钙粘蛋白：A549细胞、HUVEC细胞的烟曲霉重要受体
摘要
随着免疫抑制人群的不断增加,机会感染的发病率急剧上升。机会感染中真菌感染死亡率高、治疗昂贵而困难,预后极差。对于移植患者来说,曲霉感染在机会真菌感染中占主要地位。移植患者中侵袭性曲霉病病死率高达60%-80%左右,严重威胁患者生命。即使及时、合理的使用抗真菌药物,侵袭性曲霉病的治疗有效率仍仅50%-70%左右。目前曲霉病中最重要的致病原为烟曲霉,占发病率的90%左右。烟曲霉是一种在广泛分布于自然界的腐生菌。正常人每天吸入烟曲霉的孢子量很多但并不发病,因为肺部功能强大吞噬细胞有效的清除了这些致病原；但免疫抑制患者的吞噬细胞功能受损,而未被吞噬的曲霉孢子就可能侵袭肺泡上皮,最后进入肺组织造成感染,侵入组织的曲霉发育成菌丝,菌丝侵袭血管、穿透内皮细胞可造成曲霉特征性病变—组织梗死和全身播散。可以看出烟曲霉侵袭宿主细胞是致病的重要环节,特别是探讨烟曲霉与肺泡上皮细胞、血管内皮细胞的相互作用不仅可以研究曲霉的致病机理,抑或可为治疗寻找新的靶点。
烟曲霉粘附、侵袭细胞可能涉及相当多的分子,包括粘附分子、模式识别分子等。较早的体外实验用纤维蛋白素原(fibrinogen)预处理烟曲霉的孢子,其粘附于肺泡上皮细胞(A549)的能力下降30%-50%。孢子并可以直接粘附于层连蛋白(laminin)、胶原(collagen)、纤连蛋白(fibronectin)。但其后相关的研究甚少。病原体如何粘附、侵袭非吞噬宿主细胞在一些微生物上有一定的研究。白色假丝酵母菌侵袭非吞噬细胞中研究得比较透彻,宿主细胞膜蛋白中的cadherin(钙粘蛋白)在白色假丝酵母菌进入宿主细胞过程中其关键作用。Cadherin是一类依赖于钙离子的细胞间粘附分子,能和其他相关的粘附分子结合介导细胞粘附。白色假丝酵母菌表面的凝集素同源物als3存在特定的β折叠结构,并能与上皮细胞、内皮细胞表达cadherin结合后介导白色假丝酵母菌进入宿主细胞。类似的产单核细胞李斯特菌细胞膜上的internalin A其膜外特定的富亮氨酸重复序列(Leucine rich repeat domain, LRR)也形成特定的β折叠结构与上皮表面的cadherin膜外结构结合而介导病原侵入宿主细胞。人肺泡上皮细胞也有E-cadherin(epithelial-type cadherin E钙粘蛋白)、内皮细胞有N-cadherin(neuron-type cadherin N钙粘蛋白)的表达；而念珠菌与烟曲霉同属真菌界,其胞膜也可能存在同源的蛋白。因此我们设想cadherin可能在烟曲霉侵袭上皮细胞时也起重要作用。因此本实验拟研究肺泡上皮细胞表达的E-cadherin、内皮细胞的N-cadherin是否在烟曲霉侵袭过程中也起特定的作用。
第一部分E-cadherin为肺泡上皮细胞粘附、吞噬烟曲霉孢子的重要受体
目的探讨E-cadherin在烟曲霉孢子粘附、侵袭肺泡上皮细胞(A549)过程中的作用。方法(1)体外培养A549细胞,提取A549总蛋白。与烟曲霉孢子共孵育,通过离心去除未与孢子结合的蛋白。EDTA解离与孢子结合的蛋白,Western-blot检测是否有E-cadherin的存在；免疫荧光法检测孢子表面是否存在E-cadherin。(2)荧光染色法建立A549粘附、吞噬烟曲霉孢子的体外模型,通过抗体阻断法、SiRNA下调A549细胞膜蛋白E-cadherin,观察A549粘附、吞噬烟曲霉孢子的能力的变化。(3)观察A549细胞膜蛋白E-cadherin是否随烟曲霉孢子侵入上皮细胞而变化。结果(1)A549的膜蛋白E-cadherin可以与烟曲霉孢子结合；(2)100个A549细胞粘附吞噬的烟曲霉孢子数在1、2、4小时分别为204±12、212±12.5、209±7.5；加入0.2mM EDTA后1小时粘附吞噬的孢子数为141±5.5,再加入钙离子后A549粘附吞噬的孢子数为218±17；而加入同浓度的镁离子后A549粘附吞噬的孢子数为147±5.5。在培养液中预先加入的1：50、1：100、1：200的E-cadherin抗体,100个A549粘附吞噬的烟曲霉孢子数为161.7±8.5、163.7±8.5、163±12。E-cadherin的SiRNA处理的A549细胞粘附吞噬的孢子数为167.67±9.5,联合1：50抗体处理后粘附吞噬的孢子数为141.3±9.6。(3) Western-blot检测发现A549在粘附吞噬烟曲霉孢子0、1、2、4小时E-cadherin的表达无明显改变。24小时10-7M的地塞米松处理A549 24小时E-cadherin的表达无明显改变。结论E-cadherin在人肺泡上皮细胞(A549)粘附、吞噬烟曲霉孢子的过程中起重要作用。
第二部分N-cadherin为人脐静脉内皮细胞粘附、吞噬烟曲霉菌丝的重要受体
目的探讨N-cadherin在HUVEC粘附、吞噬烟曲霉菌丝过程中的作用。方法(1)体外培养]HUVEC细胞,提取总蛋白。与烟曲霉菌丝共孵育,通过离心去除未与孢子结合的蛋白。EDTA解离与菌丝结合的蛋白,Western-blot检测是否有N-cadherin的存在；免疫荧光法检测孢子表面是否存在N-cadherin。(2)荧光染色法建立HUVEC粘附、吞噬烟曲霉菌丝的体外模型,通过抗体阻断细胞膜蛋白N-cadherin,观察HUVEC粘附、吞噬烟曲霉的能力的变化。(3)观察HUVEC细胞膜蛋白N-cadherin是否随烟曲霉孢子侵入上皮细胞而变化。(4)免疫荧光观察N-cadherin的定位是否与烟曲霉相关。结果(1)HUVEC的膜蛋白可以与烟曲霉菌丝结合。(2)正常]HUVEC在1小时后粘附吞噬烟曲霉菌丝为235±9.2,加入0.2mM EDTA后1小时粘附吞噬的菌丝数为126.3±11.6,再加入钙离子后粘附吞噬的菌丝数为239±24；而加入同浓度的镁离子后A549粘附吞噬的孢子数为137±18.4。在培养液中预先加入的1：50、1：100、1：200的N-cadherin抗体,100个HUVEC粘附吞噬的烟曲霉数为133.3±23、148±13、171±16。(3)流式细胞仪、Western-blot检测发HUVEC在粘附吞噬烟曲霉1、2、4小时N-cadherin的表达无明显改变。(4)免疫荧光法提示N-cadherin可以随烟曲霉菌丝而进入细胞内。结论N-cadherin在HUVEC粘附、吞噬烟曲霉菌丝的过程中起重要作用。
Aspergillus fumigatus is an ubiquitous sapropHytic fungus responsible for the majority of invasive mold infections. Airborne conidia (spores) are inhaled into the small airways, where those escape from pHagocytose of pulmonary pHagocytic cells may germinate and initiate an infection. The invasion of airway epithelial cells is therefore a key step in the etiology of aspergillosis, but little is known of the factors involved in this interaction.
Many receptors including adhesion molecules and pattern recognition receptors are the promising candidates. Pattern recognition receptors and the associated adaptor molecules play a role in mediating the inflammatory response to A.fumigatus, but few research indicated that they also could get involved in invasion. Cadherin belong to adhensive molecule familys serves as an endothelial cell receptor, which mediates the endocytosis of C. albicans. The listerial protein internalin (InlA) mediate Listerial adhesion and invasion of epithelial cell through the exact interreaction with the receptor cadherin. N-terminal domain of cadherin is recognized and engulfed by InlA with its'leucine rich repeat (LRR) domain. We have found that there are some homologous or similar molecules to InlA in Aspergillus fumigatus through BLASTp in bioinformatics.Could e-cadherin (epithelial type cadherin) be a receptor for adhesion and endocytosis of Aspergillus fumigatus blastospores.
PartⅠE-cadherin:As a receptor for adhesion and endocytosis of Aspergillus fumigatus blastospores by A549
Objective:To study the receptor for adhesion and endocytosis of Aspergillus fumigatus blastospores by A549. Methods:Aspergillus fumigatus blastospores were incubated with the total protein of A549 for investigating the binding of e-cadherin and blastospore. After establishing the model of adhesion and endocytosis of Aspergillus fumigatus blastospores by A549, the capacity of adherion and endocytosis was evaluated with the existence of the antibody for e-cadherin. Result:E-cadherin sticked to the surface of Aspergillus fumigatus blastospore. Adherion and endocytosis was weaken with the existence of the antibody for e-cadherin. Conclusion:E-cadherin is a receptor for adhesion and endocytosis of Aspergillus fumigatus blastospores by A549.
