Inflammatory Monocytes Orchestrate Innate Antifungal Immunity in the Lung

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Aspergillus fumigatus is an environmental fungus that causes invasive aspergillosis (IA) in immunocompromised patients. Although -CC-chemokine receptor-2 (CCR2) and Ly6C-expressing inflammatory monocytes (CCR2⁺Mo) and their derivatives initiate adaptive pulmonary immune responses, their role in coordinating innate immune responses in the lung remain poorly defined. Using conditional and antibody-mediated cell ablation strategies, we found that CCR2⁺Mo and monocyte-derived dendritic cells (Mo-DCs) are essential for innate defense against inhaled conidia. By harnessing fluorescent Aspergillus reporter (FLARE) conidia that report fungal cell association and viability in vivo, we identify two mechanisms by which CCR2⁺Mo and Mo-DCs exert innate antifungal activity. First, CCR2⁺Mo and Mo-DCs condition the lung inflammatory milieu to augment neutrophil conidiacidal activity. Second, conidial uptake by CCR2⁺Mo temporally coincided with their differentiation into Mo-DCs, a process that resulted in direct conidial killing. Our findings illustrate both indirect and direct functions for CCR2⁺Mo and their derivatives in innate antifungal immunity in the lung.

Vyšlo v časopise: Inflammatory Monocytes Orchestrate Innate Antifungal Immunity in the Lung. PLoS Pathog 10(2): e32767. doi:10.1371/journal.ppat.1003940
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003940

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Zdroje

1. CassoneA, CasadevallA (2012) Recent progress in vaccines against fungal diseases. Curr Opin Microbiol 15: 427–433.

2. CramerRA, RiveraA, HohlTM (2011) Immune responses against Aspergillus fumigatus: what have we learned? Curr Opin Infect Dis 24: 315–322.

3. BrownGD, DenningDW, LevitzSM (2012) Tackling human fungal infections. Science 336: 647.

4. HohlTM, FeldmesserM (2007) Aspergillus fumigatus: principles of pathogenesis and host defense. Eukaryot Cell 6: 1953–1963.

5. Ben-AmiR, LewisRE, KontoyiannisDP (2010) Enemy of the (immunosuppressed) state: an update on the pathogenesis of Aspergillus fumigatus infection. Br J Haematol 150: 406–417.

6. NeteaMG, BrownGD (2012) Fungal infections: the next challenge. Curr Opin Microbiol 15: 403–405.

7. PettitAC, KropskiJA, CastilhoJL, SchmitzJE, RauchCA, et al. (2012) The Index Case for the Fungal Meningitis Outbreak in the United States. N Engl J Med

8. HebartH, BollingerC, FischP, SarfatiJ, MeisnerC, et al. (2002) Analysis of T-cell responses to Aspergillus fumigatus antigens in healthy individuals and patients with hematologic malignancies. Blood 100: 4521–4528.

9. ChaiLY, van de VeerdonkF, MarijnissenRJ, ChengSC, KhooAL, et al. (2010) Anti-Aspergillus human host defence relies on type 1 T helper (Th1), rather than type 17 T helper (Th17), cellular immunity. Immunology 130: 46–54.

10. De LucaA, IannittiRG, BozzaS, BeauR, CasagrandeA, et al. (2012) CD4(+) T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous disease. J Clin Invest 122: 1816–1831.

11. Diaz-ArevaloD, BagramyanK, HongTB, ItoJI, KalkumM (2011) CD4+ T cells mediate the protective effect of the recombinant Asp f3-based anti-aspergillosis vaccine. Infect Immun 79: 2257–2266.

12. MorrisonBE, ParkSJ, MooneyJM, MehradB (2003) Chemokine-mediated recruitment of NK cells is a critical host defense mechanism in invasive aspergillosis. J Clin Invest 112: 1862–1870.

13. StuehlerC, KhannaN, BozzaS, ZelanteT, MorettiS, et al. (2011) Cross-protective TH1 immunity against Aspergillus fumigatus and Candida albicans. Blood 117: 5881–5891.

14. BeckO, ToppMS, KoehlU, RoilidesE, SimitsopoulouM, et al. (2006) Generation of highly purified and functionally active human TH1 cells against Aspergillus fumigatus. Blood 107: 2562–2569.

