Candida albicans triggers NADPH oxidase-independent neutrophil extracellular traps through dectin-2

English version

Autoři: Sheng-Yang Wu ^aff001; Chia-Lin Weng ^aff001; Min-Jhen Jheng ^aff001; Hung-Wei Kan ^aff002; Sung-Tsang Hsieh ^aff002; Fu-Tong Liu ^aff003; Betty A. Wu-Hsieh ^aff001
Působiště autorů: Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan ^aff001; Department of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan ^aff002; Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan ^aff003
Vyšlo v časopise: Candida albicans triggers NADPH oxidase-independent neutrophil extracellular traps through dectin-2. PLoS Pathog 15(11): e1008096. doi:10.1371/journal.ppat.1008096
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008096

Souhrn

Candida albicans is one of the top leading causes of healthcare-associated bloodstream infection. Neutrophil extracellular traps (NET) are known to capture and kill pathogens. It is reported that opsonized C. albicans-triggered NETosis is NADPH oxidase-dependent. We discovered a NADPH oxidase-independent NETosis pathway in neutrophil response to unopsonized C. albicans. While CR3 engagement with opsonized C. albicans triggered NET, dectin-2 recognized unopsonized C. albicans and mediated NET formation. Engagement of dectin-2 activated the downstream Syk-Ca²⁺-PKCδ-protein arginine deiminase 4 (PAD4) signaling pathway which modulated nuclear translocation of neutrophil elastase (NE), histone citrullination and NETosis. In a C. albicans peritonitis model we observed Ki67⁺Ly6G⁺ NETotic cells in the peritoneal exudate and mesenteric tissues within 3 h of infection. Treatment with PAD4 inhibitor GSK484 or dectin-2 deficiency reduced % Ki67⁺Ly6G⁺ cells and the intensity of Ki67 in peritoneal neutrophils. Employing DNA digestion enzyme micrococcal nuclease, GSK484 as well as dectin-2-deficient mice, we further showed that dectin-2-mediated PAD4-dependent NET formation in vivo restrained the spread of C. albicans from the peritoneal cavity to kidney. Taken together, this study reveals that unopsonized C. albicans evokes NADPH oxidase-independent NETosis through dectin-2 and its downstream signaling pathway and dectin-2-mediated NET helps restrain fungal dissemination.

Klíčová slova:

Candida albicans – Cell staining – Fluorescence imaging – Fluorescence microscopy – Histones – Intraperitoneal injections – Kidneys – Neutrophils

Zdroje

1. Kullberg BJ, Arendrup MC. Invasive Candidiasis. N Engl J Med. 2015;373(15):1445–56. doi: 10.1056/NEJMra1315399 26444731.

2. Chen PY, Chuang YC, Wang JT, Sheng WH, Yu CJ, Chu CC, et al. Comparison of epidemiology and treatment outcome of patients with candidemia at a teaching hospital in Northern Taiwan, in 2002 and 2010. J Microbiol Immunol Infect. 2014;47(2):95–103. doi: 10.1016/j.jmii.2012.08.025 23063082.

3. Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, White TC. Hidden killers: human fungal infections. Sci Transl Med. 2012;4(165):165rv13. doi: 10.1126/scitranslmed.3004404 23253612.

4. Yang YL, Wang AH, Wang CW, Cheng WT, Li SY, Lo HJ, et al. Susceptibilities to amphotericin B and fluconazole of Candida species in Taiwan Surveillance of Antimicrobial Resistance of Yeasts 2006. Diagnostic microbiology and infectious disease. 2008;61(2):175–80. doi: 10.1016/j.diagmicrobio.2008.01.011 18304773.

5. Gullo A. Invasive fungal infections: the challenge continues. Drugs. 2009;69 Suppl 1:65–73. doi: 10.2165/11315530-000000000-00000 19877737.

6. Petry A, Weitnauer M, Gorlach A. Receptor activation of NADPH oxidases. Antioxidants & redox signaling. 2010;13(4):467–87. doi: 10.1089/ars.2009.3026 20001746.