PartⅡN-cadherin:As a receptor for adhesion and endocytosis of Aspergillus fumigatus by HUVEC
Objective:To evaluate role of n-cadherin as the receptor for adhesion and endocytosis of Aspergillus fumigatus hypHae by HUVEC. Methods:Aspergillus fumigatus hypHae were incubated with the total protein of HUVEC for fingding out the binding of e-cadherin and Aspergillus fumigatus hypHae. After establishing the model of adhesion and endocytosis of Aspergillus fumigatus hypHae by HUVEC, the amount of hypHae of adherion and endocytosis was recorded with the existence of the antibody for N-cadherin. Result: N-cadherin sticked to the surface of Aspergillus fumigatus hypHae. The amount of hypHae of adherion and endocytosis decreased with the existence of the antibody for N-cadherin. Conclusion:N-cadherin is a receptor for adhesion and endocytosis of Aspergillus fumigatus hypHae by HUVEC.
烟曲霉粘附、侵袭细胞可能涉及相当多的分子,包括粘附分子、模式识别分子等。较早的体外实验用纤维蛋白素原(fibrinogen)预处理烟曲霉的孢子,其粘附于肺泡上皮细胞(A549)的能力下降30%-50%。孢子并可以直接粘附于层连蛋白(laminin)、胶原(collagen)、纤连蛋白(fibronectin)。但其后相关的研究甚少。病原体如何粘附、侵袭非吞噬宿主细胞在一些微生物上有一定的研究。白色假丝酵母菌侵袭非吞噬细胞中研究得比较透彻,宿主细胞膜蛋白中的cadherin(钙粘蛋白)在白色假丝酵母菌进入宿主细胞过程中其关键作用。Cadherin是一类依赖于钙离子的细胞间粘附分子,能和其他相关的粘附分子结合介导细胞粘附。白色假丝酵母菌表面的凝集素同源物als3存在特定的β折叠结构,并能与上皮细胞、内皮细胞表达cadherin结合后介导白色假丝酵母菌进入宿主细胞。类似的产单核细胞李斯特菌细胞膜上的internalin A其膜外特定的富亮氨酸重复序列(Leucine rich repeat domain, LRR)也形成特定的β折叠结构与上皮表面的cadherin膜外结构结合而介导病原侵入宿主细胞。人肺泡上皮细胞也有E-cadherin(epithelial-type cadherin E钙粘蛋白)、内皮细胞有N-cadherin(neuron-type cadherin N钙粘蛋白)的表达；而念珠菌与烟曲霉同属真菌界,其胞膜也可能存在同源的蛋白。因此我们设想cadherin可能在烟曲霉侵袭上皮细胞时也起重要作用。因此本实验拟研究肺泡上皮细胞表达的E-cadherin、内皮细胞的N-cadherin是否在烟曲霉侵袭过程中也起特定的作用。
第一部分E-cadherin为肺泡上皮细胞粘附、吞噬烟曲霉孢子的重要受体
目的探讨E-cadherin在烟曲霉孢子粘附、侵袭肺泡上皮细胞(A549)过程中的作用。方法(1)体外培养A549细胞,提取A549总蛋白。与烟曲霉孢子共孵育,通过离心去除未与孢子结合的蛋白。EDTA解离与孢子结合的蛋白,Western-blot检测是否有E-cadherin的存在；免疫荧光法检测孢子表面是否存在E-cadherin。(2)荧光染色法建立A549粘附、吞噬烟曲霉孢子的体外模型,通过抗体阻断法、SiRNA下调A549细胞膜蛋白E-cadherin,观察A549粘附、吞噬烟曲霉孢子的能力的变化。(3)观察A549细胞膜蛋白E-cadherin是否随烟曲霉孢子侵入上皮细胞而变化。结果(1)A549的膜蛋白E-cadherin可以与烟曲霉孢子结合；(2)100个A549细胞粘附吞噬的烟曲霉孢子数在1、2、4小时分别为204±12、212±12.5、209±7.5；加入0.2mM EDTA后1小时粘附吞噬的孢子数为141±5.5,再加入钙离子后A549粘附吞噬的孢子数为218±17；而加入同浓度的镁离子后A549粘附吞噬的孢子数为147±5.5。在培养液中预先加入的1：50、1：100、1：200的E-cadherin抗体,100个A549粘附吞噬的烟曲霉孢子数为161.7±8.5、163.7±8.5、163±12。E-cadherin的SiRNA处理的A549细胞粘附吞噬的孢子数为167.67±9.5,联合1：50抗体处理后粘附吞噬的孢子数为141.3±9.6。(3) Western-blot检测发现A549在粘附吞噬烟曲霉孢子0、1、2、4小时E-cadherin的表达无明显改变。24小时10-7M的地塞米松处理A549 24小时E-cadherin的表达无明显改变。结论E-cadherin在人肺泡上皮细胞(A549)粘附、吞噬烟曲霉孢子的过程中起重要作用。
第二部分N-cadherin为人脐静脉内皮细胞粘附、吞噬烟曲霉菌丝的重要受体
目的探讨N-cadherin在HUVEC粘附、吞噬烟曲霉菌丝过程中的作用。方法(1)体外培养]HUVEC细胞,提取总蛋白。与烟曲霉菌丝共孵育,通过离心去除未与孢子结合的蛋白。EDTA解离与菌丝结合的蛋白,Western-blot检测是否有N-cadherin的存在；免疫荧光法检测孢子表面是否存在N-cadherin。(2)荧光染色法建立HUVEC粘附、吞噬烟曲霉菌丝的体外模型,通过抗体阻断细胞膜蛋白N-cadherin,观察HUVEC粘附、吞噬烟曲霉的能力的变化。(3)观察HUVEC细胞膜蛋白N-cadherin是否随烟曲霉孢子侵入上皮细胞而变化。(4)免疫荧光观察N-cadherin的定位是否与烟曲霉相关。结果(1)HUVEC的膜蛋白可以与烟曲霉菌丝结合。(2)正常]HUVEC在1小时后粘附吞噬烟曲霉菌丝为235±9.2,加入0.2mM EDTA后1小时粘附吞噬的菌丝数为126.3±11.6,再加入钙离子后粘附吞噬的菌丝数为239±24；而加入同浓度的镁离子后A549粘附吞噬的孢子数为137±18.4。在培养液中预先加入的1：50、1：100、1：200的N-cadherin抗体,100个HUVEC粘附吞噬的烟曲霉数为133.3±23、148±13、171±16。(3)流式细胞仪、Western-blot检测发HUVEC在粘附吞噬烟曲霉1、2、4小时N-cadherin的表达无明显改变。(4)免疫荧光法提示N-cadherin可以随烟曲霉菌丝而进入细胞内。结论N-cadherin在HUVEC粘附、吞噬烟曲霉菌丝的过程中起重要作用。
Aspergillus fumigatus is an ubiquitous sapropHytic fungus responsible for the majority of invasive mold infections. Airborne conidia (spores) are inhaled into the small airways, where those escape from pHagocytose of pulmonary pHagocytic cells may germinate and initiate an infection. The invasion of airway epithelial cells is therefore a key step in the etiology of aspergillosis, but little is known of the factors involved in this interaction.
Many receptors including adhesion molecules and pattern recognition receptors are the promising candidates. Pattern recognition receptors and the associated adaptor molecules play a role in mediating the inflammatory response to A.fumigatus, but few research indicated that they also could get involved in invasion. Cadherin belong to adhensive molecule familys serves as an endothelial cell receptor, which mediates the endocytosis of C. albicans. The listerial protein internalin (InlA) mediate Listerial adhesion and invasion of epithelial cell through the exact interreaction with the receptor cadherin. N-terminal domain of cadherin is recognized and engulfed by InlA with its'leucine rich repeat (LRR) domain. We have found that there are some homologous or similar molecules to InlA in Aspergillus fumigatus through BLASTp in bioinformatics.Could e-cadherin (epithelial type cadherin) be a receptor for adhesion and endocytosis of Aspergillus fumigatus blastospores.
PartⅠE-cadherin:As a receptor for adhesion and endocytosis of Aspergillus fumigatus blastospores by A549
Objective:To study the receptor for adhesion and endocytosis of Aspergillus fumigatus blastospores by A549. Methods:Aspergillus fumigatus blastospores were incubated with the total protein of A549 for investigating the binding of e-cadherin and blastospore. After establishing the model of adhesion and endocytosis of Aspergillus fumigatus blastospores by A549, the capacity of adherion and endocytosis was evaluated with the existence of the antibody for e-cadherin. Result:E-cadherin sticked to the surface of Aspergillus fumigatus blastospore. Adherion and endocytosis was weaken with the existence of the antibody for e-cadherin. Conclusion:E-cadherin is a receptor for adhesion and endocytosis of Aspergillus fumigatus blastospores by A549.
PartⅡN-cadherin:As a receptor for adhesion and endocytosis of Aspergillus fumigatus by HUVEC
Objective:To evaluate role of n-cadherin as the receptor for adhesion and endocytosis of Aspergillus fumigatus hypHae by HUVEC. Methods:Aspergillus fumigatus hypHae were incubated with the total protein of HUVEC for fingding out the binding of e-cadherin and Aspergillus fumigatus hypHae. After establishing the model of adhesion and endocytosis of Aspergillus fumigatus hypHae by HUVEC, the amount of hypHae of adherion and endocytosis was recorded with the existence of the antibody for N-cadherin. Result: N-cadherin sticked to the surface of Aspergillus fumigatus hypHae. The amount of hypHae of adherion and endocytosis decreased with the existence of the antibody for N-cadherin. Conclusion:N-cadherin is a receptor for adhesion and endocytosis of Aspergillus fumigatus hypHae by HUVEC.
引文
1. Groll AH, Shah PM, Mentzel C, et al.Trends in the Postmorteme Pidemiology of invasive fungal infections at a university hospital. J Infect,1996,33:23-32.
2.邹先彪.肺部真菌感染概述//赵蓓蕾,施毅,桑红.现代肺部真菌病学.北京：人民军医出版社,2004：18-21.