15. ChaudharyN, StaabJF, MarrKA (2010) Healthy human T-Cell Responses to Aspergillus fumigatus antigens. PLoS One 5: e9036.

16. GarlandaC, HirschE, BozzaS, SalustriA, De AcetisM, et al. (2002) Non-redundant role of the long pentraxin PTX3 in anti-fungal innate immune response. Nature 420: 182–186.

17. Ramirez-OrtizZG, LeeCK, WangJP, BoonL, SpechtCA, et al. (2011) A nonredundant role for plasmacytoid dendritic cells in host defense against the human fungal pathogen Aspergillus fumigatus. Cell Host Microbe 9: 415–424.

18. SegalBH (2009) Aspergillosis. The New England journal of medicine 360: 1870–1884.

19. BonnettCR, CornishEJ, HarmsenAG, BurrittJB (2006) Early neutrophil recruitment and aggregation in the murine lung inhibit germination of Aspergillus fumigatus Conidia. Infect Immun 74: 6528–6539.

20. FeldmesserM (2006) Role of neutrophils in invasive aspergillosis. Infect Immun 74: 6514–6516.

21. MircescuMM, LipumaL, van RooijenN, PamerEG, HohlTM (2009) Essential role for neutrophils but not alveolar macrophages at early time points following Aspergillus fumigatus infection. J Infect Dis 200: 647–656.

22. Stephens-RomeroSD, MednickAJ, FeldmesserM (2005) The pathogenesis of fatal outcome in murine pulmonary aspergillosis depends on the neutrophil depletion strategy. Infect Immun 73: 114–125.

23. PollockJD, WilliamsDA, GiffordMA, LiLL, DuX, et al. (1995) Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nature genetics 9: 202–209.

24. ParkSJ, HughesMA, BurdickM, StrieterRM, MehradB (2009) Early NK cell-derived IFN-{gamma} is essential to host defense in neutropenic invasive aspergillosis. J Immunol 182: 4306–4312.

25. ParkSJ, BurdickMD, BrixWK, StolerMH, AskewDS, et al. (2010) Neutropenia enhances lung dendritic cell recruitment in response to Aspergillus via a cytokine-to-chemokine amplification loop. J Immunol 185: 6190–6197.

26. PhilippeB, Ibrahim-GranetO, PrevostMC, Gougerot-PocidaloMA, Sanchez PerezM, et al. (2003) Killing of Aspergillus fumigatus by alveolar macrophages is mediated by reactive oxidant intermediates. Infection and immunity 71: 3034–3042.

27. JhingranA, MarKB, KumasakaDK, KnoblaughSE, NgoLY, et al. (2012) Tracing conidial fate and measuring host cell antifungal activity using a reporter of microbial viability in the lung. Cell reports 2: 1762–1773.

28. DunayIR, FuchsA, SibleyLD (2010) Inflammatory monocytes but not neutrophils are necessary to control infection with Toxoplasma gondii in mice. Infection and immunity 78: 1564–1570.

29. ShiC, HohlTM, LeinerI, EquindaMJ, FanX, et al. (2011) Ly6G+ neutrophils are dispensable for defense against systemic Listeria monocytogenes infection. J Immunol 187: 5293–5298.

30. DunayIR, DamattaRA, FuxB, PrestiR, GrecoS, et al. (2008) Gr1(+) inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii. Immunity 29: 306–317.

31. SerbinaNV, Salazar-MatherTP, BironCA, KuzielWA, PamerEG (2003) TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19: 59–70.

32. SerbinaNV, JiaT, HohlTM, PamerEG (2008) Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol 26: 421–452.

33. TezukaH, AbeY, IwataM, TakeuchiH, IshikawaH, et al. (2007) Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells. Nature 448: 929–933.

34. SundquistM, WickMJ (2005) TNF-alpha-dependent and -independent maturation of dendritic cells and recruited CD11c(int)CD11b+ Cells during oral Salmonella infection. J Immunol 175: 3287–3298.

35. SerbinaNV, PamerEG (2006) Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol 7: 311–317.

36. ShiC, VelazquezP, HohlTM, LeinerI, DustinML, et al. (2010) Monocyte trafficking to hepatic sites of bacterial infection is chemokine independent and directed by focal intercellular adhesion molecule-1 expression. J Immunol 184: 6266–6274.

