IL-23 supports host defense against systemic Candida albicans infection by ensuring myeloid cell survival

Autoři: Selim Nur aff001;  Florian Sparber aff001;  Christina Lemberg aff001;  Eva Guiducci aff001;  Tiziano A. Schweizer aff001;  Pascale Zwicky aff002;  Burkhard Becher aff002;  Salomé LeibundGut-Landmann aff001
Působiště autorů: Section of Immunology, Vetsuisse Faculty, University of Zürich, Zürich, Switzerland aff001;  Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland aff002
Vyšlo v časopise: IL-23 supports host defense against systemic Candida albicans infection by ensuring myeloid cell survival. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1008115
Kategorie: Research Article


The opportunistic fungal pathogen Candida albicans can cause invasive infections in susceptible hosts and the innate immune system, in particular myeloid cell-mediated immunity, is critical for rapid immune protection and host survival during systemic candidiasis. Using a mouse model of the human disease, we identified a novel role of IL-23 in antifungal defense. IL-23-deficient mice are highly susceptible to systemic infection with C. albicans. We found that this results from a drastic reduction in all subsets of myeloid cells in the infected kidney, which in turn leads to rapid fungal overgrowth and renal tissue injury. The loss in myeloid cells is not due to a defect in emergency myelopoiesis or the recruitment of newly generated cells to the site of infection but, rather, is a consequence of impaired survival of myeloid cells at the site of infection. In fact, the absence of a functional IL-23 pathway causes massive myeloid cell apoptosis upon C. albicans infection. Importantly, IL-23 protects myeloid cells from apoptosis independently of the IL-23-IL-17 immune axis and independently of lymphocytes and innate lymphoid cells. Instead, our results suggest that IL-23 acts in a partially autocrine but not cell-intrinsic manner within the myeloid compartment to promote host protection from systemic candidiasis. Collectively, our data highlight an unprecedented and non-canonical role of IL-23 in securing survival of myeloid cells, which is key for maintaining sufficient numbers of cells at the site of infection to ensure efficient host protection.

Klíčová slova:

Bone marrow cells – Candida albicans – Candidiasis – Flow cytometry – Fungal diseases – Kidneys – Monocytes – Neutrophils


1. Lionakis MS. New insights into innate immune control of systemic candidiasis. Med Mycol. 2014; 52: 555–564. doi: 10.1093/mmy/myu029 25023483

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

3. Kullberg BJ, Arendrup MC. Invasive Candidiasis. N Engl J Med. 2015; 373: 1445–1456. doi: 10.1056/NEJMra1315399 26444731

4. Uzun O, Ascioglu S, Anaissie EJ, Rex JH. Risk factors and predictors of outcome in patients with cancer and breakthrough candidemia. Clin Infect Dis. 2001; 32: 1713–1717. doi: 10.1086/320757 11360213

5. Horn DL, Neofytos D, Anaissie EJ, Fishman JA, Steinbach WJ, Olyaei AJ, et al. Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis. 2009; 48: 1695–1703. doi: 10.1086/599039 19441981

6. Fulurija A, Ashman RB, Papadimitriou JM. Neutrophil depletion increases susceptibility to systemic and vaginal candidiasis in mice, and reveals differences between brain and kidney in mechanisms of host resistance. Microbiology (Reading, Engl). 1996; 142 (Pt 12): 3487–3496. doi: 10.1099/13500872-142-12-3487 9004511

7. Ngo LY, Kasahara S, Kumasaka DK, Knoblaugh SE, Jhingran A, Hohl TM. Inflammatory Monocytes Mediate Early and Organ-Specific Innate Defense During Systemic Candidiasis. J Infect Dis. 2014; 209: 109–119. doi: 10.1093/infdis/jit413 23922372

8. Lionakis MS, Swamydas M, Fischer BG, Plantinga TS, Johnson MD, Jaeger M, et al. CX3CR1-dependent renal macrophage survival promotes Candida control and host survival. J Clin Invest. 2013; 123: 5035–5051. doi: 10.1172/JCI71307 24177428

9. 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: 630–638. doi: 10.1038/ni1460 17450144

10. Whitney PG, Bär E, Osorio F, Rogers NC, Schraml BU, Deddouche S, et al. Syk Signaling in Dendritic Cells Orchestrates Innate Resistance to Systemic Fungal Infection. PLOS Pathogens. 2014; 10: e1004276. doi: 10.1371/journal.ppat.1004276 25033445

11. McGeachy MJ, Cua DJ, Gaffen SL. The IL-17 Family of Cytokines in Health and Disease. Immunity. 2019; 50: 892–906. doi: 10.1016/j.immuni.2019.03.021 30995505