3. Thompson GR 3rd, Patterson TF. Pulmonary aspergillosis. Semin Respir Crit Care Med,2008,29 (2):103-110.
4. Patterson TF, Kirkpatrick WR, White M, et al. Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes.13 Aspergillus Study Group.Medicine, 2000,79 (4):250-260.
5. Lopes Bezerra LM, Filler SG. Interactions of Aspergillus fumigatus with endothelial cells:internalization, injury, and stimulation of tissue factor activity. Blood,2004,103 (6):2143-2149.
6. Filler SG, Sheppard DC. Fungal invasion of normally non-pHagocytic host cells. PLoS Pathog,2006,2 (12):el29,1099-1105.
7. Bellocchio S, Moretti S, Perruccio K, et al. TLRs govern neutropHil activity in aspergillosis. J Immunol,2004,173 (12):7406-7415.
8. 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 (3):238-243.
9. Bellocchio S, Montagnoli C, Bozza S, et al. The contribution of Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo. J Immunol,2004,172 (5):3059-3069.
10. Bretz C, Gersuk G, Knoblaugh S, et al. MyD88 signaling contributes to early pulmonary responses to Aspergillus fumigatus. Infect Immun,2008,76 (3):952-958.
11. 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 (17):1766-1777.
12. Balloy V, Si-Tahar M, Takeuchi O, et al. Involvement of toll-like receptor 2 in experimental invasive pulmonary aspergillosis. Infect Immun,2005,73 (9):5420-5425.
13. Hohl TM. Stage-specific innate immune recognition of Aspergillus fumigatus and modulation by echinocandin drugs. Med Mycol,2008, Apr 23:1-7.
14. Steele C, Rapaka RR, Metz A,et al. The beta-glucan receptor dectin-1 recognizes specific morpHologies of Aspergillus fumigatus. PLoS Pathog,2005, (4):e42.
15. da Silva Tatley F, Aldwell FE, Dunbier AK, et al. N-terminal E-cadherin peptides act as decoy receptors for Listeria monocytogenes. Infect Immun,2003,71 (3):1580-1583.
16. Anderton JM, Rajam G, Romero-Steiner S, et al. E-cadherin is a receptor for the common protein pneumococcal surface adhesin A (PsaA) of Streptococcus pneumoniae. Microb Pathog,2007,42 (5-6):225-236.
17. PHan QT, Fratti RA, Prasadarao NV,et al. N-cadherin mediates endocytosis of Candida albicans by endothelial cells. J Biol Chem,2005,280 (11):10455-10461.
18. 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(3):e64.
19. Angst BD, Marcozzi C, Magee AI. The cadherin superfamily:diversity in form and function. J Cell Sci,2001,114:629-641.
20. Halbleib JM, Nelson WJ. Cadherins in development:cell adhesion, sorting, and tissue morpHogenesis. Genes Dev,2006,20:3199-3214.
21. Weis WI, Nelson WJ. Re-solving the cadherin-catenin-actin conundrum. J Biol Chem, 2006,281 (47):35593-35597.
22. Schubert WD, Urbanke C, Ziehm T, et al. Structure of internalin, a major invasion protein of Listeria monocytogenes, in complex with its human receptor E-cadherin. Cell,2002,111 (6):825-836.
23. Nierman WC, Pain A, Anderson MJ, et al. Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature,2005,438 (7071):1151-1156.
24. Isberg RR, Leong JM. Multiple beta 1 chain integrins are receptors for invasin, a protein that promotes bacterial penetration into mammalian cells. Cell,1990,60 (5):861-871.
25. Carayol N, Vachier I, Campbell A, et al. Regulation of E-cadherin expression by dexamethasone and tumour necrosis factor-alpHa in nasal epithelium. Eur Respir J, 2002,20 (6):1430-1436.
26. Blecharz KG, Drenckhahn D, Forster CY. Glucocorticoids increase VE-cadherin expression and cause cytoskeletal rearrangements in murine brain endothelial cEND cells. J Cereb Blood Flow Metab,2008,28 (6):1139-1149.
27. 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 (6):3156-3163.
28. Sturtevant J, Latge JP. Participation of complement in the pHagocytosis of the conidia of Aspergillus fumigatus by human polymorpHonuclear cells. J Infect Dis,1992,166 (3):580-586.
29. Ruchel R, Schaffrinski M. Versatile fluorescent staining of fungi in clinical specimens by using the optical brightener BlankopHor. J Clin Microbiol,1999,37 (8):2694-2696.
30. Meersseman W, Lagrou K, Maertens J, et al. Invasive aspergillosis in the intensive care unit.Clin Infect Dis,2007,45 (2):205-216.
31. Meersseman W, Vandecasteele SJ, Wilmer A, et alInvasive aspergillosis in critically ill patients without malignancy. Am J Respir Crit Care Med,2004,170 (6):621-625
32. Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary aspergillosis Chest,2002,121 (6):1988-1999
33. Lo HJ, Kohler JR, DiDomenico B,et al. Nonfilamentous C. albicans mutants are avirulent. Cell,1997,90 (5):939-949.
34. Fortwendel JR, Zhao W, Bhabhra R,et al. A fungus-specific ras homolog contributes to the hypHal growth and virulence of Aspergillus fumigatus. Eukaryot Cell,2005,4 (12):1982-1989
35. 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 (8):4938-4946.
36. Hohl TM. Stage-specific innate immune recognition of Aspergillus fumigatus and modulation by echinocandin drugs. Med Mycol,2008,1:1-7.
37. Dennehy KM;Brown GD. The role of the beta-glucan receptor Dectin-1 in control of fungal infection. J Leukoc Biol,2007,82 (2):253-258.
38. Goodridge HS, Wolf AJ, Underhill DM. Beta-glucan recognition by the innate immune system. Immunol Rev,2009,230, (1):38-50.
39. Avadhanula V, Rodriguez CA, Ulett GC, et al. Nontypeable HaemopHilus influenzae adheres to intercellular adhesion molecule 1 (ICAM-1) on respiratory epithelial cells and upregulates ICAM-1 expression. Infect Immun 2006;74:830-838.
40. Kamai Y, Lossinsky AS, Liu H, et al. Polarized response of endothelial cells to invasion by Aspergillus fumigatus. Cell Microbiol,2009,11 (1):170-182.
41. Dagenais TR, Keller NP. Pathogenesis of Aspergillus fumigatus in Invasive Aspergillosis. Clin Microbiol Rev,2009,22 (3):447-465.
42. Lai CC, Liaw SJ, Lee I N,et al. Invasive pulmonary apergillosis:hish incidence of disseminated intmvascular coagulation in fatal cases. J Microbiol lmmunol Infect, 2007,40:141-147.
43. Sturtevant J, Latge JP:Participation of complement in the pHagocytosis of the conidia of Aspergillus fumigatus by human polymorpHonuclear cells. J Infect Dis 1992, 166:580-586.
[1]邹先彪.肺部真菌感染概述//赵蓓蕾,施毅,桑红.现代肺部真菌病学.北京：人民军医出版社,2004：18-21.
[2]Meersseman W, Lagrou K, Maertens J, et al. Invasive aspergillosis in the intensive care unit.Clin Infect Dis,2007,45 (2):205-216.
[3]Meersseman W, Vandecasteele SJ, Wilmer A, et alInvasive aspergillosis in critically ill patients without malignancy. Am J Respir Crit Care Med,2004,_170 (6):621-625
[4]Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary aspergillosis Chest,2002,121 (6):1988-1999.
[5]Thompson GR 3rd, Patterson TF. Pulmonary aspergillosis. Semin Respir Crit Care Med, 2008,29 (2)::103-110.
[6]Patterson TF, Kirkpatrick WR, White M,et al. Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes.13'Aspergillus Study Group.Medicine,2000,79 (4):250-260.
[7]Sanchez AA, Johnston DA, Myers C, Edwards JE Jr., Mitchell AP, et al. Relationship between Candida albicans virulence during experimental hematogenously disseminated Infection and endothelial cell damage in vitro. Infect Immun,2004,72 (1):598-601.
[8]Lopes Bezerra LM, Filler SG Interactions of Aspergillus fumigatus with endothelial cells:internalization, injury, and stimulation of tissue factor activity. Blood,2004,103 (6):2143-2149.
[9]Paris S, Boisvieux-Ulrich E, Crestani B,et al. Internalization of Aspergillus fumigatus conidia by epithelial and endothelial cells. Infect Immun,1997,_65 (4):1510-1514.
[10]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 (6):3156-3163.
[11]Bromley IM, Donaldson K. Binding of Aspergillus fumigatus spores to lung epithelial cells and basement membrane proteins:relevance to the asthmatic lung.Thorax,1996,51 (12):1203-1209.
[12]Warwas, M. L., J. N. Watson, A. J. Bennet, and M. M. Moore. Structure and role of sialic acids on the surface of Aspergillus fumigatus conidiospores. Glycobiology,2007,17 (4):401-410.
[13]Tronchin G, Esnault K, Renier G,et al. Expression and identification of a laminin-binding protein in Aspergillus fumigatus conidia. Infect Immun,1997,_65 (1):9-15.
[14]Zhang Z, Liu R, Noordhoek JA,et al. Interaction of airway epithelial cells (A549) with spores and mycelium of Aspergillus fumigatus. J Infect,2005,51 (5):375-382.
[15]Blander JM, Medzhitov R. Regulation of pHagosome maturation by signals from toll-like receptors. Science,2004,304 (5673):1014-1018
[16]韩黎,纪蕾,王菡,等.Toll样受体在烟曲霉侵染宿主细胞过程中作用的研究进展.微生物学通报,2007,34：973-975.
[17]Lo HJ, Kohler JR, DiDomenico B,et al. Nonfilamentous C. albicans mutants are avirulent. Cell,1997,90 (5):939-949.