37. RiveraA, HohlTM, CollinsN, LeinerI, GallegosA, et al. (2011) Dectin-1 diversifies Aspergillus fumigatus-specific T cell responses by inhibiting T helper type 1 CD4 T cell differentiation. J Exp Med 208(2): 369–81.

38. HohlTM, RiveraA, LipumaL, GallegosA, ShiC, et al. (2009) Inflammatory monocytes facilitate adaptive CD4 T cell responses during respiratory fungal infection. Cell Host Microbe 6: 470–481.

39. WuthrichM, ErslandK, SullivanT, GallesK, KleinBS (2012) Fungi subvert vaccine T cell priming at the respiratory mucosa by preventing chemokine-induced influx of inflammatory monocytes. Immunity 36: 680–692.

40. RoyRM, KleinBS (2012) Dendritic cells in antifungal immunity and vaccine design. Cell host & microbe 11: 436–446.

41. OsterholzerJJ, ChenGH, OlszewskiMA, CurtisJL, HuffnagleGB, et al. (2009) Accumulation of CD11b+ lung dendritic cells in response to fungal infection results from the CCR2-mediated recruitment and differentiation of Ly-6Chigh monocytes. J Immunol 183: 8044–8053.

42. ErslandK, WuthrichM, KleinBS (2010) Dynamic interplay among monocyte-derived, dermal, and resident lymph node dendritic cells during the generation of vaccine immunity to fungi. Cell host & microbe 7: 474–487.

43. CortezKJ, LymanCA, KottililS, KimHS, RoilidesE, et al. (2006) Functional genomics of innate host defense molecules in normal human monocytes in response to Aspergillus fumigatus. Infection and immunity 74: 2353–2365.

44. KimHS, ChoiEH, KhanJ, RoilidesE, FrancesconiA, et al. (2005) Expression of genes encoding innate host defense molecules in normal human monocytes in response to Candida albicans. Infection and immunity 73: 3714–3724.

45. SerbinaNV, ChernyM, ShiC, BleauSA, CollinsNH, et al. (2009) Distinct responses of human monocyte subsets to Aspergillus fumigatus conidia. J Immunol 183: 2678–2687.

46. RoilidesE, HolmesA, BlakeC, VenzonD, PizzoPA, et al. (1994) Antifungal activity of elutriated human monocytes against Aspergillus fumigatus hyphae: enhancement by granulocyte-macrophage colony-stimulating factor and interferon-gamma. The Journal of infectious diseases 170: 894–899.

47. QuintinJ, SaeedS, MartensJH, Giamarellos-BourboulisEJ, IfrimDC, et al. (2012) Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12: 223–232.

48. NgoLY, KasaharaS, KumasakaDK, KnoblaughSE, JhingranA, et al. (2013) Inflammatory monocytes mediate early and organ-specific innate defense during systemic candidiasis. J Infect Dis 209(1): 109–19.

49. MausUA, WaelschK, KuzielWA, DelbeckT, MackM, et al. (2003) Monocytes are potent facilitators of alveolar neutrophil emigration during lung inflammation: role of the CCL2-CCR2 axis. Journal of immunology 170: 3273–3278.

50. RiveraA, RoG, Van EppsHL, SimpsonT, LeinerI, et al. (2006) Innate immune activation and CD4+ T cell priming during respiratory fungal infection. Immunity 25: 665–675.

51. RiveraA, Van EppsHL, HohlTM, RizzutoG, PamerEG (2005) Distinct CD4+-T-cell responses to live and heat-inactivated Aspergillus fumigatus conidia. Infect Immun 73: 7170–7179.

52. MillerJC, BrownBD, ShayT, GautierEL, JojicV, et al. (2012) Deciphering the transcriptional network of the dendritic cell lineage. Nature immunology 13: 888–899.

53. HartiganAJ, WestwickJ, JaraiG, HogaboamCM (2009) CCR7 deficiency on dendritic cells enhances fungal clearance in a murine model of pulmonary invasive aspergillosis. Journal of immunology 183: 5171–5179.