12. Sparber F, LeibundGut-Landmann S. Interleukin-17 in Antifungal Immunity. Pathogens. 2019; 8: 54. doi: 10.3390/pathogens8020054 31013616

13. Huang W, Na L, Fidel PL, Schwarzenberger P. Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis. 2004; 190: 624–631. doi: 10.1086/422329 15243941

14. Bär E, Whitney PG, Moor K, Reis e Sousa C, LeibundGut-Landmann S. IL-17 regulates systemic fungal immunity by controlling the functional competence of NK cells. Immunity. 2014; 40: 117–127. doi: 10.1016/j.immuni.2013.12.002 24412614

15. Ramani K, Garg AV, Jawale CV, Conti HR, Whibley N, Jackson EK, et al. The Kallikrein-Kinin System: A Novel Mediator of IL-17-Driven Anti-Candida Immunity in the Kidney. PLoS Pathog. 2016; 12: e1005952. doi: 10.1371/journal.ppat.1005952 27814401

16. Codarri L, Gyülvészi G, Tosevski V, Hesske L, Fontana A, Magnenat L, et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol. 2011; 12: 560–567. doi: 10.1038/ni.2027 21516112

17. El-Behi M, Ciric B, Dai H, Yan Y, Cullimore M, Safavi F, et al. The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol. 2011; 12: 568–575. doi: 10.1038/ni.2031 21516111

18. Chan JR, Blumenschein W, Murphy E, Diveu C, Wiekowski M, Abbondanzo S, et al. IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med. 2006; 203: 2577–2587. doi: 10.1084/jem.20060244 17074928

19. Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature. 2007; 445: 648–651. doi: 10.1038/nature05505 17187052

20. Taylor PR, Roy S, Leal SM, Sun Y, Howell SJ, Cobb BA, et al. Autocrine IL-17A–IL-17RC neutrophil activation in fungal infections is regulated by IL-6, IL-23, RORγt and Dectin-2. Nat Immunol. 2014; 15: 143–151. doi: 10.1038/ni.2797 24362892

21. Werner JL, Gessner MA, Lilly LM, Nelson MP, Metz AE, Horn D, et al. Neutrophils produce interleukin 17A (IL-17A) in a dectin-1- and IL-23-dependent manner during invasive fungal infection. Infection and Immunity. 2011; 79: 3966–3977. doi: 10.1128/IAI.05493-11 21807912

22. Chen F, Cao A, Yao S, Evans-Marin HL, Liu H, Wu W, et al. mTOR Mediates IL-23 Induction of Neutrophil IL-17 and IL-22 Production. J Immunol. 2016; 196: 4390–4399. doi: 10.4049/jimmunol.1501541 27067005

23. Chen L, Wei X-Q, Evans B, Jiang W, Aeschlimann D. IL-23 promotes osteoclast formation by up-regulation of receptor activator of NF-kappaB (RANK) expression in myeloid precursor cells. Eur J Immunol. 2008; 38: 2845–2854. doi: 10.1002/eji.200838192 18958885

24. Li Y, Zhu L, Chu Z, Yang T, Sun H-X, Yang F, et al. Characterization and biological significance of IL-23-induced neutrophil polarization. Cell Mol Immunol. 2018; 15: 518–530. doi: 10.1038/cmi.2017.39 28690333

25. Awasthi A, Riol-Blanco L, Jäger A, Korn T, Pot C, Galileos G, et al. Cutting edge. IL-23 receptor gfp reporter mice reveal distinct populations of IL-17-producing cells. J Immunol. 2009; 182: 5904–5908. doi: 10.4049/jimmunol.0900732 19414740

26. Spellberg B, Ibrahim AS, Edwards JE, Filler SG. Mice with disseminated candidiasis die of progressive sepsis. J Infect Dis. 2005; 192: 336–343. doi: 10.1086/430952 15962230

27. Lionakis MS, Lim JK, Lee C-CR, Murphy PM. Organ-specific innate immune responses in a mouse model of invasive candidiasis. J Innate Immun. 2011; 3: 180–199. doi: 10.1159/000321157 21063074

28. Qian Q, Jutila MA, van Rooijen N, Cutler JE. Elimination of mouse splenic macrophages correlates with increased susceptibility to experimental disseminated candidiasis. The Journal of Immunology. 1994; 152: 5000–5008. 8176217

29. Buttgereit A, Lelios I, Yu X, Vrohlings M, Krakoski NR, Gautier EL, et al. Sall1 is a transcriptional regulator defining microglia identity and function. Nat Immunol. 2016; 17: 1397–1406. doi: 10.1038/ni.3585 27776109

30. deCathelineau AM, Henson PM. The final step in programmed cell death: phagocytes carry apoptotic cells to the grave. Essays Biochem. 2003; 39: 105–117. doi: 10.1042/bse0390105 14585077