[18]Fortwendel JR, Zhao W, Bhabhra R,et al. A fungus-specific ras homolog contributes to the hypHal growth and virulence of Aspergillus fumigatus. Eukaryot Cell,2005,4 (12):1982-1989.
[19]Shaukat A, Bakri F, Young P, et al. Invasive filamentous fungal infections in allogeneic hematopoietic stem cell transplant recipients after recovery from neutropenia: Clinical, radiologic, and pathologic characteristics.Mycopathologia,2005,159 (2):181-188.
[20]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 (8):3429-3438.
[21]Filler SG, Sheppard DC. Fungal invasion of normally non-pHagocytic host cells. PLoS Pathog,2006,2 (12):e129,1099-1105.
[22]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 (3):e64,543-557.
[23]PHan QT, Fratti RA, Prasadarao NV,et al. N-cadherin mediates endocytosis of Candida albicans by endothelial cells. J Biol Chem,2005,280 (11):10455-10461.
[24]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 (2):141-150.
[25]Paris S, Debeaupuis JP, Crameri R,et al. Conidial hydropHobins of Aspergillus fumigatus. Appl Environ Microbiol,2003,69 (3):1581-1588.
[26]Brakhage, A. A, and B. Liebmann. Aspergillus fumigatus conidial pigment and cAMP signal transduction:significance for virulence. Med Mycol,43 Suppl 1:S75-82.
[27]Li, H., H. Zhou, Y. Luo, et al. GlycosylpHospHatidylinositol (GPI) anchor is required in Aspergillus fumigatus for morpHogenesis and virulence. Mol Microbiol,2007,64 (4):1014-1027.
[28]Nierman WC, Pain A, Anderson MJ,et al. Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature,2005,438 (7071):1151-1156.
[29]Comera C, Andre K, Laffitte J,et al. Gliotoxin from Aspergillus fumigatus affects pHagocytosis and the organization of the actin cytoskeleton by distinct signalling pathways in human neutropHils. Microbes Infect,9 (1):47-54.
[30]Sugui JA, Pardo J, Chang YC,et al. Gliotoxin is a virulence factor of Aspergillus fumigatus:gliP deletion attenuates virulence in mice immunosuppressed with hydrocortisone. Eukaryot Cell,2007,6 (9):1562-1569.
[31]Kwon-Chung KJ, Sugui JA. What do we know about the role of gliotoxin in the pathobiology of Aspergillus fumigatus? Med Mycol,2008,May 2:1-7.
[32]Lefkove B, Govindarajan B, Arbiser JL. Fumagillin:an anti-infective as a parent molecule for novel angiogenesis inhibitors. Expert Rev Anti Infect Ther,2007,_5 (4):573-579
[33]Stevanovic J, Stanimirovic Z, Radakovic M,et al. In vitro evaluation of the clastogenicity of fumagillin. Environ Mol Mutagen,2008,49 (8):594-601.
[34]Bunger J, WestpHal G, Monnich A,et al. Cytotoxicity of occupationally and environmentally relevant mycotoxins. Toxicology,2004,202 (3):199-211.
[35]Wu xF, Fei MJ, Shu RG,et al. Fumigaclavine C, an fungal metabolite, improves experimental colitis in mice via downregulating Thl cytokine production and matrix metalloproteinase activity. Int ImmunopHarmacol,2005,5 (10):1543-1553.
[36]Paris, S., D. Wysong, J. P. Debeaupuis, K. Shibuya, B. PHilippe, R. D.Diamond, and J. P. Latge. Catalases of Aspergillus fumigatus. Infect Immun,2003,71 (6):3551-3562.
[1]Filler SG, Sheppard DC. Fungal invasion of normally non-pHagocytic host cells, PLoS Pathog,2006,2 (12):e129.
[2]Sturtevant J, Latge JP. Participation of complement in the pHagocytosis of the conidia of Aspergillus fumigatus by human polymorpHonuclear cells. J Infect Dis,1992,166 (3):580-586.
[3]Ruchel R, Schaffrinski M. Versatile fluorescent staining of fungi in clinical specimens by using the optical brightener BlankopHor. J Clin Microbiol,1999,37 (8).2694-2696.
[4]Lopes-Bezerra, L.M., Filler, S.G.,. 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 (6):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 (1):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 (4):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 (4):2402-2406.
[9]Antachopoulos C, Roilides E. Cytokines and fungal infections. Br J Haematol,2005,129 (5):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 (42):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 (8):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 (45):16309-16314.
[13]Bellocchio S, Moretti S, Perruccio K, et al. TLRs govern neutropHil activity in aspergillosis. J Immunol,2004,173 (12) 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 (3):238-243.
[15]Bellocchio S, Montagnoli C, Bozza S, et al. The contribution of Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo. J Immunol,2004,172 (5):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 (3):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 (17):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 (9):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, (4):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.Cellular Microbiology,2007,9 (2):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 (3):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 (2):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 (6):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 (8):4938-4946.
[26]Bals R, Hiemstra PS. Innate immunity in the lung:how epithelial cells fight against respiratory pathogens. Eur Respir J,2004,23 (2):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 (45):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, Femenia F,et al. Inducible expression of beta defensins by human respiratory epithelial cells exposed to Aspergillus fumigatus organisms. BMC Microbiol,2009,9:33.
[30]Femenia 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 (5):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 (8):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 (1):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 (3):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 (11):10455-10461.
[1]National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2003, issued August 2003. Am J Infect Control,2003,31 (8):481-498.
[21窦懿,张勤,廖镇江.11年间烧伤病房铜绿假单胞菌耐药率调查.中华烧伤杂志,2004,20(1)：6-9.
[3]Stover CK, PHam×Q, Erwin AL,et al.Complete genome sequence of Pseudomonas aeruginosa PA01, an opportunistic pathogen. Nature,2000,406 (6799):959-964.
[4]Lambert PA. Mechanisms of antibiotic resistance in Pseudomonas aeruginosa. J R Soc Med,2002,95 Suppl 41:22-26.
[5]Hatch RA, Schiller NL. Alginate lyase promotes diffusion of aminoglycosides through the extracellular polysaccharide of mucoid Pseudomonas aeruginosa. Antimicrob Agents Chemother,1998,42 (4):974-977.
[6]Ciofu O, Fussing V, Bagge N,et al. Characterization of paired mucoid/non-mucoid Pseudomonas aeruginosa isolates from Danish cystic fibrosis patients:antibiotic resistance, b-lactamase activity and Riboprinting. J Antimicrob Chemother,2001,48 (3):391-396.
[7]Ernst RK, Yi EC, Guo L,et al.Specific Lipopolysaccharide Found in Cystic Fibrosis Airway Pseudomonas aeruginosa. Science,1999,286 (5444):1561-1565.
[8]Farra A, Islam S, Stralfors A, et al. Role of outer membrane protein OprD and penicillin-binding proteins in resistance of Pseudomonas aeruginosa to imipenem and meropenem.Int J Antimicrob Agents,2008,31 (5):427-433.
[9]Giske CG, Buarφ L, Sundsfjord A, et al. Alterations of porin, pumps, and penicillin-binding proteins in carbapenem resistant clinical isolates of Pseudomonas aeruginosa. Microb Drug Resist,2008,14 (1):23-30
[10]Vincent H. Tam, Kai-Tai Chang, Mark T. LaRocco, et al. Prevalence, mechanisms, and risk factors of carbapenem resistance in bloodstream isolates of Pseudomonas aeruginosa. Diagn Microbiol Infect Dis,2007,58 (3):309-314.
[11]Epp SF, Kohler T, Plesiat P, et al. C-Terminal Region of Pseudomonas aeruginosa Outer Membrane Porin OprD Modulates Susceptibility to Meropenem. Antimicrob Agents Chemother, 2001,45 (6):1780-1787.
[12]Walsh F, Amyes SG. Carbapenem resistance in clinical isolates of Pseudomonas aeruginosa. J Chemother,2007,19 (4):376-381.
[13]Young ML, Bains M, Bell A, et al. Role of Pseudomonas aeruginosa Outer Membrane Protein OprH in Polymyxin and Gentamicin Resistance:Isolation of an OprH-Deficient Mutant by Gene Replacement Techniques. Antimicrob Agents Chemother,1992,36 (11):2566-2568.
[14]Kwon DH, Lu CD. Polyamines induce resistance to cationic peptide, aminoglycoside, and quinolone antibiotics in Pseudomonas aeruginosa PAO1.Antimicrob Agents Chemother,2006, 50 (5):1615-1622.
[15]Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa:our worst nightmare? Clin Infect Dis,2002,34 (5):634-640.
[16]Bonomo RA, Szabo D. Mechanisms of Multidrug Resistance in Acinetobacter Species and Pseudomonas aeruginosa. Clin Infect Dis,2006,43 Suppl 2:S49-56.
[17]Hocquet D, Roussel-Delvallez M, Cavallo JD.et al. Me×AB-OprM- and MexxY-overproducing mutants are very prevalent among clinical strains of Pseudomonas aeruginosa with reduced susceptibility to ticarcillin. Antimicrob. Agents Chemother,2007,51 (4):1582-1583.
[18]Kohler T, Michea-Hamzehpour M, Epp SF, et al. Carbapenem activities against Pseudomonas aeruginosa:respective contributions of OprD and efflux systems. Antimicrob Agents Chemother,1999,43 (2).424-427.
[19]Masuda N, Sakagawa E.Ohya S, et al. Substrate specificities of Me×AB-OprM, Me×CD-OprJ, and Me××YOprM efflu× pumps in Pseudomonas aeruginosa. Antimicrob Agents Chemother,2000,44 (12):3322-3327.