7. Brechard S, Plancon S, Tschirhart EJ. New insights into the regulation of neutrophil NADPH oxidase activity in the phagosome: a focus on the role of lipid and Ca(2+) signaling. Antioxidants & redox signaling. 2013;18(6):661–76. doi: 10.1089/ars.2012.4773 22867131.

8. Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. Nature reviews Microbiology. 2007;5(8):577–82. Epub 2007/07/17. doi: 10.1038/nrmicro1710 17632569.

9. Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A. Neutrophil function: from mechanisms to disease. Annual review of immunology. 2012;30:459–89. doi: 10.1146/annurev-immunol-020711-074942 22224774.

10. Brinkmann V, Zychlinsky A. Neutrophil extracellular traps: is immunity the second function of chromatin? The Journal of cell biology. 2012;198(5):773–83. doi: 10.1083/jcb.201203170 22945932.

11. Urban CF, Reichard U, Brinkmann V, Zychlinsky A. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cellular microbiology. 2006;8(4):668–76. doi: 10.1111/j.1462-5822.2005.00659.x 16548892.

12. 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. doi: 10.1182/blood-2014-01-551473 24948657.

13. Amulic B, Knackstedt SL, Abu Abed U, Deigendesch N, Harbort CJ, Caffrey BE, et al. Cell-Cycle Proteins Control Production of Neutrophil Extracellular Traps. Dev Cell. 2017;43(4):449–62 e5. Epub 2017/11/07. doi: 10.1016/j.devcel.2017.10.013 29103955.

14. Leshner M, Wang S, Lewis C, Zheng H, Chen XA, Santy L, et al. PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures. Frontiers in immunology. 2012;3:307. Epub 2012/10/13. doi: 10.3389/fimmu.2012.00307 23060885.

15. Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. The Journal of cell biology. 2010;191(3):677–91. doi: 10.1083/jcb.201006052 20974816.

16. Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nature reviews Immunology. 2018;18(2):134–47. doi: 10.1038/nri.2017.105 28990587.

17. Kenny EF, Herzig A, Kruger R, Muth A, Mondal S, Thompson PR, et al. Diverse stimuli engage different neutrophil extracellular trap pathways. Elife. 2017;6. Epub 2017/06/03. doi: 10.7554/eLife.24437 28574339.

18. Wu SY, Huang JH, Chen WY, Chan YC, Lin CH, Chen YC, et al. Cell Intrinsic Galectin-3 Attenuates Neutrophil ROS-Dependent Killing of Candida by Modulating CR3 Downstream Syk Activation. Frontiers in immunology. 2017;8:48. doi: 10.3389/fimmu.2017.00048 28217127.

19. Ifrim DC, Bain JM, Reid DM, Oosting M, Verschueren I, Gow NA, et al. Role of Dectin-2 for host defense against systemic infection with Candida glabrata. Infection and immunity. 2014;82(3):1064–73. doi: 10.1128/IAI.01189-13 24343653.

20. Branzk N, Lubojemska A, Hardison SE, Wang Q, Gutierrez MG, Brown GD, et al. Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens. Nature immunology. 2014;15(11):1017–25. doi: 10.1038/ni.2987 25217981.

21. Byrd AS, O’Brien XM, Johnson CM, Lavigne LM, Reichner JS. An extracellular matrix-based mechanism of rapid neutrophil extracellular trap formation in response to Candida albicans. Journal of immunology. 2013;190(8):4136–48. Epub 2013/03/20. doi: 10.4049/jimmunol.1202671 23509360.

22. Kenno S, Perito S, Mosci P, Vecchiarelli A, Monari C. Autophagy and Reactive Oxygen Species Are Involved in Neutrophil Extracellular Traps Release Induced by C. albicans Morphotypes. Front Microbiol. 2016;7:879. Epub 2016/07/05. doi: 10.3389/fmicb.2016.00879 27375599.

