#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Compartment-Specific and Sequential Role of MyD88 and CARD9 in Chemokine Induction and Innate Defense during Respiratory Fungal Infection


Our understanding of how epithelial and hematopoietic cells in the lung coordinate immunity against inhaled fungal conidia (spores) remains limited. The mold Aspergillus fumigatus is a major cause of infectious mortality in immune compromised patients. Host defense against A. fumigatus involves the activation of two host signal transducers, MyD88 and CARD9, leading to neutrophil recruitment to the infection site. In this study, we define how MyD88- and CARD9-coupled signals operate in epithelial and hematopoietic compartments to regulate neutrophil-mediated defense against A. fumigatus. Our studies support a two-stage model in which MyD88 activation in epithelial cells, via the interleukin-1 receptor, supports the rapid induction of neutrophil-recruiting chemokines. This process is essential for the first phase of neutrophil recruitment. Mortality observed in MyD88-deficient mice can be significantly reversed by administration of a chemokine termed CXCL1 to infected airways. The second phase of neutrophil recruitment is initiated by CARD9 signaling in hematopoietic cells. Loss of both phases of chemokine induction and neutrophil recruitment dramatically increases murine susceptibility to tissue-invasive disease. In sum, our study defines a temporal sequence of events, initiated by interleukin-1 receptor/MyD88 signaling in the pulmonary epithelium and propagated by CARD9 signaling in hematopoietic cells, that induces protective immunity against inhaled fungal conidia.


Vyšlo v časopise: Compartment-Specific and Sequential Role of MyD88 and CARD9 in Chemokine Induction and Innate Defense during Respiratory Fungal Infection. PLoS Pathog 11(1): e32767. doi:10.1371/journal.ppat.1004589
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004589

Souhrn

Our understanding of how epithelial and hematopoietic cells in the lung coordinate immunity against inhaled fungal conidia (spores) remains limited. The mold Aspergillus fumigatus is a major cause of infectious mortality in immune compromised patients. Host defense against A. fumigatus involves the activation of two host signal transducers, MyD88 and CARD9, leading to neutrophil recruitment to the infection site. In this study, we define how MyD88- and CARD9-coupled signals operate in epithelial and hematopoietic compartments to regulate neutrophil-mediated defense against A. fumigatus. Our studies support a two-stage model in which MyD88 activation in epithelial cells, via the interleukin-1 receptor, supports the rapid induction of neutrophil-recruiting chemokines. This process is essential for the first phase of neutrophil recruitment. Mortality observed in MyD88-deficient mice can be significantly reversed by administration of a chemokine termed CXCL1 to infected airways. The second phase of neutrophil recruitment is initiated by CARD9 signaling in hematopoietic cells. Loss of both phases of chemokine induction and neutrophil recruitment dramatically increases murine susceptibility to tissue-invasive disease. In sum, our study defines a temporal sequence of events, initiated by interleukin-1 receptor/MyD88 signaling in the pulmonary epithelium and propagated by CARD9 signaling in hematopoietic cells, that induces protective immunity against inhaled fungal conidia.


Zdroje

1. Brown GD, Denning DW, Gow NA, Levitz SM, Netea MG, et al. (2012) Hidden killers: human fungal infections. Sci Transl Med 4: 165rv113. doi: 10.1126/scitranslmed.3004404 23253612

2. Segal BH (2009) Aspergillosis. N Engl J Med 360: 1870–1884. doi: 10.1056/NEJMra0808853 19403905

3. Latge JP (1999) Aspergillus fumigatus and aspergillosis. Clin Microbiol Rev 12: 310–350. 10194462

4. Latge JP (2001) The pathobiology of Aspergillus fumigatus. Trends Microbiol 9: 382–389. 11514221

5. Schaffner A, Douglas H, Braude A (1982) Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus. Observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes. J Clin Invest 69: 617–631. doi: 10.1172/JCI110489 7037853

6. Mircescu MM, Lipuma L, van Rooijen N, Pamer EG, Hohl TM (2009) Essential Role for Neutrophils but not Alveolar Macrophages at Early Time Points following Aspergillus fumigatus Infection. J Infect Dis 200: 647–656. doi: 10.1086/600380 19591573

7. Bonnett CR, Cornish EJ, Harmsen AG, Burritt JB (2006) Early neutrophil recruitment and aggregation in the murine lung inhibit germination of Aspergillus fumigatus Conidia. Infect Immun 74: 6528–6539. doi: 10.1128/IAI.00909-06 16920786

8. Mehrad B, Strieter RM, Moore TA, Tsai WC, Lira SA, et al. (1999) CXC chemokine receptor-2 ligands are necessary components of neutrophil-mediated host defense in invasive pulmonary aspergillosis. J Immunol 163: 6086–6094. 10570298

9. Mehrad B, Wiekowski M, Morrison BE, Chen SC, Coronel EC, et al. (2002) Transient lung-specific expression of the chemokine KC improves outcome in invasive aspergillosis. Am J Respir Crit Care Med 166: 1263–1268. 12403697

10. Hohl TM, Van Epps HL, Rivera A, Morgan LA, Chen PL, et al. (2005) Aspergillus fumigatus triggers inflammatory responses by stage-specific beta-glucan display. PLoS Pathog 1: e30. doi: 10.1371/journal.ppat.0010030 16304610

11. Steele C, Rapaka RR, Metz A, Pop SM, Williams DL, et al. (2005) The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus. PLoS Pathog 1: e42. doi: 10.1371/journal.ppat.0010042 16344862

12. Sainz J, Lupianez CB, Segura-Catena J, Vazquez L, Rios R, et al. (2012) Dectin-1 and DC-SIGN Polymorphisms Associated with Invasive Pulmonary Aspergillosis Infection. PLoS One 7: e32273. doi: 10.1371/journal.pone.0032273 22384201

13. Said-Sadier N, Padilla E, Langsley G, Ojcius DM (2010) Aspergillus fumigatus stimulates the NLRP3 inflammasome through a pathway requiring ROS production and the Syk tyrosine kinase. PLoS One 5: e10008. doi: 10.1371/journal.pone.0010008 20368800

14. Werner JL, Metz AE, Horn D, Schoeb TR, Hewitt MM, et al. (2009) Requisite role for the dectin-1 beta-glucan receptor in pulmonary defense against Aspergillus fumigatus. J Immunol 182: 4938–4946. doi: 10.4049/jimmunol.0804250 19342673

15. Bellocchio S, Moretti S, Perruccio K, Fallarino F, Bozza S, et al. (2004) TLRs govern neutrophil activity in aspergillosis. J Immunol 173: 7406–7415. 15585866

16. Brown GD, Gordon S (2001) Immune recognition. A new receptor for beta-glucans. Nature 413: 36–37. 11544516

17. Rogers NC, Slack EC, Edwards AD, Nolte MA, Schulz O, et al. (2005) Syk-dependent cytokine induction by Dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity 22: 507–517. 15845454

18. Zhu LL, Zhao XQ, Jiang C, You Y, Chen XP, et al. (2013) C-type lectin receptors Dectin-3 and Dectin-2 form a heterodimeric pattern-recognition receptor for host defense against fungal infection. Immunity 39: 324–334. doi: 10.1016/j.immuni.2013.05.017 23911656

19. Saijo S, Ikeda S, Yamabe K, Kakuta S, Ishigame H, et al. (2010) Dectin-2 recognition of alpha-mannans and induction of Th17 cell differentiation is essential for host defense against Candida albicans. Immunity 32: 681–691. doi: 10.1016/j.immuni.2010.05.001 20493731

20. Gross O, Gewies A, Finger K, Schafer M, Sparwasser T, et al. (2006) Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity. Nature 442: 651–656. 16862125

21. Hara H, Ishihara C, Takeuchi A, Imanishi T, Xue L, et al. (2007) The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors. Nat Immunol 8: 619–629. 17486093

22. Strasser D, Neumann K, Bergmann H, Marakalala MJ, Guler R, et al. (2012) Syk Kinase-Coupled C-type Lectin Receptors Engage Protein Kinase C-delta to Elicit Card9 Adaptor-Mediated Innate Immunity. Immunity 36: 32–42. doi: 10.1016/j.immuni.2011.11.015 22265677

23. Jhingran A, Mar KB, Kumasaka DK, Knoblaugh SE, Ngo LY, et al. (2012) Tracing conidial fate and measuring host cell antifungal activity using a reporter of microbial viability in the lung. Cell Rep 2: 1762–1773. doi: 10.1016/j.celrep.2012.10.026 23200858

24. Gross O, Poeck H, Bscheider M, Dostert C, Hannesschlager N, et al. (2009) Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459: 433–436. doi: 10.1038/nature07965 19339971

25. Gringhuis SI, Kaptein TM, Wevers BA, Theelen B, van der Vlist M, et al. (2012) Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1 beta via a noncanonical caspase-8 inflammasome. Nature Immunology 13: 246–U263. doi: 10.1038/ni.2222 22267217

26. Vonk AG, Netea MG, van Krieken JH, Iwakura Y, van der Meer JW, et al. (2006) Endogenous interleukin (IL)-1 alpha and IL-1 beta are crucial for host defense against disseminated candidiasis. J Infect Dis 193: 1419–1426. 16619190

27. Mambula SS, Sau K, Henneke P, Golenbock DT, Levitz SM (2002) Toll-like receptor (TLR) signaling in response to Aspergillus fumigatus. J Biol Chem 277: 39320–39326. 12171914

28. Gersuk GM, Underhill DM, Zhu L, Marr KA (2006) Dectin-1 and TLRs permit macrophages to distinguish between different Aspergillus fumigatus cellular states. J Immunol 176: 3717–3724. 16517740

29. Bretz C, Gersuk G, Knoblaugh S, Chaudhary N, Randolph-Habecker J, et al. (2008) MyD88 signaling contributes to early pulmonary responses to Aspergillus fumigatus. Infect Immun 76: 952–958. doi: 10.1128/IAI.00927-07 18039832

30. Netea MG, Warris A, Van der Meer JW, Fenton MJ, Verver-Janssen TJ, et al. (2003) Aspergillus fumigatus evades immune recognition during germination through loss of toll-like receptor-4-mediated signal transduction. J Infect Dis 188: 320–326. 12854089

31. Gantner BN, Simmons RM, Canavera SJ, Akira S, Underhill DM (2003) Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2. J Exp Med 197: 1107–1117. doi: 10.1084/jem.20021787 12719479

32. LeibundGut-Landmann S, Weidner K, Hilbi H, Oxenius A (2011) Nonhematopoietic cells are key players in innate control of bacterial airway infection. J Immunol 186: 3130–3137. doi: 10.4049/jimmunol.1003565 21270399

33. Mijares LA, Wangdi T, Sokol C, Homer R, Medzhitov R, et al. (2011) Airway epithelial MyD88 restores control of Pseudomonas aeruginosa murine infection via an IL-1-dependent pathway. J Immunol 186: 7080–7088. doi: 10.4049/jimmunol.1003687 21572023

34. Barry KC, Fontana MF, Portman JL, Dugan AS, Vance RE (2013) IL-1alpha signaling initiates the inflammatory response to virulent Legionella pneumophila in vivo. J Immunol 190: 6329–6339. doi: 10.4049/jimmunol.1300100 23686480

35. Jia T, Leiner I, Dorothee G, Brandl K, Pamer EG (2009) MyD88 and Type I Interferon Receptor-Mediated Chemokine Induction and Monocyte Recruitment during Listeria monocytogenes Infection. J Immunol 183: 1271–1278. doi: 10.4049/jimmunol.0900460 19553532

36. Herjan T, Yao P, Qian W, Li X, Liu C, et al. (2013) HuR is required for IL-17-induced Act1-mediated CXCL1 and CXCL5 mRNA stabilization. J Immunol 191: 640–649. doi: 10.4049/jimmunol.1203315 23772036

37. Stripp BR, Sawaya PL, Luse DS, Wikenheiser KA, Wert SE, et al. (1992) cis-acting elements that confer lung epithelial cell expression of the CC10 gene. J Biol Chem 267: 14703–14712. 1634515

38. Drewniak A, Gazendam RP, Tool AT, van Houdt M, Jansen MH, et al. (2013) Invasive fungal infection and impaired neutrophil killing in human CARD9 deficiency. Blood 121: 2385–2392. doi: 10.1182/blood-2012-08-450551 23335372

39. Batra S, Cai S, Balamayooran G, Jeyaseelan S (2012) Intrapulmonary administration of leukotriene B(4) augments neutrophil accumulation and responses in the lung to Klebsiella infection in CXCL1 knockout mice. J Immunol 188: 3458–3468. doi: 10.4049/jimmunol.1101985 22379035

40. Kolaczkowska E, Kubes P (2013) Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 13: 159–175. doi: 10.1038/nri3399 23435331

41. Cai S, Batra S, Lira SA, Kolls JK, Jeyaseelan S (2010) CXCL1 regulates pulmonary host defense to Klebsiella Infection via CXCL2, CXCL5, NF-kappaB, and MAPKs. J Immunol 185: 6214–6225. doi: 10.4049/jimmunol.0903843 20937845

42. Balloy V, Sallenave JM, Wu Y, Touqui L, Latge JP, et al. (2008) Aspergillus fumigatus-induced interleukin-8 synthesis by respiratory epithelial cells is controlled by the phosphatidylinositol 3-kinase, p38 MAPK, and ERK1/2 pathways and not by the toll-like receptor-MyD88 pathway. J Biol Chem 283: 30513–30521. doi: 10.1074/jbc.M803149200 18703508

43. Marriott HM, Gascoyne KA, Gowda R, Geary I, Nicklin MJ, et al. (2012) Interleukin-1beta regulates CXCL8 release and influences disease outcome in response to Streptococcus pneumoniae, defining intercellular cooperation between pulmonary epithelial cells and macrophages. Infect Immun 80: 1140–1149. doi: 10.1128/IAI.05697-11 22158745

44. Miller LS, O’Connell RM, Gutierrez MA, Pietras EM, Shahangian A, et al. (2006) MyD88 mediates neutrophil recruitment initiated by IL-1R but not TLR2 activation in immunity against Staphylococcus aureus. Immunity 24: 79–91. 16413925

45. Miller LS, Pietras EM, Uricchio LH, Hirano K, Rao S, et al. (2007) Inflammasome-mediated production of IL-1beta is required for neutrophil recruitment against Staphylococcus aureus in vivo. J Immunol 179: 6933–6942. 17982084

46. Cornish EJ, Hurtgen BJ, McInnerney K, Burritt NL, Taylor RM, et al. (2008) Reduced nicotinamide adenine dinucleotide phosphate oxidase-independent resistance to Aspergillus fumigatus in alveolar macrophages. J Immunol 180: 6854–6867. 18453606

47. Shepardson KM, Jhingran A, Caffrey A, Obar JJ, Suratt BT, et al. (2014) Myeloid Derived Hypoxia Inducible Factor 1-alpha Is Required for Protection against Pulmonary Aspergillus fumigatus Infection. PLoS Pathog 10: e1004378. doi: 10.1371/journal.ppat.1004378 25255025

48. Garlanda C, Dinarello CA, Mantovani A (2013) The interleukin-1 family: back to the future. Immunity 39: 1003–1018. doi: 10.1016/j.immuni.2013.11.010 24332029

49. Rider P, Carmi Y, Voronov E, Apte RN (2013) Interleukin-1alpha. Semin Immunol 25: 430–438. doi: 10.1016/j.smim.2013.10.005 24183701

50. Grahl N, Puttikamonkul S, Macdonald JM, Gamcsik MP, Ngo LY, et al. (2011) In vivo hypoxia and a fungal alcohol dehydrogenase influence the pathogenesis of invasive pulmonary aspergillosis. PLoS Pathog 7: e1002145. doi: 10.1371/journal.ppat.1002145 21811407

51. Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, et al. (2009) RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325: 332–336. doi: 10.1126/science.1172308 19498109

52. Berkova N, Lair-Fulleringer S, Femenia F, Huet D, Wagner MC, et al. (2006) Aspergillus fumigatus conidia inhibit tumour necrosis factor- or staurosporine-induced apoptosis in epithelial cells. Int Immunol 18: 139–150. 16357007

53. Volling K, Brakhage AA, Saluz HP (2007) Apoptosis inhibition of alveolar macrophages upon interaction with conidia of Aspergillus fumigatus. FEMS Microbiol Lett 275: 250–254. 17714483

54. Volling K, Thywissen A, Brakhage AA, Saluz HP (2011) Phagocytosis of melanized Aspergillus conidia by macrophages exerts cytoprotective effects by sustained PI3K/Akt signalling. Cell Microbiol 13: 1130–1148. doi: 10.1111/j.1462-5822.2011.01605.x 21501368

55. England H, Summersgill HR, Edye ME, Rothwell NJ, Brough D (2014) Release of IL-1alpha or IL-1beta depends on mechanism of cell death. J Biol Chem.

56. Gresnigt MS, Rosler B, Jacobs CW, Becker KL, Joosten LA, et al. (2013) The IL-36 receptor pathway regulates Aspergillus fumigatus-induced Th1 and Th17 responses. Eur J Immunol 43: 416–426. doi: 10.1002/eji.201242711 23147407

57. Gresnigt MS, Bozza S, Becker KL, Joosten LA, Abdollahi-Roodsaz S, et al. (2014) A polysaccharide virulence factor from Aspergillus fumigatus elicits anti-inflammatory effects through induction of Interleukin-1 receptor antagonist. PLoS Pathog 10: e1003936. doi: 10.1371/journal.ppat.1003936 24603878

58. Wang L, Fuster M, Sriramarao P, Esko JD (2005) Endothelial heparan sulfate deficiency impairs L-selectin- and chemokine-mediated neutrophil trafficking during inflammatory responses. Nat Immunol 6: 902–910. 16056228

59. Massena S, Christoffersson G, Hjertstrom E, Zcharia E, Vlodavsky I, et al. (2010) A chemotactic gradient sequestered on endothelial heparan sulfate induces directional intraluminal crawling of neutrophils. Blood 116: 1924–1931. doi: 10.1182/blood-2010-01-266072 20530797

60. von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, et al. (2008) Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321: 691–696. doi: 10.1126/science.1158298 18669862

61. Glocker EO, Hennigs A, Nabavi M, Schaffer AA, Woellner C, et al. (2009) A homozygous CARD9 mutation in a family with susceptibility to fungal infections. N Engl J Med 361: 1727–1735. doi: 10.1056/NEJMoa0810719 19864672

62. Lanternier F, Pathan S, Vincent QB, Liu L, Cypowyj S, et al. (2013) Deep dermatophytosis and inherited CARD9 deficiency. N Engl J Med 369: 1704–1714. doi: 10.1056/NEJMoa1208487 24131138

63. Romani L (2011) Immunity to fungal infections. Nature Reviews Immunology 11: 275–288. doi: 10.1038/nri2939 21394104

64. Sainz J, Perez E, Gomez-Lopera S, Jurado M (2008) IL1 gene cluster polymorphisms and its haplotypes may predict the risk to develop invasive pulmonary aspergillosis and modulate C-reactive protein level. J Clin Immunol 28: 473–485. doi: 10.1007/s10875-008-9197-0 18484169

65. Bochud PY, Chien JW, Marr KA, Leisenring WM, Upton A, et al. (2008) Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med 359: 1766–1777. doi: 10.1056/NEJMoa0802629 18946062

66. Lamoth F, Rubino I, Bochud PY (2011) Immunogenetics of invasive aspergillosis. Medical Mycology 49 Suppl 1: S125–136. doi: 10.3109/13693786.2010.516408 20840014

67. Cunha C, Di Ianni M, Bozza S, Giovannini G, Zagarella S, et al. (2010) Dectin-1 Y238X polymorphism associates with susceptibility to invasive aspergillosis in hematopoietic transplantation through impairment of both recipient- and donor-dependent mechanisms of antifungal immunity. Blood 116: 5394–5402. doi: 10.1182/blood-2010-04-279307 20807886

68. Cunha C, Aversa F, Romani L, Carvalho A (2013) Human genetic susceptibility to invasive aspergillosis. PLoS Pathog 9: e1003434. doi: 10.1371/journal.ppat.1003434 23950708

69. Hsu YM, Zhang Y, You Y, Wang D, Li H, et al. (2007) The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens. Nat Immunol 8: 198–205. 17187069

70. Gong S, Yang XW, Li C, Heintz N (2002) Highly efficient modification of bacterial artificial chromosomes (BACs) using novel shuttle vectors containing the R6Kgamma origin of replication. Genome Res 12: 1992–1998. doi: 10.1101/gr.476202 12466304

71. Serbina NV, Hohl TM, Cherny M, Pamer EG (2009) Selective expansion of the monocytic lineage directed by bacterial infection. J Immunol 183: 1900–1910. doi: 10.4049/jimmunol.0900612 19596996

72. Hohl TM, Rivera A, Lipuma L, Gallegos A, Shi C, et al. (2009) Inflammatory monocytes facilitate adaptive CD4 T cell responses during respiratory fungal infection. Cell Host Microbe 6: 470–481. doi: 10.1016/j.chom.2009.10.007 19917501

73. Li H, Barker BM, Grahl N, Puttikamonkul S, Bell JD, et al. (2011) The small GTPase RacA mediates intracellular reactive oxygen species production, polarized growth, and virulence in the human fungal pathogen Aspergillus fumigatus. Eukaryot Cell 10: 174–186. doi: 10.1128/EC.00288-10 21183690

74. Fallert BA, Reinhart TA (2002) Improved detection of simian immunodeficiency virus RNA by in situ hybridization in fixed tissue sections: combined effects of temperatures for tissue fixation and probe hybridization. J Virol Methods 99: 23–32. 11684300

75. Reinhart TA, Fallert BA, Pfeifer ME, Sanghavi S, Capuano S 3rd, et al. (2002) Increased expression of the inflammatory chemokine CXC chemokine ligand 9/monokine induced by interferon-gamma in lymphoid tissues of rhesus macaques during simian immunodeficiency virus infection and acquired immunodeficiency syndrome. Blood 99: 3119–3128. 11964273

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2015 Číslo 1
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Získaná hemofilie - Povědomí o nemoci a její diagnostika
nový kurz

Eozinofilní granulomatóza s polyangiitidou
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#