[20]Bush K, Jacoby GA, Medeiros AA. A functional classification scheme for beta lactamases and its correlation with molecular structure. Antimicrob Agents Chemother,1995, 39 (6):1211-1233.
[21]Bush K. New beta-lactamases in gram-negative bacteria:diversity and impact on the selection of antimicrobial therapy. Clin Infect Dis,2001,1;32 (7):1085-1089.
[22]Mugnier P, Dubrous P, Casin I, et al. A TEM-derived extended-spectrum beta-lactamase in Pseudomonas aeruginosa. Antimicrob Agents Chemother,1996,40 (11):2488-2493.
[23]Girlich D, Naas T, Nordmann P. Biochemical characterization of the naturally occurring oxacillinase OxA-50 of Pseudomonas aeruginosa. Antimicrob Agents Chemother,2004,48 (6):2043-2048.
[24]Bonfiglio G, Russo G, Nicoletti G. Recent developments in carbapenems.Expert Opin Investig Drugs,2002,11 (4):529-544.
[25]胡波,宋勇,张方,等.铜绿假单胞菌ampC基因分布和产酶状况对药物敏感性的影响.医学研究生学报,2008,21(1)：11-15.
[26]Lister PD, Gardner VM, Sanders CC. Clavulanate induces expression of the Pseudomonas aeruginosa AmpC cepHalosporinase at pHysiologically relevant concentrations and antagonizes the antibacterial activity of ticarcillin.Antimicrob Agents Chemother.1999 Apr;43 (4):882-889.
[27]Walsh TR, Toleman MA, Poirel L, et al. Metallo-β-Lactamases:the quiet before the storm?[J]. Clin Microbiol Rev,2005,18 (2):306-325.
[28]Varaiya A, Kulkarni M, Bhalekar P,et al. Incidence of metallo beta lactamase producing Pseudomonas aeruginosa in ICU patients. Indian J Pathol Microbiol,2008,51 (2):200-203.
[291王卫萍,邵海枫,韩丽丽,等.铜绿假单胞菌对亚胺培南耐药机制的研究.医学研究生学报,2006,19(11)：970-972.
[30]Azucena E, Mobashery S. Aminoglycoside-modifying enzymes:mechanisms of catalytic processes and inhibition. Drug Resist Updat,2001,4 (2):106-117.
[31]Liao x, Hancock RE. Susceptibility to beta-lactam antibiotics of Pseudomonas aeruginosa overproducing penicillin-binding protein 3. Antimicrob Agents Chemother,1997,41 (5):1158-1161.
[32]Akasaka T, Tanaka M, Yamaguchi A,et al. Type Ⅱ topoisomerase mutations in fluoroquinolone-resistant clinical strains of Pseudomonas aeruginosa isolated in 1998 and 1999:role of target enzyme in mechanism of fluoroquinolone resistance. Antimicrob Agents Chemother,2001,45 (8):2263-2268.
[331王洁,邵海枫.肠杆菌科质粒介导喹诺酮类抗菌药耐药的研究.医学研究生学报,2008,21(1)：91-94.
1.Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, et al. Treatment of aspergillosis:clinical practice guidelines of the Infectious Diseases Society of America (IDSA). Clin Infect Dis 2008;46 (3):327-360
2.Patterson TF, Kirkpatrick WR, White M, et al. Invasive aspergillosis:disease spectrum, treatment practices, and outcomes.13 Aspergillus Study Group. Medicine 2000;79:250-260
3. Anaissie EJ, Stratton SL, Dignani MC, et al. Pathogenic Aspergillus species recovered from a hospital water system:a 3-year prospective study. Clin Infect Dis 2002;34:780-789
4. Warns A, Voss A, Abrahamsen TG, Verweij PE. Contamination of hospital water with Aspergillus fumigatus and other molds. Clin Infect Dis 2002;34:1159-1160
5. Torres HA, Rivero GA, Lewis RE, et al. Aspergillosis caused by non-fumigatus Aspergillus species:risk factors and in vitro susceptibility compared with Aspergillus fumigatus. Diagn Microbiol Infect Dis 2003;46:25-28
6. Patterson JE, Peters J, Calhoon JH, et al. Investigation and control of aspergillosis and other filamentous fungal infections in solid organ transplant recipients. Transpl Infect Dis 2000;2:22-28
7. Paterson DL, Singh N. Invasive aspergillosis in transplant recipients. Medicine 1999;78:123-138
8. Warris A, Bjorneklett A, Gaustad P. Invasive pulmonary aspergillosis associated with infliximab therapy. N Engl J Med 2001;344:1099-1100
9. Cohen MS, Isturiz RE, Malech HL, et al. Fungal infection in chronic granulomatous disease:the importance of the pHagocyte in defense against fungi. Am J Med 1981,71:59-66
10. Denning DW. Aspergillosis in "nonimmunocompromised" critically ill patients. Am J Respir Crit Care Med 2004;170:580-581
11. Gerson SL, Talbot GH, Hurwitz S, et al. Prolonged granulocytopenia:the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann Intern Med 1984;100:345-351
12. Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 1997; 175:1459-1466
13. Denning DW. Invasive aspergillosis. Clin Infect Dis 1998; 26:781-803
14. Greene R. The radiological spectrum of pulmonary aspergillosis. Med Mycol 2005;43 (Suppl 1):S147-S154
15. Denning DW, Follansbee SE, Scolaro M, et al. Pulmonary aspergillosis in the acquired immunodeficiency syndrome. N Engl J Med 1991;324:654-662
16. Kramer MR, Denning DW, Marshall SE, et al. Ulcerative tracheobronchitis after lung transplantation:a new form of invasive aspergillosis. Am Rev Respir Dis 1991; 144 (3 Pt 1):552-556
17. Binder RE, Faling LJ, Pugatch RD, Mahasaen C, Snider GL. Chronic necrotizing pulmonary aspergillosis:a discrete clinical entity. Medicine 1982;61:109-124
18. Gefter WB, Weingrad TR, Epstein DM, Ochs RH, Miller WT. "Semi-invasive" pulmonary aspergillosis:a new look at the spectrum of aspergillus infections of the lung. Radiology 1981;140:313-321
19. Hope WW, Walsh TJ, Denning DW. The invasive and sapropHytic syndromes due to Aspergillus spp. Med Mycol 2005;43 (Suppl 1):S207-S238
20. Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic cavitary and fibrosing pulmonary and pleural aspergillosis:case series, proposed nomenclature change, and review. Clin Infect Dis 2003;37 (Suppl 3):S265-S280
21. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate:systematic review of the literature. Clin Infect Dis 2001;32:358-366
22. Greenberger PA. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 2002; 110:685-692
23. Stevens DA, Schwartz HJ, Lee JY, et al. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med 2000;342:756-762
24. Munoz P, Alcala L, Sanchez Conde M, et al. The isolation of Aspergillus fumigatus from respiratory tract specimens in heart transplant recipients is highly predictive of invasive aspergillosis. Transplantation 2003;75:326-329
25. Horvath JA, Dummer S. The use of respiratory-tract cultures in the diagnosis of invasive pulmonary aspergillosis. Am J Med 1996;100:171-178
26. Herbrecht R, Letscher-Bru V, Oprea C, et al. Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients. J Clin Oncol 2002;20:1898-1906
27. Maertens J, Verhaegen J, Lagrou K, Van Eldere J, Boogaerts M. Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients:a prospective validation. Blood 2001;97:1604-1610
28. Verweij PE, Mennink-Kersten MA. Issues with galactomannan testing. Med Mycol 2006;44 (Suppl):179-183
29. Odabasi Z, Mattiuzzi G, Estey E, et al. Beta-D-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis 2004;39:199-205
30. Donnelly JP. Polymerase chain reaction for diagnosing invasive aspergillosis:getting closer but still a ways to go.Clin Infect Dis 2006;42:487-489
31. Bates DW, Su L, Yu DT, et al. Mortality and costs of acute renal failure associated with ampHotericin B therapy. Clin Infect Dis 2001;32:686-693
32. Comely OA, Maertens J, Bresnik M, et al. Liposomal ampHotericin B as initial therapy for invasive mold infection:a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis 2007; 44:1289-1297
33. Eiden C, Peyriere H, Cociglio M, et al. Adverse effects of voriconazole:analysis of the French PHarmacovigilance Database. Ann PHarmacother 2007;41:755-763
34. Steinbach WJ, Stevens DA. Review of newer antifungal and immunomodulatory strategies for invasive aspergillosis. Clin Infect Dis 2003;37 (Suppl 3):S157-S187
35. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus ampHotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408-415
36. De Beule K, Van Gestel J. PHarmacology of itraconazole. Drugs 2001;61 (Suppl 1):27-37
37. Courtney R, Wexler D, Radwanski E, Lim J, Laughlin M. Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults. Br J Clin PHarmacol 2004;57:218-222
38. Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for propHylaxis in severe graft-versus-host disease. N Engl J Med 2007;356:335-347
39. Comely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole propHylaxis in patients with neutropenia. N Engl J Med 2007;356:348-359
40. Bennett JE. Echinocandins for candidemia in adults without neutropenia. N Engl J Med 2006;355:1154- 1159
41. Marr KA, Boeckh M, Carter RA, Kim HW, Corey L. Combination antifungal therapy for invasive aspergillosis.Clin Infect Dis 2004;39:797-802
2.邹先彪.肺部真菌感染概述//赵蓓蕾,施毅,桑红.现代肺部真菌病学.北京：人民军医出版社,2004：18-21.
3. Thompson GR 3rd, Patterson TF. Pulmonary aspergillosis. Semin Respir Crit Care Med,2008,29 (2):103-110.
4. Patterson TF, Kirkpatrick WR, White M, et al. Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes.13 Aspergillus Study Group.Medicine, 2000,79 (4):250-260.