23. Guiducci E, Lemberg C, Kung N, Schraner E, Theocharides APA, LeibundGut-Landmann S. Candida albicans-Induced NETosis Is Independent of Peptidylarginine Deiminase 4. Frontiers in immunology. 2018;9:1573. Epub 2018/07/25. doi: 10.3389/fimmu.2018.01573 30038623.

24. Neeli I, Radic M. Opposition between PKC isoforms regulates histone deimination and neutrophil extracellular chromatin release. Frontiers in immunology. 2013;4:38. doi: 10.3389/fimmu.2013.00038 23430963.

25. Li P, Li M, Lindberg MR, Kennett MJ, Xiong N, Wang Y. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. The Journal of experimental medicine. 2010;207(9):1853–62. Epub 2010/08/25. doi: 10.1084/jem.20100239 20733033.

26. Delgado-Rizo V, Martinez-Guzman MA, Iniguez-Gutierrez L, Garcia-Orozco A, Alvarado-Navarro A, Fafutis-Morris M. Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview. Frontiers in immunology. 2017;8:81. Epub 2017/02/22. doi: 10.3389/fimmu.2017.00081 28220120.

27. Strasser D, Neumann K, Bergmann H, Marakalala MJ, Guler R, Rojowska A, et al. Syk kinase-coupled C-type lectin receptors engage protein kinase C-sigma to elicit Card9 adaptor-mediated innate immunity. Immunity. 2012;36(1):32–42. Epub 2012/01/24. doi: 10.1016/j.immuni.2011.11.015 22265677.

28. Metzler KD, Goosmann C, Lubojemska A, Zychlinsky A, Papayannopoulos V. A myeloperoxidase-containing complex regulates neutrophil elastase release and actin dynamics during NETosis. Cell Rep. 2014;8(3):883–96. Epub 2014/07/30. doi: 10.1016/j.celrep.2014.06.044 25066128.

29. Ermert D, Niemiec MJ, Rohm M, Glenthoj A, Borregaard N, Urban CF. Candida albicans escapes from mouse neutrophils. Journal of leukocyte biology. 2013;94(2):223–36. doi: 10.1189/jlb.0213063 23650619.

30. Urban CF, Ermert D, Schmid M, Abu-Abed U, Goosmann C, Nacken W, et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS pathogens. 2009;5(10):e1000639. doi: 10.1371/journal.ppat.1000639 19876394.

31. Rohm M, Grimm MJ, D’Auria AC, Almyroudis NG, Segal BH, Urban CF. NADPH oxidase promotes neutrophil extracellular trap formation in pulmonary aspergillosis. Infection and immunity. 2014;82(5):1766–77. Epub 2014/02/20. doi: 10.1128/IAI.00096-14 24549323.

32. Saijo S, Ikeda S, Yamabe K, Kakuta S, Ishigame H, Akitsu A, et al. Dectin-2 recognition of alpha-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans. Immunity. 2010;32(5):681–91. doi: 10.1016/j.immuni.2010.05.001 20493731.

33. Chao CC, Hsu PC, Jen CF, Chen IH, Wang CH, Chan HC, et al. Zebrafish as a model host for Candida albicans infection. Infection and immunity. 2010;78(6):2512–21. doi: 10.1128/IAI.01293-09 20308295.

34. Gratacap RL, Rawls JF, Wheeler RT. Mucosal candidiasis elicits NF-kappaB activation, proinflammatory gene expression and localized neutrophilia in zebrafish. Dis Model Mech. 2013;6(5):1260–70. Epub 2013/05/31. doi: 10.1242/dmm.012039 23720235.

35. Taylor PR, Tsoni SV, Willment JA, Dennehy KM, Rosas M, Findon H, et al. Dectin-1 is required for beta-glucan recognition and control of fungal infection. Nature immunology. 2007;8(1):31–8. doi: 10.1038/ni1408 17159984.

36. Lee S-H. Flow Cytometric Analysis of Calcium Influx Assay in T cells. Bio-protocol. 2013;3(18):e910. doi: 10.21769/BioProtoc.910