54. De TrezC, MagezS, AkiraS, RyffelB, CarlierY, et al. (2009) iNOS-producing inflammatory dendritic cells constitute the major infected cell type during the chronic Leishmania major infection phase of C57BL/6 resistant mice. PLoS pathogens 5: e1000494.

55. GoncalvesR, ZhangX, CohenH, DebrabantA, MosserDM (2011) Platelet activation attracts a subpopulation of effector monocytes to sites of Leishmania major infection. The Journal of experimental medicine 208: 1253–1265.

56. LeonB, Lopez-BravoM, ArdavinC (2007) Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania. Immunity 26: 519–531.

57. YonaS, KimKW, WolfY, MildnerA, VarolD, et al. (2013) Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38: 79–91.

58. CornishEJ, HurtgenBJ, McInnerneyK, BurrittNL, TaylorRM, et al. (2008) Reduced nicotinamide adenine dinucleotide phosphate oxidase-independent resistance to Aspergillus fumigatus in alveolar macrophages. J Immunol 180: 6854–6867.

59. VethanayagamRR, AlmyroudisNG, GrimmMJ, LewandowskiDC, PhamCT, et al. (2011) Role of NADPH oxidase versus neutrophil proteases in antimicrobial host defense. PLoS One 6: e28149.

60. Narni-MancinelliE, SoudjaSM, CrozatK, DalodM, GounonP, et al. (2011) Inflammatory monocytes and neutrophils are licensed to kill during memory responses in vivo. PLoS pathogens 7: e1002457.

61. RoilidesE, TsaparidouS, KadiltsoglouI, SeinT, WalshTJ (1999) Interleukin-12 enhances antifungal activity of human mononuclear phagocytes against Aspergillus fumigatus: implications for a gamma interferon-independent pathway. Infection and immunity 67: 3047–3050.

62. RoilidesE, SeinT, HolmesA, ChanockS, BlakeC, et al. (1995) Effects of macrophage colony-stimulating factor on antifungal activity of mononuclear phagocytes against Aspergillus fumigatus. The Journal of infectious diseases 172: 1028–1034.

63. GeissmannF, JungS, LittmanDR (2003) Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19: 71–82.

64. HsuAP, SampaioEP, KhanJ, CalvoKR, LemieuxJE, et al. (2011) Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 118: 2653–2655.

65. SpinnerMA, SanchezLA, HsuAP, ShawPA, ZerbeCS, et al. (2013) GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics and immunity. Blood

66. VinhDC, PatelSY, UzelG, AndersonVL, FreemanAF, et al. (2010) Autosomal dominant and sporadic monocytopenia with susceptibility to mycobacteria, fungi, papillomaviruses, and myelodysplasia. Blood 115: 1519–1529.

67. Garcia-VidalC, UptonA, KirbyKA, MarrKA (2008) Epidemiology of invasive mold infections in allogeneic stem cell transplant recipients: biological risk factors for infection according to time after transplantation. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 47: 1041–1050.

68. WeinbergerM, ElattarI, MarshallD, SteinbergSM, RednerRL, et al. (1992) Patterns of infection in patients with aplastic anemia and the emergence of Aspergillus as a major cause of death. Medicine 71: 24–43.

69. SerbinaNV, HohlTM, ChernyM, PamerEG (2009) Selective expansion of the monocytic lineage directed by bacterial infection. J Immunol 183: 1900–1910.

70. LealSMJr, CowdenS, HsiaYC, GhannoumMA, MomanyM, et al. (2010) Distinct roles for Dectin-1 and TLR4 in the pathogenesis of Aspergillus fumigatus keratitis. PLoS pathogens 6: e1000976.

71. ChenF, LiuZ, WuW, RozoC, BowdridgeS, et al. (2012) An essential role for TH2-type responses in limiting acute tissue damage during experimental helminth infection. Nat Med 18: 260–266.

72. TrapnellC, PachterL, SalzbergSL (2009) TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25: 1105–1111.

73. TrapnellC, WilliamsBA, PerteaG, MortazaviA, KwanG, et al. (2010) Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotech 28: 511–515.

74. SwamydasM, LionakisMS (2013) Isolation, purification and labeling of mouse bone marrow neutrophils for functional studies and adoptive transfer experiments. J Vis Exp e50586.