5. Lopes Bezerra LM, Filler SG. Interactions of Aspergillus fumigatus with endothelial cells:internalization, injury, and stimulation of tissue factor activity. Blood,2004,103 (6):2143-2149.
6. Filler SG, Sheppard DC. Fungal invasion of normally non-pHagocytic host cells. PLoS Pathog,2006,2 (12):el29,1099-1105.
7. Bellocchio S, Moretti S, Perruccio K, et al. TLRs govern neutropHil activity in aspergillosis. J Immunol,2004,173 (12):7406-7415.
8. 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 (3):238-243.
9. Bellocchio S, Montagnoli C, Bozza S, et al. The contribution of Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo. J Immunol,2004,172 (5):3059-3069.
10. Bretz C, Gersuk G, Knoblaugh S, et al. MyD88 signaling contributes to early pulmonary responses to Aspergillus fumigatus. Infect Immun,2008,76 (3):952-958.
11. 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 (17):1766-1777.
12. Balloy V, Si-Tahar M, Takeuchi O, et al. Involvement of toll-like receptor 2 in experimental invasive pulmonary aspergillosis. Infect Immun,2005,73 (9):5420-5425.
13. Hohl TM. Stage-specific innate immune recognition of Aspergillus fumigatus and modulation by echinocandin drugs. Med Mycol,2008, Apr 23:1-7.
14. Steele C, Rapaka RR, Metz A,et al. The beta-glucan receptor dectin-1 recognizes specific morpHologies of Aspergillus fumigatus. PLoS Pathog,2005, (4):e42.
15. da Silva Tatley F, Aldwell FE, Dunbier AK, et al. N-terminal E-cadherin peptides act as decoy receptors for Listeria monocytogenes. Infect Immun,2003,71 (3):1580-1583.
16. Anderton JM, Rajam G, Romero-Steiner S, et al. E-cadherin is a receptor for the common protein pneumococcal surface adhesin A (PsaA) of Streptococcus pneumoniae. Microb Pathog,2007,42 (5-6):225-236.
17. PHan QT, Fratti RA, Prasadarao NV,et al. N-cadherin mediates endocytosis of Candida albicans by endothelial cells. J Biol Chem,2005,280 (11):10455-10461.
18. 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(3):e64.
19. Angst BD, Marcozzi C, Magee AI. The cadherin superfamily:diversity in form and function. J Cell Sci,2001,114:629-641.
20. Halbleib JM, Nelson WJ. Cadherins in development:cell adhesion, sorting, and tissue morpHogenesis. Genes Dev,2006,20:3199-3214.
21. Weis WI, Nelson WJ. Re-solving the cadherin-catenin-actin conundrum. J Biol Chem, 2006,281 (47):35593-35597.
22. Schubert WD, Urbanke C, Ziehm T, et al. Structure of internalin, a major invasion protein of Listeria monocytogenes, in complex with its human receptor E-cadherin. Cell,2002,111 (6):825-836.
23. Nierman WC, Pain A, Anderson MJ, et al. Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature,2005,438 (7071):1151-1156.
24. Isberg RR, Leong JM. Multiple beta 1 chain integrins are receptors for invasin, a protein that promotes bacterial penetration into mammalian cells. Cell,1990,60 (5):861-871.
25. Carayol N, Vachier I, Campbell A, et al. Regulation of E-cadherin expression by dexamethasone and tumour necrosis factor-alpHa in nasal epithelium. Eur Respir J, 2002,20 (6):1430-1436.
26. Blecharz KG, Drenckhahn D, Forster CY. Glucocorticoids increase VE-cadherin expression and cause cytoskeletal rearrangements in murine brain endothelial cEND cells. J Cereb Blood Flow Metab,2008,28 (6):1139-1149.
27. 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 (6):3156-3163.
28. Sturtevant J, Latge JP. Participation of complement in the pHagocytosis of the conidia of Aspergillus fumigatus by human polymorpHonuclear cells. J Infect Dis,1992,166 (3):580-586.
29. Ruchel R, Schaffrinski M. Versatile fluorescent staining of fungi in clinical specimens by using the optical brightener BlankopHor. J Clin Microbiol,1999,37 (8):2694-2696.
30. Meersseman W, Lagrou K, Maertens J, et al. Invasive aspergillosis in the intensive care unit.Clin Infect Dis,2007,45 (2):205-216.
31. Meersseman W, Vandecasteele SJ, Wilmer A, et alInvasive aspergillosis in critically ill patients without malignancy. Am J Respir Crit Care Med,2004,170 (6):621-625
32. Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary aspergillosis Chest,2002,121 (6):1988-1999
33. Lo HJ, Kohler JR, DiDomenico B,et al. Nonfilamentous C. albicans mutants are avirulent. Cell,1997,90 (5):939-949.
34. Fortwendel JR, Zhao W, Bhabhra R,et al. A fungus-specific ras homolog contributes to the hypHal growth and virulence of Aspergillus fumigatus. Eukaryot Cell,2005,4 (12):1982-1989
35. 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 (8):4938-4946.
36. Hohl TM. Stage-specific innate immune recognition of Aspergillus fumigatus and modulation by echinocandin drugs. Med Mycol,2008,1:1-7.
37. Dennehy KM;Brown GD. The role of the beta-glucan receptor Dectin-1 in control of fungal infection. J Leukoc Biol,2007,82 (2):253-258.
38. Goodridge HS, Wolf AJ, Underhill DM. Beta-glucan recognition by the innate immune system. Immunol Rev,2009,230, (1):38-50.
39. Avadhanula V, Rodriguez CA, Ulett GC, et al. Nontypeable HaemopHilus influenzae adheres to intercellular adhesion molecule 1 (ICAM-1) on respiratory epithelial cells and upregulates ICAM-1 expression. Infect Immun 2006;74:830-838.
40. Kamai Y, Lossinsky AS, Liu H, et al. Polarized response of endothelial cells to invasion by Aspergillus fumigatus. Cell Microbiol,2009,11 (1):170-182.
41. Dagenais TR, Keller NP. Pathogenesis of Aspergillus fumigatus in Invasive Aspergillosis. Clin Microbiol Rev,2009,22 (3):447-465.
42. Lai CC, Liaw SJ, Lee I N,et al. Invasive pulmonary apergillosis:hish incidence of disseminated intmvascular coagulation in fatal cases. J Microbiol lmmunol Infect, 2007,40:141-147.
43. Sturtevant J, Latge JP:Participation of complement in the pHagocytosis of the conidia of Aspergillus fumigatus by human polymorpHonuclear cells. J Infect Dis 1992, 166:580-586.
[1]邹先彪.肺部真菌感染概述//赵蓓蕾,施毅,桑红.现代肺部真菌病学.北京：人民军医出版社,2004：18-21.
[2]Meersseman W, Lagrou K, Maertens J, et al. Invasive aspergillosis in the intensive care unit.Clin Infect Dis,2007,45 (2):205-216.
[3]Meersseman W, Vandecasteele SJ, Wilmer A, et alInvasive aspergillosis in critically ill patients without malignancy. Am J Respir Crit Care Med,2004,_170 (6):621-625
[4]Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary aspergillosis Chest,2002,121 (6):1988-1999.
[5]Thompson GR 3rd, Patterson TF. Pulmonary aspergillosis. Semin Respir Crit Care Med, 2008,29 (2)::103-110.
[6]Patterson TF, Kirkpatrick WR, White M,et al. Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes.13'Aspergillus Study Group.Medicine,2000,79 (4):250-260.
[7]Sanchez AA, Johnston DA, Myers C, Edwards JE Jr., Mitchell AP, et al. Relationship between Candida albicans virulence during experimental hematogenously disseminated Infection and endothelial cell damage in vitro. Infect Immun,2004,72 (1):598-601.
[8]Lopes Bezerra LM, Filler SG Interactions of Aspergillus fumigatus with endothelial cells:internalization, injury, and stimulation of tissue factor activity. Blood,2004,103 (6):2143-2149.
[9]Paris S, Boisvieux-Ulrich E, Crestani B,et al. Internalization of Aspergillus fumigatus conidia by epithelial and endothelial cells. Infect Immun,1997,_65 (4):1510-1514.
[10]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 (6):3156-3163.
[11]Bromley IM, Donaldson K. Binding of Aspergillus fumigatus spores to lung epithelial cells and basement membrane proteins:relevance to the asthmatic lung.Thorax,1996,51 (12):1203-1209.
[12]Warwas, M. L., J. N. Watson, A. J. Bennet, and M. M. Moore. Structure and role of sialic acids on the surface of Aspergillus fumigatus conidiospores. Glycobiology,2007,17 (4):401-410.
[13]Tronchin G, Esnault K, Renier G,et al. Expression and identification of a laminin-binding protein in Aspergillus fumigatus conidia. Infect Immun,1997,_65 (1):9-15.
[14]Zhang Z, Liu R, Noordhoek JA,et al. Interaction of airway epithelial cells (A549) with spores and mycelium of Aspergillus fumigatus. J Infect,2005,51 (5):375-382.
[15]Blander JM, Medzhitov R. Regulation of pHagosome maturation by signals from toll-like receptors. Science,2004,304 (5673):1014-1018
[16]韩黎,纪蕾,王菡,等.Toll样受体在烟曲霉侵染宿主细胞过程中作用的研究进展.微生物学通报,2007,34：973-975.
[17]Lo HJ, Kohler JR, DiDomenico B,et al. Nonfilamentous C. albicans mutants are avirulent. Cell,1997,90 (5):939-949.
