and related chemotactic cytokines. Clin Investig. 1993;71(10):812–4.CrossRefPubMedGoogle Scholar
  27. 27.
    Cassatella MA. The production of cytokines by polymorphonuclear neutrophils. Immunol Today. 1995;16(1):21–6.CrossRefPubMedGoogle Scholar
  28. 28.
    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.Google Scholar
  29. 29.
    Lee A, Whyte MK, Haslett C. Inhibition of apoptosis and prolongation of neutrophil functional longevity by inflammatory mediators. J Leukoc Biol. 1993;54(4):283–8.PubMedGoogle Scholar
  30. 30.
    Hume DA, Ross IL, Himes SR, Sasmono RT, Wells CA, Ravasi T. The mononuclear phagocyte system revisited. J Leukoc Biol. 2002;72(4):621–7.PubMedGoogle Scholar
  31. 31.
    Takano T, Azuma N, Satoh M, Toda A, Hashida Y, Satoh R, et al. Neutrophil survival factors (TNF-alpha, GM-CSF, and G-CSF) produced by macrophages in cats infected with feline infectious peritonitis virus contribute to the pathogenesis of granulomatous lesions. Arch Virol. 2009;154(5):775–81.CrossRefPubMedGoogle Scholar
  32. 32.
    Reed RK, Rubin K. Transcapillary exchange: role and importance of the interstitial fluid pressure and the extracellular matrix. Cardiovasc Res. 2010;87(2):211–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Aukland K, Nicolaysen G. Interstitial fluid volume: local regulatory mechanisms. Physiol Rev. 1981;61(3):556–643.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  1. 1.Department of DermatologyPeking University First HospitalBeijingChina
  2. 2.Research Center for Medical MycologyPeking UniversityBeijingChina
  3. 3.Beijing Key Laboratory of Molecular Diagnosis on DermatosesBeijingChina
  4. 4.Department of Immunology, School of Basic Medical Sciences, Peking University Health Science Center, Peking University Center for Human Disease Genomics, Key Laboratory of Medical ImmunologyMinistry of HealthBeijingChina

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