31. Zheng X, Wang Y, Wang Y. Hgc1, a novel hypha-specific G1 cyclin-related protein regulates Candida albicans hyphal morphogenesis. EMBO J. 2004; 23: 1845–1856. doi: 10.1038/sj.emboj.7600195 15071502

32. Rauch S, DeDent AC, Kim HK, Wardenburg JB, Missiakas DM, Schneewind O. Abscess Formation and Alpha-Hemolysin Induced Toxicity in a Mouse Model of Staphylococcus aureus Peritoneal Infection. Infection and Immunity. 2012; 80: 3721–3732. doi: 10.1128/IAI.00442-12 22802349

33. Pollitt EJG, Szkuta PT, Burns N, Foster SJ. Staphylococcus aureus infection dynamics. PLoS Pathog. 2018; 14: e1007112. doi: 10.1371/journal.ppat.1007112 29902272

34. Cho JS, Pietras EM, Garcia NC, Ramos RI, Farzam DM, Monroe HR, et al. IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. J Clin Invest. 2010; 120: 1762–1773. doi: 10.1172/JCI40891 20364087

35. Lai C, Stepniak D, Sias L, Funatake C. A sensitive flow cytometric method for multi-parametric analysis of microRNA, messenger RNA and protein in single cells. Methods. 2018; 134–135: 136–148. doi: 10.1016/j.ymeth.2017.12.016 29277634

36. Sparber F, Gregorio C de, Steckholzer S, Ferreira FM, Dolowschiak T, Ruchti F, et al. The Skin Commensal Yeast Malassezia Triggers a Type 17 Response that Coordinates Anti-fungal Immunity and Exacerbates Skin Inflammation. Cell Host & Microbe. 2019; 25: 389–403.e6. doi: 10.1016/j.chom.2019.02.002 30870621

37. Sawai H, Domae N. Discrimination between primary necrosis and apoptosis by necrostatin-1 in Annexin V-positive/propidium iodide-negative cells. Biochem Biophys Res Commun. 2011; 411: 569–573. doi: 10.1016/j.bbrc.2011.06.186 21763280

38. Caserta TM, Smith AN, Gultice AD, Reedy MA, Brown TL. Q-VD-OPh, a broad spectrum caspase inhibitor with potent antiapoptotic properties. Apoptosis. 2003; 8: 345–352. doi: 10.1023/a:1024116916932 12815277

39. Takahashi N, Duprez L, Grootjans S, Cauwels A, Nerinckx W, DuHadaway JB, et al. Necrostatin-1 analogues: critical issues on the specificity, activity and in vivo use in experimental disease models. Cell Death Dis. 2012; 3: e437. doi: 10.1038/cddis.2012.176 23190609

40. Urban CF, Reichard U, Brinkmann V, Zychlinsky A. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol. 2006; 8: 668–676. doi: 10.1111/j.1462-5822.2005.00659.x 16548892

41. Buhr N de, Kockritz-Blickwede M von. How Neutrophil Extracellular Traps Become Visible. J Immunol Res. 2016; 2016: 4604713. doi: 10.1155/2016/4604713 27294157

42. Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, Lindemann MJ, et al. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med. 2009; 206: 299–311. doi: 10.1084/jem.20081463 19204111

43. Gladiator A, Wangler N, Trautwein-Weidner K, LeibundGut-Landmann S. Cutting edge: IL-17-secreting innate lymphoid cells are essential for host defense against fungal infection. J Immunol. 2013; 190: 521–525. doi: 10.4049/jimmunol.1202924 23255360

44. Sparber F, Dolowschiak T, Mertens S, Lauener L, Clausen BE, Joller N, et al. Langerin+ DCs regulate innate IL-17 production in the oral mucosa during Candida albicans-mediated infection. PLoS Pathog. 2018; 14: e1007069. doi: 10.1371/journal.ppat.1007069 29782555

45. Mrdjen D, Pavlovic A, Hartmann FJ, Schreiner B, Utz SG, Leung BP, et al. High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease. Immunity. 2018; 48: 380–395.e6. doi: 10.1016/j.immuni.2018.01.011 29426702

46. Swamydas M, Gao J-L, Break TJ, Johnson MD, Jaeger M, Rodriguez CA, et al. CXCR1-mediated Neutrophil Degranulation and Fungal Killing Promotes Candida Clearance and Host Survival. Sci Transl Med. 2016; 8: 322ra10. doi: 10.1126/scitranslmed.aac7718 26791948

47. Kleinschek MA, Muller U, Brodie SJ, Stenzel W, Kohler G, Blumenschein WM, et al. IL-23 enhances the inflammatory cell response in Cryptococcus neoformans infection and induces a cytokine pattern distinct from IL-12. J Immunol. 2006; 176: 1098–1106. doi: 10.4049/jimmunol.176.2.1098 16393998