[18]Fortwendel JR, Zhao W, Bhabhra R,et al. A fungus-specific ras homolog contributes to the hypHal growth and virulence of Aspergillus fumigatus. Eukaryot Cell,2005,4 (12):1982-1989.
[19]Shaukat A, Bakri F, Young P, et al. Invasive filamentous fungal infections in allogeneic hematopoietic stem cell transplant recipients after recovery from neutropenia: Clinical, radiologic, and pathologic characteristics.Mycopathologia,2005,159 (2):181-188.
[20]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 (8):3429-3438.
[21]Filler SG, Sheppard DC. Fungal invasion of normally non-pHagocytic host cells. PLoS Pathog,2006,2 (12):e129,1099-1105.
[22]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 (3):e64,543-557.
[23]PHan QT, Fratti RA, Prasadarao NV,et al. N-cadherin mediates endocytosis of Candida albicans by endothelial cells. J Biol Chem,2005,280 (11):10455-10461.
[24]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 (2):141-150.
[25]Paris S, Debeaupuis JP, Crameri R,et al. Conidial hydropHobins of Aspergillus fumigatus. Appl Environ Microbiol,2003,69 (3):1581-1588.
[26]Brakhage, A. A, and B. Liebmann. Aspergillus fumigatus conidial pigment and cAMP signal transduction:significance for virulence. Med Mycol,43 Suppl 1:S75-82.
[27]Li, H., H. Zhou, Y. Luo, et al. GlycosylpHospHatidylinositol (GPI) anchor is required in Aspergillus fumigatus for morpHogenesis and virulence. Mol Microbiol,2007,64 (4):1014-1027.
[28]Nierman WC, Pain A, Anderson MJ,et al. Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature,2005,438 (7071):1151-1156.
[29]Comera C, Andre K, Laffitte J,et al. Gliotoxin from Aspergillus fumigatus affects pHagocytosis and the organization of the actin cytoskeleton by distinct signalling pathways in human neutropHils. Microbes Infect,9 (1):47-54.
[30]Sugui JA, Pardo J, Chang YC,et al. Gliotoxin is a virulence factor of Aspergillus fumigatus:gliP deletion attenuates virulence in mice immunosuppressed with hydrocortisone. Eukaryot Cell,2007,6 (9):1562-1569.
[31]Kwon-Chung KJ, Sugui JA. What do we know about the role of gliotoxin in the pathobiology of Aspergillus fumigatus? Med Mycol,2008,May 2:1-7.
[32]Lefkove B, Govindarajan B, Arbiser JL. Fumagillin:an anti-infective as a parent molecule for novel angiogenesis inhibitors. Expert Rev Anti Infect Ther,2007,_5 (4):573-579
[33]Stevanovic J, Stanimirovic Z, Radakovic M,et al. In vitro evaluation of the clastogenicity of fumagillin. Environ Mol Mutagen,2008,49 (8):594-601.
[34]Bunger J, WestpHal G, Monnich A,et al. Cytotoxicity of occupationally and environmentally relevant mycotoxins. Toxicology,2004,202 (3):199-211.
[35]Wu xF, Fei MJ, Shu RG,et al. Fumigaclavine C, an fungal metabolite, improves experimental colitis in mice via downregulating Thl cytokine production and matrix metalloproteinase activity. Int ImmunopHarmacol,2005,5 (10):1543-1553.
[36]Paris, S., D. Wysong, J. P. Debeaupuis, K. Shibuya, B. PHilippe, R. D.Diamond, and J. P. Latge. Catalases of Aspergillus fumigatus. Infect Immun,2003,71 (6):3551-3562.
[1]Filler SG, Sheppard DC. Fungal invasion of normally non-pHagocytic host cells, PLoS Pathog,2006,2 (12):e129.
[2]Sturtevant J, Latge JP. Participation of complement in the pHagocytosis of the conidia of Aspergillus fumigatus by human polymorpHonuclear cells. J Infect Dis,1992,166 (3):580-586.
[3]Ruchel R, Schaffrinski M. Versatile fluorescent staining of fungi in clinical specimens by using the optical brightener BlankopHor. J Clin Microbiol,1999,37 (8).2694-2696.
[4]Lopes-Bezerra, L.M., Filler, S.G.,. 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 (6):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 (1):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 (4):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 (4):2402-2406.
[9]Antachopoulos C, Roilides E. Cytokines and fungal infections. Br J Haematol,2005,129 (5):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 (42):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 (8):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 (45):16309-16314.
[13]Bellocchio S, Moretti S, Perruccio K, et al. TLRs govern neutropHil activity in aspergillosis. J Immunol,2004,173 (12) 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 (3):238-243.
[15]Bellocchio S, Montagnoli C, Bozza S, et al. The contribution of Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo. J Immunol,2004,172 (5):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 (3):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 (17):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 (9):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, (4):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.Cellular Microbiology,2007,9 (2):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 (3):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 (2):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 (6):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 (8):4938-4946.
[26]Bals R, Hiemstra PS. Innate immunity in the lung:how epithelial cells fight against respiratory pathogens. Eur Respir J,2004,23 (2):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 (45):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, Femenia F,et al. Inducible expression of beta defensins by human respiratory epithelial cells exposed to Aspergillus fumigatus organisms. BMC Microbiol,2009,9:33.
[30]Femenia 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 (5):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 (8):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 (1):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 (3):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 (11):10455-10461.
[1]National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2003, issued August 2003. Am J Infect Control,2003,31 (8):481-498.
[21窦懿,张勤,廖镇江.11年间烧伤病房铜绿假单胞菌耐药率调查.中华烧伤杂志,2004,20(1)：6-9.
[3]Stover CK, PHam×Q, Erwin AL,et al.Complete genome sequence of Pseudomonas aeruginosa PA01, an opportunistic pathogen. Nature,2000,406 (6799):959-964.
[4]Lambert PA. Mechanisms of antibiotic resistance in Pseudomonas aeruginosa. J R Soc Med,2002,95 Suppl 41:22-26.
[5]Hatch RA, Schiller NL. Alginate lyase promotes diffusion of aminoglycosides through the extracellular polysaccharide of mucoid Pseudomonas aeruginosa. Antimicrob Agents Chemother,1998,42 (4):974-977.
[6]Ciofu O, Fussing V, Bagge N,et al. Characterization of paired mucoid/non-mucoid Pseudomonas aeruginosa isolates from Danish cystic fibrosis patients:antibiotic resistance, b-lactamase activity and Riboprinting. J Antimicrob Chemother,2001,48 (3):391-396.
[7]Ernst RK, Yi EC, Guo L,et al.Specific Lipopolysaccharide Found in Cystic Fibrosis Airway Pseudomonas aeruginosa. Science,1999,286 (5444):1561-1565.
[8]Farra A, Islam S, Stralfors A, et al. Role of outer membrane protein OprD and penicillin-binding proteins in resistance of Pseudomonas aeruginosa to imipenem and meropenem.Int J Antimicrob Agents,2008,31 (5):427-433.
[9]Giske CG, Buarφ L, Sundsfjord A, et al. Alterations of porin, pumps, and penicillin-binding proteins in carbapenem resistant clinical isolates of Pseudomonas aeruginosa. Microb Drug Resist,2008,14 (1):23-30
[10]Vincent H. Tam, Kai-Tai Chang, Mark T. LaRocco, et al. Prevalence, mechanisms, and risk factors of carbapenem resistance in bloodstream isolates of Pseudomonas aeruginosa. Diagn Microbiol Infect Dis,2007,58 (3):309-314.
[11]Epp SF, Kohler T, Plesiat P, et al. C-Terminal Region of Pseudomonas aeruginosa Outer Membrane Porin OprD Modulates Susceptibility to Meropenem. Antimicrob Agents Chemother, 2001,45 (6):1780-1787.
[12]Walsh F, Amyes SG. Carbapenem resistance in clinical isolates of Pseudomonas aeruginosa. J Chemother,2007,19 (4):376-381.
[13]Young ML, Bains M, Bell A, et al. Role of Pseudomonas aeruginosa Outer Membrane Protein OprH in Polymyxin and Gentamicin Resistance:Isolation of an OprH-Deficient Mutant by Gene Replacement Techniques. Antimicrob Agents Chemother,1992,36 (11):2566-2568.
[14]Kwon DH, Lu CD. Polyamines induce resistance to cationic peptide, aminoglycoside, and quinolone antibiotics in Pseudomonas aeruginosa PAO1.Antimicrob Agents Chemother,2006, 50 (5):1615-1622.
[15]Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa:our worst nightmare? Clin Infect Dis,2002,34 (5):634-640.
[16]Bonomo RA, Szabo D. Mechanisms of Multidrug Resistance in Acinetobacter Species and Pseudomonas aeruginosa. Clin Infect Dis,2006,43 Suppl 2:S49-56.
[17]Hocquet D, Roussel-Delvallez M, Cavallo JD.et al. Me×AB-OprM- and MexxY-overproducing mutants are very prevalent among clinical strains of Pseudomonas aeruginosa with reduced susceptibility to ticarcillin. Antimicrob. Agents Chemother,2007,51 (4):1582-1583.
[18]Kohler T, Michea-Hamzehpour M, Epp SF, et al. Carbapenem activities against Pseudomonas aeruginosa:respective contributions of OprD and efflux systems. Antimicrob Agents Chemother,1999,43 (2).424-427.
[19]Masuda N, Sakagawa E.Ohya S, et al. Substrate specificities of Me×AB-OprM, Me×CD-OprJ, and Me××YOprM efflu× pumps in Pseudomonas aeruginosa. Antimicrob Agents Chemother,2000,44 (12):3322-3327.
