• 南京軍區(qū)南京總醫(yī)院呼吸內(nèi)科（江蘇南京 210002）通訊作者：施毅，E-mail shiyi56@126.com;

隨著免疫抑制人群的增多、檢測(cè)技術(shù)的發(fā)展, 深部真菌感染日益受到人們的關(guān)注。真菌中的曲霉屬成了這些免疫功能低下患者致病性感染的重要原因, 而煙曲霉在侵襲性曲
霉病例中最常見(jiàn)。侵襲力是煙曲霉菌極為重要的致病原因;病原菌侵入上皮、內(nèi)皮細(xì)胞等組織細(xì)胞后才導(dǎo)致了可怕的侵襲性感染。從上世紀(jì)90 年代來(lái), 對(duì)于侵襲的研究已逐步深
入, 為探討復(fù)雜的致病機(jī)制打下了基礎(chǔ)。侵襲性煙曲霉病一般的致病過(guò)程認(rèn)為是煙曲霉孢子被宿主吸入下呼吸道, 侵入呼吸道上皮細(xì)胞后發(fā)育成菌絲, 菌絲進(jìn)一步生長(zhǎng), 可侵入血管、進(jìn)入血液, 造成全身播散[ 1] 。因此曲霉與宿主細(xì)胞( 上皮細(xì)胞、內(nèi)皮細(xì)胞等) 的相互作用成了致病過(guò)程的重要環(huán)節(jié)。目前對(duì)病原體與宿主細(xì)胞作用的研究取得了一些進(jìn)展, 對(duì)闡明致病機(jī)制、研究治療靶點(diǎn)等有重要意義。

引用本文： 徐小勇,施毅. 煙曲霉侵襲機(jī)制的研究. 中國(guó)呼吸與危重監(jiān)護(hù)雜志, 2010, 9(1): 94-96. doi: 復(fù)制

1. Filler SG,Sheppard DC.Fungal invasion of normally non-phagocytic host cells.PLoS Pathog,2006,2:e129.
2. Sturtevant J,Latgé JP.Participation of complement in the phagocytosis of the conidia of Aspergillus fumigatus by human polymorphonuclear cells.J Infect Dis,1992,166:580-586.
3. Rüchel R,Schaffrinski M.Versatile fluorescent staining of fungi in clinical specimens by using the optical brightener Blankophor.J Clin Microbiol,1999,37:2694-2696.
4. Lopes Bezerra LM,Filler SG.Interactions of Aspergillus fumigatus with endothelial cells: internalization,injury,and stimulation of tissue factor activity.Blood,2004,103:2143-2149.
5. Wasylnka JA,Moore MM.Uptake of Aspergillus fumigatus Conidia by phagocytic and nonphagocytic cells in vitro: quantitation using strains expressing green fluorescent protein.Infect Immun,2002,70:3156-3163.
6. Luther K,Rohde M,Heesemann J,et al.Quantification of phagocytosis of Aspergillus conidia by macrophages using a novel antibody-independent assay.J Microbiol Methods,2006,66:170-173.
7. Paris S,Boisvieux-Ulrich E,Crestani B,et al.Internalization of Aspergillus fumigatus conidia by epithelial and endothelial cells.Infect Immun,1997,65:1510-1514.
8. Wang JE,Warris A,Ellingsen EA,et al.Involvement of CD14 and toll-like receptors in activation of human monocytes by Aspergillus fumigatus hyphae.Infect Immun,2001,69:2402-2406.
9. Antachopoulos C,Roilides E.Cytokines and fungal infections.Br J Haematol,2005,129:583-596.
10. Mambula SS,Sau K,Henneke P,et al.Toll-like receptor (TLR) signaling in response to Aspergillus fumigatus.J Biol Chem,2002,277:39320-39326.
11. Meier A,Kirschning CJ,Nikolaus T,et al.Toll-like receptor (TLR) 2 and TLR4 are essential for Aspergillus-induced activation of murine macrophages.Cell Microbiol,2003,5:561-570.