48. Kagami S, Rizzo HL, Kurtz SE, Miller LS, Blauvelt A. IL-23 and IL-17A, but not IL-12 and IL-22, are required for optimal skin host defense against Candida albicans. J Immunol. 2010; 185: 5453–5462. doi: 10.4049/jimmunol.1001153 20921529

49. El Malki K, Karbach SH, Huppert J, Zayoud M, Reissig S, Schuler R, et al. An alternative pathway of imiquimod-induced psoriasis-like skin inflammation in the absence of interleukin-17 receptor a signaling. J Invest Dermatol. 2013; 133: 441–451. doi: 10.1038/jid.2012.318 22951726

50. Trautwein-Weidner K, Gladiator A, Nur S, Diethelm P, LeibundGut-Landmann S. IL-17-mediated antifungal defense in the oral mucosa is independent of neutrophils. Mucosal Immunol. 2015; 8: 221–231. doi: 10.1038/mi.2014.57 25005360

51. Stark MA, Huo Y, Burcin TL, Morris MA, Olson TS, Ley K. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity. 2005; 22: 285–294. doi: 10.1016/j.immuni.2005.01.011 15780986

52. Verma AH, Zafar H, Ponde NO, Hepworth OW, Sihra D, Aggor FEY, et al. IL-36 and IL-1/IL-17 Drive Immunity to Oral Candidiasis via Parallel Mechanisms. The Journal of Immunology. 2018: ji1800515. doi: 10.4049/jimmunol.1800515 29891557

53. Miyajima A, Kitamura T, Harada N, Yokota T, Arai K. Cytokine receptors and signal transduction. Annu Rev Immunol. 1992; 10: 295–331. doi: 10.1146/annurev.iy.10.040192.001455 1590989

54. Kobayashi SD, Voyich JM, Whitney AR, DeLeo FR. Spontaneous neutrophil apoptosis and regulation of cell survival by granulocyte macrophage-colony stimulating factor. J Leukoc Biol. 2005; 78: 1408–1418. doi: 10.1189/jlb.0605289 16204629

55. Hunter M, Wang Y, Eubank T, Baran C, Nana-Sinkam P, Marsh C. Survival of monocytes and macrophages and their role in health and disease. Front Biosci (Landmark Ed). 2009; 14: 4079–4102.

56. Souza LR, Silva E, Calloway E, Cabrera C, McLemore ML. G-CSF activation of AKT is not sufficient to prolong neutrophil survival. J Leukoc Biol. 2013; 93: 883–893. doi: 10.1189/jlb.1211591 23559492

57. van den Berg J M, Weyer S, Weening JJ, Roos D, Kuijpers TW. Divergent effects of tumor necrosis factor alpha on apoptosis of human neutrophils. J Leukoc Biol. 2001; 69: 467–473. 11261795

58. Becker C, Dornhoff H, Neufert C, Fantini MC, Wirtz S, Huebner S, et al. Cutting edge. IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis. J Immunol. 2006; 177: 2760–2764. doi: 10.4049/jimmunol.177.5.2760 16920909

59. Shinkai Y, Rathbun G, Lam KP, Oltz EM, Stewart V, Mendelsohn M, et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992; 68: 855–867. doi: 10.1016/0092-8674(92)90029-c 1547487

60. DiSanto JP, Müller W, Guy-Grand D, Fischer A, Rajewsky K. Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. Proc Natl Acad Sci U S A. 1995; 92: 377–381. doi: 10.1073/pnas.92.2.377 7831294

61. Dranoff G, Crawford AD, Sadelain M, Ream B, Rashid A, Bronson RT, et al. Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science. 1994; 264: 713–716. doi: 10.1126/science.8171324 8171324

62. Odds FC, Brown AJP, Gow NAR. Candida albicans genome sequence: a platform for genomics in the absence of genetics. Genome Biol. 2004; 5: 230. doi: 10.1186/gb-2004-5-7-230 15239821

63. Duthie ES, Lorenz LL. Staphylococcal coagulase; mode of action and antigenicity. J Gen Microbiol. 1952; 6: 95–107. doi: 10.1099/00221287-6-1-2-95 14927856

64. Guillot J, Guého E. The diversity of Malassezia yeasts confirmed by rRNA sequence and nuclear DNA comparisons. Antonie Van Leeuwenhoek. 1995; 67: 297–314. doi: 10.1007/bf00873693 7778898

65. Cossarizza A, Chang H-D, Radbruch A, Akdis M, Andrä I, Annunziato F, et al. Guidelines for the use of flow cytometry and cell sorting in immunological studies. Eur J Immunol. 2017; 47: 1584–1797. doi: 10.1002/eji.201646632 29023707

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