[20]Bush K, Jacoby GA, Medeiros AA. A functional classification scheme for beta lactamases and its correlation with molecular structure. Antimicrob Agents Chemother,1995, 39 (6):1211-1233.
[21]Bush K. New beta-lactamases in gram-negative bacteria:diversity and impact on the selection of antimicrobial therapy. Clin Infect Dis,2001,1;32 (7):1085-1089.
[22]Mugnier P, Dubrous P, Casin I, et al. A TEM-derived extended-spectrum beta-lactamase in Pseudomonas aeruginosa. Antimicrob Agents Chemother,1996,40 (11):2488-2493.
[23]Girlich D, Naas T, Nordmann P. Biochemical characterization of the naturally occurring oxacillinase OxA-50 of Pseudomonas aeruginosa. Antimicrob Agents Chemother,2004,48 (6):2043-2048.
[24]Bonfiglio G, Russo G, Nicoletti G. Recent developments in carbapenems.Expert Opin Investig Drugs,2002,11 (4):529-544.
[25]胡波,宋勇,张方,等.铜绿假单胞菌ampC基因分布和产酶状况对药物敏感性的影响.医学研究生学报,2008,21(1)：11-15.
[26]Lister PD, Gardner VM, Sanders CC. Clavulanate induces expression of the Pseudomonas aeruginosa AmpC cepHalosporinase at pHysiologically relevant concentrations and antagonizes the antibacterial activity of ticarcillin.Antimicrob Agents Chemother.1999 Apr;43 (4):882-889.
[27]Walsh TR, Toleman MA, Poirel L, et al. Metallo-β-Lactamases:the quiet before the storm?[J]. Clin Microbiol Rev,2005,18 (2):306-325.
[28]Varaiya A, Kulkarni M, Bhalekar P,et al. Incidence of metallo beta lactamase producing Pseudomonas aeruginosa in ICU patients. Indian J Pathol Microbiol,2008,51 (2):200-203.
[291王卫萍,邵海枫,韩丽丽,等.铜绿假单胞菌对亚胺培南耐药机制的研究.医学研究生学报,2006,19(11)：970-972.
[30]Azucena E, Mobashery S. Aminoglycoside-modifying enzymes:mechanisms of catalytic processes and inhibition. Drug Resist Updat,2001,4 (2):106-117.
[31]Liao x, Hancock RE. Susceptibility to beta-lactam antibiotics of Pseudomonas aeruginosa overproducing penicillin-binding protein 3. Antimicrob Agents Chemother,1997,41 (5):1158-1161.
[32]Akasaka T, Tanaka M, Yamaguchi A,et al. Type Ⅱ topoisomerase mutations in fluoroquinolone-resistant clinical strains of Pseudomonas aeruginosa isolated in 1998 and 1999:role of target enzyme in mechanism of fluoroquinolone resistance. Antimicrob Agents Chemother,2001,45 (8):2263-2268.
[331王洁,邵海枫.肠杆菌科质粒介导喹诺酮类抗菌药耐药的研究.医学研究生学报,2008,21(1)：91-94.
1.Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, et al. Treatment of aspergillosis:clinical practice guidelines of the Infectious Diseases Society of America (IDSA). Clin Infect Dis 2008;46 (3):327-360
2.Patterson TF, Kirkpatrick WR, White M, et al. Invasive aspergillosis:disease spectrum, treatment practices, and outcomes.13 Aspergillus Study Group. Medicine 2000;79:250-260
3. Anaissie EJ, Stratton SL, Dignani MC, et al. Pathogenic Aspergillus species recovered from a hospital water system:a 3-year prospective study. Clin Infect Dis 2002;34:780-789
4. Warns A, Voss A, Abrahamsen TG, Verweij PE. Contamination of hospital water with Aspergillus fumigatus and other molds. Clin Infect Dis 2002;34:1159-1160
5. Torres HA, Rivero GA, Lewis RE, et al. Aspergillosis caused by non-fumigatus Aspergillus species:risk factors and in vitro susceptibility compared with Aspergillus fumigatus. Diagn Microbiol Infect Dis 2003;46:25-28
6. Patterson JE, Peters J, Calhoon JH, et al. Investigation and control of aspergillosis and other filamentous fungal infections in solid organ transplant recipients. Transpl Infect Dis 2000;2:22-28
7. Paterson DL, Singh N. Invasive aspergillosis in transplant recipients. Medicine 1999;78:123-138
8. Warris A, Bjorneklett A, Gaustad P. Invasive pulmonary aspergillosis associated with infliximab therapy. N Engl J Med 2001;344:1099-1100
9. Cohen MS, Isturiz RE, Malech HL, et al. Fungal infection in chronic granulomatous disease:the importance of the pHagocyte in defense against fungi. Am J Med 1981,71:59-66
10. Denning DW. Aspergillosis in "nonimmunocompromised" critically ill patients. Am J Respir Crit Care Med 2004;170:580-581
11. Gerson SL, Talbot GH, Hurwitz S, et al. Prolonged granulocytopenia:the major risk factor for invasive pulmonary aspergillosis in patients with acute leukemia. Ann Intern Med 1984;100:345-351
12. Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 1997; 175:1459-1466
13. Denning DW. Invasive aspergillosis. Clin Infect Dis 1998; 26:781-803
14. Greene R. The radiological spectrum of pulmonary aspergillosis. Med Mycol 2005;43 (Suppl 1):S147-S154
15. Denning DW, Follansbee SE, Scolaro M, et al. Pulmonary aspergillosis in the acquired immunodeficiency syndrome. N Engl J Med 1991;324:654-662
16. Kramer MR, Denning DW, Marshall SE, et al. Ulcerative tracheobronchitis after lung transplantation:a new form of invasive aspergillosis. Am Rev Respir Dis 1991; 144 (3 Pt 1):552-556
17. Binder RE, Faling LJ, Pugatch RD, Mahasaen C, Snider GL. Chronic necrotizing pulmonary aspergillosis:a discrete clinical entity. Medicine 1982;61:109-124
18. Gefter WB, Weingrad TR, Epstein DM, Ochs RH, Miller WT. "Semi-invasive" pulmonary aspergillosis:a new look at the spectrum of aspergillus infections of the lung. Radiology 1981;140:313-321
19. Hope WW, Walsh TJ, Denning DW. The invasive and sapropHytic syndromes due to Aspergillus spp. Med Mycol 2005;43 (Suppl 1):S207-S238
20. Denning DW, Riniotis K, Dobrashian R, Sambatakou H. Chronic cavitary and fibrosing pulmonary and pleural aspergillosis:case series, proposed nomenclature change, and review. Clin Infect Dis 2003;37 (Suppl 3):S265-S280
21. Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate:systematic review of the literature. Clin Infect Dis 2001;32:358-366
22. Greenberger PA. Allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 2002; 110:685-692
23. Stevens DA, Schwartz HJ, Lee JY, et al. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med 2000;342:756-762
24. Munoz P, Alcala L, Sanchez Conde M, et al. The isolation of Aspergillus fumigatus from respiratory tract specimens in heart transplant recipients is highly predictive of invasive aspergillosis. Transplantation 2003;75:326-329
25. Horvath JA, Dummer S. The use of respiratory-tract cultures in the diagnosis of invasive pulmonary aspergillosis. Am J Med 1996;100:171-178
26. Herbrecht R, Letscher-Bru V, Oprea C, et al. Aspergillus galactomannan detection in the diagnosis of invasive aspergillosis in cancer patients. J Clin Oncol 2002;20:1898-1906
27. Maertens J, Verhaegen J, Lagrou K, Van Eldere J, Boogaerts M. Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients:a prospective validation. Blood 2001;97:1604-1610
28. Verweij PE, Mennink-Kersten MA. Issues with galactomannan testing. Med Mycol 2006;44 (Suppl):179-183
29. Odabasi Z, Mattiuzzi G, Estey E, et al. Beta-D-glucan as a diagnostic adjunct for invasive fungal infections: validation, cutoff development, and performance in patients with acute myelogenous leukemia and myelodysplastic syndrome. Clin Infect Dis 2004;39:199-205
30. Donnelly JP. Polymerase chain reaction for diagnosing invasive aspergillosis:getting closer but still a ways to go.Clin Infect Dis 2006;42:487-489
31. Bates DW, Su L, Yu DT, et al. Mortality and costs of acute renal failure associated with ampHotericin B therapy. Clin Infect Dis 2001;32:686-693
32. Comely OA, Maertens J, Bresnik M, et al. Liposomal ampHotericin B as initial therapy for invasive mold infection:a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis 2007; 44:1289-1297
33. Eiden C, Peyriere H, Cociglio M, et al. Adverse effects of voriconazole:analysis of the French PHarmacovigilance Database. Ann PHarmacother 2007;41:755-763
34. Steinbach WJ, Stevens DA. Review of newer antifungal and immunomodulatory strategies for invasive aspergillosis. Clin Infect Dis 2003;37 (Suppl 3):S157-S187
35. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus ampHotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408-415
36. De Beule K, Van Gestel J. PHarmacology of itraconazole. Drugs 2001;61 (Suppl 1):27-37
37. Courtney R, Wexler D, Radwanski E, Lim J, Laughlin M. Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults. Br J Clin PHarmacol 2004;57:218-222
38. Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for propHylaxis in severe graft-versus-host disease. N Engl J Med 2007;356:335-347
39. Comely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole propHylaxis in patients with neutropenia. N Engl J Med 2007;356:348-359
40. Bennett JE. Echinocandins for candidemia in adults without neutropenia. N Engl J Med 2006;355:1154- 1159
41. Marr KA, Boeckh M, Carter RA, Kim HW, Corey L. Combination antifungal therapy for invasive aspergillosis.Clin Infect Dis 2004;39:797-802
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |