单核细胞抗烟曲霉感染作用的研究进展
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摘要
烟曲霉是临床常见的机会性致病真菌,好发于免疫低下人群,常因吸入孢子导致肺部感染,治疗困难。烟曲霉的致病性与其较强的生存能力有关,但主要取决于宿主免疫状态,尤其是天然免疫功能。单核细胞是天然免疫的重要效应细胞,可分化为树突细胞和巨噬细胞。依据其表面分子分型,单核细胞功能上分别以吞噬抗原、呈递抗原和杀伤抗原为特点,在抗烟曲霉感染中具有较高的抵御能力和诊断价值。现阶段研究基于不断发展的荧光标记、灌流培养、光谱成像、基因敲除等技术,通过体外细胞实验和小鼠体内实验,观察到单核细胞与烟曲霉相互作用。在烟曲霉孢子入侵早期,单核细胞即启动基因表达,直接杀灭孢子,也可通过增强中性粒细胞杀孢子活性间接参与抗感染免疫调节,其中白细胞介素家族可能是关键信号分子。
Aspergillus fumigatus(A.fumigatus)is an ubiquitous opportunistic fungus,which could cause serious pulmonary infection through inhalation of conidia.The infection is difficult to treat,and severity is strongly related to host immune status,especially innate immune functions.Monocytes are important effector cells in innate immune,which could be differentiated into dendritic cells and macrophages.Three subsets of monocytes defined by specific surface molecules exert distinguished functions in phagocytosis,antigen-presentation and conidiacidal activity.Based on the continuous development of assays,such as fluorescent tag,perfusion culture,spectral imaging,gene knockout technology,it is proven that monocytes play important roles in control of A.fumigatus infection in human and mouse.Monocytes could directly kill spores or improve neutrophil conidiacidal activity in the early A.fumigatus infection via interleukins signaling molecules.
Aspergillus fumigatus(A.fumigatus)is an ubiquitous opportunistic fungus,which could cause serious pulmonary infection through inhalation of conidia.The infection is difficult to treat,and severity is strongly related to host immune status,especially innate immune functions.Monocytes are important effector cells in innate immune,which could be differentiated into dendritic cells and macrophages.Three subsets of monocytes defined by specific surface molecules exert distinguished functions in phagocytosis,antigen-presentation and conidiacidal activity.Based on the continuous development of assays,such as fluorescent tag,perfusion culture,spectral imaging,gene knockout technology,it is proven that monocytes play important roles in control of A.fumigatus infection in human and mouse.Monocytes could directly kill spores or improve neutrophil conidiacidal activity in the early A.fumigatus infection via interleukins signaling molecules.
引文
[1]施毅,史家欣.肺真菌病的临床诊断与实验室检查进展[J].临床检验杂志,2017,35(10):725-728.
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[3]Kwon-Chung KJ,Sugui JA.Aspergillus fumigatus-what makes the species a ubiquitous human fungal pathogen?[J].PLoS Pathog,2013,9(12):e1003743.
[4]Espinosa V,Jhingran A,Dutta O,Kasahara S,Donnelly R,Du P,Rosenfeld J,Leiner I,Chen CC,Ron Y,Hohl TM,Rivera A.Inflammatory monocytes orchestrate innate antifungal immunity in the lung[J].PLoS Pathog,2014,10(2):e1003940.
[5]Jhingran A,Mar KB,Kumasaka DK,Knoblaugh SE,Ngo LY,Segal BH,Iwakura Y,Lowell CA,Hamerman JA,Lin X,Hohl TM.Tracing conidial fate and measuring host cell antifungal activity using a reporter of microbial viability in the lung[J].Cell Rep,2012,2(6):1762-1773.
[6]Albrecht D,Guthke R,Brakhage AA,Kniemeyer O.Integrative analysis of the heat shock response in Aspergillus fumigatus[J].BMC Genomics,2010,11:32.doi:10.1186/1471-2164-11-32.
[7]Paris S,Debeaupuis JP,Crameri R,Carey M,Charlès F,Prévost MC,Schmitt C,Philippe B,LatgéJP.Conidial hydrophobins of Aspergillus fumigatus[J].Appl Environ Microbiol,2003,69(3):1581-1588.
[8]Wasylnka JA,Simmer MI,Moore MM.Differences in sialic acid density in pathogenic and non-pathogenic Aspergillus species[J].Microbiology,2001,147(Pt 4):869-877.
[9]Aimanianda V,Bayry J,Bozza S,Kniemeyer O,Perruccio K,Elluru SR,Clavaud C,Paris S,Brakhage AA,Kaveri SV,Romani L,LatgéJP.Surface hydrophobin prevents immune recognition of airborne fungal spores[J].Nature,2009,460(7259):1117-1121.