12. Netea MG,Azam T,Ferwerda G,et al.IL-32 synergizes with nucleotide oligomerization domain (NOD) 1 and NOD2 ligands for IL-1beta and IL-6 production through a caspase 1-dependent mechanism.Proc Natl Acad Sci U S A,2005,102:16309-16314.
13. Bellocchio S,Moretti S,Perruccio K,et al.TLRs govern neutrophil activity in aspergillosis.J Immunol,2004,173:7406-7415.
14. Chignard M,Balloy V,Sallenave JM,et al.Role of Toll-like receptors in lung innate defense against invasive aspergillosis.Distinct impact in immunocompetent and immunocompromized hosts.Clin Immunol,2007,124:238-243.
15. Bellocchio S,Montagnoli C,Bozza S,et al.The contribution of the Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo.J Immunol,2004,172:3059-3069.
16. Bretz C,Gersuk G,Knoblaugh S,et al.MyD88 signaling contributes to early pulmonary responses to Aspergillus fumigatus.Infect Immun,2008,76:952-958.
17. Bochud PY,Chien JW,Marr KA,et al.Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation.N Engl J Med,2008,359:1766-1777.
18. Balloy V,Si-Tahar M,Takeuchi O,et al.Involvement of toll-like receptor 2 in experimental invasive pulmonary aspergillosis.Infect Immun,2005,73:5420-5425.
19. Hohl TM.Stage-specific innate immune recognition of Aspergillus fumigatus and modulation by echinocandin drugs.Med Mycol,2008,Apr 23:1-7.
20. Steele C,Rapaka RR,Metz A,et al.The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus.PLoS Pathog,2005,1:e42.
21. Luther K,Torosantucci A,Brakhage AA,et al.Phagocytosis of Aspergillus fumigatus conidia by murine macrophages involves recognition by the dectin-1 beta-glucan receptor and Toll-like receptor 2.Cell Microbiol,2007,9:368-381.
22. Bretz C,Gersuk G,Knoblaugh S,et al.MyD88 signaling contributes to early pulmonary responses to Aspergillus fumigatus.Infect Immun,2008,76:952-958.
23. Toyotome T,Adachi Y,Watanabe A,et al.Activator protein 1 is triggered by Aspergillus fumigatus beta-glucans surface-exposed during specific growth stages.Microb Pathog,2008,44:141-150.
24. Gersuk GM,Underhill DM,Zhu L,et al.Dectin-1 and TLRs permit macrophages to distinguish between different Aspergillus fumigatus cellular states.J Immunol,2006,176:3717-3724.
25. Werner JL,Metz AE,Horn D,et al.Requisite role for the dectin-1 beta-glucan receptor in pulmonary defense against Aspergillus fumigatus.J Immunol,2009,182:4938-4946.
26. Bals R,Hiemstra PS.Innate immunity in the lung: how epithelial cells fight against respiratory pathogens.Eur Respir J,2004,23:327-333.
27. Balloy V,Sallenave JM,Wu Y,et al.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,2008,283:30513-30521.
28. Bellanger AP,Millon L,Khoufache K,et al.Aspergillus fumigatus germ tube growth and not conidia ingestion induces expression of inflammatory mediator genes in the human lung epithelial cell line A549.J Med Microbiol,2009,58(Pt 2):174-179.
29. Alekseeva L,Huet D,Féménia F,et al.Inducible expression of beta defensins by human respiratory epithelial cells exposed to Aspergillus fumigatus organisms.BMC Microbiol,2009,9:33.
30. Féménia F,Huet D,Lair-Fulleringer S,et al.Effects of conidia of various Aspergillus species on apoptosis of human pneumocytes and bronchial epithelial cells.Mycopathologia,2009,167:249-262.
31. Chiang LY,Sheppard DC,Gravelat FN,et al.Aspergillus fumigatus stimulates leukocyte adhesion molecules and cytokine production by endothelial cells in vitro and during invasive pulmonary disease.Infect Immun,2008,76:3429-3438.
32. Kamai Y,Lossinsky AS,Liu H,et al.Polarized response of endothelial cells to invasion by Aspergillus fumigatus.Cell Microbiol,2009,11:170-182.
33. Phan QT,Myers CL,Fu Y,et al.Als3 is a Candida albicans invasin that binds to cadherins and induces endocytosis by host cells.PLoS Biol,2007,5:e64.
34. Phan QT,Fratti RA,Prasadarao NV,et al N-cadherin mediates endocytosis of Candida albicans by endothelial cells.J Biol Chem,2005,280:10455-10461.
  1. 1. Filler SG,Sheppard DC.Fungal invasion of normally non-phagocytic host cells.PLoS Pathog,2006,2:e129.
  2. 2. Sturtevant J,Latgé JP.Participation of complement in the phagocytosis of the conidia of Aspergillus fumigatus by human polymorphonuclear cells.J Infect Dis,1992,166:580-586.
  3. 3. Rüchel R,Schaffrinski M.Versatile fluorescent staining of fungi in clinical specimens by using the optical brightener Blankophor.J Clin Microbiol,1999,37:2694-2696.
  4. 4. Lopes Bezerra LM,Filler SG.Interactions of Aspergillus fumigatus with endothelial cells: internalization,injury,and stimulation of tissue factor activity.Blood,2004,103:2143-2149.
  5. 5. Wasylnka JA,Moore MM.Uptake of Aspergillus fumigatus Conidia by phagocytic and nonphagocytic cells in vitro: quantitation using strains expressing green fluorescent protein.Infect Immun,2002,70:3156-3163.
  6. 6. Luther K,Rohde M,Heesemann J,et al.Quantification of phagocytosis of Aspergillus conidia by macrophages using a novel antibody-independent assay.J Microbiol Methods,2006,66:170-173.
  7. 7. Paris S,Boisvieux-Ulrich E,Crestani B,et al.Internalization of Aspergillus fumigatus conidia by epithelial and endothelial cells.Infect Immun,1997,65:1510-1514.
  8. 8. Wang JE,Warris A,Ellingsen EA,et al.Involvement of CD14 and toll-like receptors in activation of human monocytes by Aspergillus fumigatus hyphae.Infect Immun,2001,69:2402-2406.
  9. 9. Antachopoulos C,Roilides E.Cytokines and fungal infections.Br J Haematol,2005,129:583-596.
  10. 10. Mambula SS,Sau K,Henneke P,et al.Toll-like receptor (TLR) signaling in response to Aspergillus fumigatus.J Biol Chem,2002,277:39320-39326.
  11. 11. Meier A,Kirschning CJ,Nikolaus T,et al.Toll-like receptor (TLR) 2 and TLR4 are essential for Aspergillus-induced activation of murine macrophages.Cell Microbiol,2003,5:561-570.
  12. 12. Netea MG,Azam T,Ferwerda G,et al.IL-32 synergizes with nucleotide oligomerization domain (NOD) 1 and NOD2 ligands for IL-1beta and IL-6 production through a caspase 1-dependent mechanism.Proc Natl Acad Sci U S A,2005,102:16309-16314.
  13. 13. Bellocchio S,Moretti S,Perruccio K,et al.TLRs govern neutrophil activity in aspergillosis.J Immunol,2004,173:7406-7415.
  14. 14. Chignard M,Balloy V,Sallenave JM,et al.Role of Toll-like receptors in lung innate defense against invasive aspergillosis.Distinct impact in immunocompetent and immunocompromized hosts.Clin Immunol,2007,124:238-243.
  15. 15. Bellocchio S,Montagnoli C,Bozza S,et al.The contribution of the Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo.J Immunol,2004,172:3059-3069.
  16. 16. Bretz C,Gersuk G,Knoblaugh S,et al.MyD88 signaling contributes to early pulmonary responses to Aspergillus fumigatus.Infect Immun,2008,76:952-958.
  17. 17. Bochud PY,Chien JW,Marr KA,et al.Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation.N Engl J Med,2008,359:1766-1777.
  18. 18. Balloy V,Si-Tahar M,Takeuchi O,et al.Involvement of toll-like receptor 2 in experimental invasive pulmonary aspergillosis.Infect Immun,2005,73:5420-5425.
  19. 19. Hohl TM.Stage-specific innate immune recognition of Aspergillus fumigatus and modulation by echinocandin drugs.Med Mycol,2008,Apr 23:1-7.
  20. 20. Steele C,Rapaka RR,Metz A,et al.The beta-glucan receptor dectin-1 recognizes specific morphologies of Aspergillus fumigatus.PLoS Pathog,2005,1:e42.
  21. 21. Luther K,Torosantucci A,Brakhage AA,et al.Phagocytosis of Aspergillus fumigatus conidia by murine macrophages involves recognition by the dectin-1 beta-glucan receptor and Toll-like receptor 2.Cell Microbiol,2007,9:368-381.
  22. 22. Bretz C,Gersuk G,Knoblaugh S,et al.MyD88 signaling contributes to early pulmonary responses to Aspergillus fumigatus.Infect Immun,2008,76:952-958.
  23. 23. Toyotome T,Adachi Y,Watanabe A,et al.Activator protein 1 is triggered by Aspergillus fumigatus beta-glucans surface-exposed during specific growth stages.Microb Pathog,2008,44:141-150.
  24. 24. Gersuk GM,Underhill DM,Zhu L,et al.Dectin-1 and TLRs permit macrophages to distinguish between different Aspergillus fumigatus cellular states.J Immunol,2006,176:3717-3724.
  25. 25. Werner JL,Metz AE,Horn D,et al.Requisite role for the dectin-1 beta-glucan receptor in pulmonary defense against Aspergillus fumigatus.J Immunol,2009,182:4938-4946.
  26. 26. Bals R,Hiemstra PS.Innate immunity in the lung: how epithelial cells fight against respiratory pathogens.Eur Respir J,2004,23:327-333.
  27. 27. Balloy V,Sallenave JM,Wu Y,et al.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,2008,283:30513-30521.
  28. 28. Bellanger AP,Millon L,Khoufache K,et al.Aspergillus fumigatus germ tube growth and not conidia ingestion induces expression of inflammatory mediator genes in the human lung epithelial cell line A549.J Med Microbiol,2009,58(Pt 2):174-179.
  29. 29. Alekseeva L,Huet D,Féménia F,et al.Inducible expression of beta defensins by human respiratory epithelial cells exposed to Aspergillus fumigatus organisms.BMC Microbiol,2009,9:33.
  30. 30. Féménia F,Huet D,Lair-Fulleringer S,et al.Effects of conidia of various Aspergillus species on apoptosis of human pneumocytes and bronchial epithelial cells.Mycopathologia,2009,167:249-262.
  31. 31. Chiang LY,Sheppard DC,Gravelat FN,et al.Aspergillus fumigatus stimulates leukocyte adhesion molecules and cytokine production by endothelial cells in vitro and during invasive pulmonary disease.Infect Immun,2008,76:3429-3438.
  32. 32. Kamai Y,Lossinsky AS,Liu H,et al.Polarized response of endothelial cells to invasion by Aspergillus fumigatus.Cell Microbiol,2009,11:170-182.
  33. 33. Phan QT,Myers CL,Fu Y,et al.Als3 is a Candida albicans invasin that binds to cadherins and induces endocytosis by host cells.PLoS Biol,2007,5:e64.
  34. 34. Phan QT,Fratti RA,Prasadarao NV,et al N-cadherin mediates endocytosis of Candida albicans by endothelial cells.J Biol Chem,2005,280:10455-10461.