[10]Shibuya K,Takaoka M,Uchida K,Wakayama M,Yamaguchi H,Takahashi K,Paris S,Latge JP,Naoe S.Histopathology of experimental invasive pulmonary aspergillosis in rats:pathological comparison of pulmonary lesions induced by specific virulent factor deficient mutants[J].Microb Pathog,1999,27(3):123-131.
[11]Brakhage AA,Liebmann B.Aspergillus fumigatus conidial pigment and cAMP signal transduction:significance for virulence[J].Med Mycol,2005,43(Suppl 1):S75-S82.
[12]Stanzani M,Orciuolo E,Lewis R,Kontoyiannis DP,Martins SL,St John LS,Komanduri KV.Aspergillus fumigatus suppresses the human cellular immune response via gliotoxin-mediated apoptosis of monocytes[J].Blood,2005,105(6):2258-2265.
[13]McDonagh A,Fedorova ND,Crabtree J,Yu Y,Kim S,Chen D,Loss O,Cairns T,Goldman G,Armstrong-James D,Haynes K,Haas H,Schrettl M,May G,Nierman WC,Bignell E.Sub-telomere directed gene expression during initiation of invasive aspergillosis[J].PLoS Pathog,2008,4(9):e1000154.
[14]Calera JA,Paris S,Monod M,Hamilton AJ,Debeaupuis JP,Diaquin M,López-Medrano R,Leal F,LatgéJP.Cloning and disruption of the antigenic catalase gene of Aspergillus fumigatus[J].Infect Immun,1997,65(11):4718-4724.
[15]Murray PJ.Immune regulation by monocytes[J].Semin Immunol,2018,35:12-18.
[16]Paul F,Arkin Y,Giladi A,Jaitin DA,Kenigsberg E,Keren-Shaul H,Winter D,Lara-Astiaso D,Gury M,Weiner A,David E,Cohen N,Lauridsen FK,Haas S,Schlitzer A,Mildner A,Ginhoux F,Jung S,Trumpp A,Porse BT,Tanay A,Amit I.Transcriptional heterogeneity and lineage commitment in myeloid progenitors[J].Cell,2015,163(7):1663-1677.
[17]Serbina NV,Cherny M,Shi C,Bleau SA,Collins NH,Young JW,Pamer EG.Distinct responses of human monocyte subsets to Aspergillus fumigatus conidia[J].JImmunol,2009,183(4):2678-2687.
[18]唐康,金伯泉.单核细胞亚群的研究进展[J].细胞与分子免疫学杂志,2016,32(6):840-844.
[19]Cros J,Cagnard N,Woollard K,Patey N,Zhang SY,Senechal B,Puel A,Biswas SK,Moshous D,Picard C,Jais JP,D’Cruz D,Casanova JL,Trouillet C,Geissmann F.Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7and TLR8receptors[J].Immunity,2010,33(3):375-386.
[20]Schmidl C,Renner K,Peter K,Eder R,Lassmann T,Balwierz PJ,Itoh M,Nagao-Sato S,Kawaji H,Carninci P,Suzuki H,Hayashizaki Y,Andreesen R,Hume DA,Hoffmann P,Forrest AR,Kreutz MP,Edinger M,Rehli M;FANTOM consortium.Transcription and enhancer profiling in human monocyte subsets[J].Blood,2014,123(17):e90-e99.
[21]Cortez KJ,Lyman CA,Kottilil S,Kim HS,Roilides E,Yang J,Fullmer B,Lempicki R,Walsh TJ.Functional genomics of innate host defense molecules in normal human monocytes in response to Aspergillus fumigatus[J].Infect Immun,2006,74(4):2353-2365.
[22]Rdland EK,Mattingsdal M,Olstad OK,OvstebR,Kierulf P,Muller F,Frland SS.Expression of genes in normal human monocytes in response to Aspergillus fumigatus[J].Med Mycol,2008,46(4):327-336.
[23]Loeffler J,Haddad Z,Bonin M,Romeike N,Mezger M,Schumacher U,Kapp M,Gebhardt F,Grigoleit GU,Stevanovic S,Einsele H,Hebart H.Interaction analyses of human monocytes co-cultured with different forms of Aspergillus fumigatus[J].J Med Microbiol,2009,58(Pt1):49-58.
[24]Wang JE,Warris A,Ellingsen EA,Jrgensen PF,Flo TH,Espevik T,Solberg R,Verweij PE,Aasen AO.Involvement of CD14and Toll-like receptors in activation of human monocytes by Aspergillus fumigatus hyphae[J].Infect Immun,2001,69(4):2402-2406.
[25]Smith NL,Hankinson J,Simpson A,Bowyer P,Denning DW.A prominent role for the IL1pathway and IL15in susceptibility to chronic cavitary pulmonary aspergillosis[J].Clin Microbiol Infect,2014,20(8):O480-O488.
[26]James ER,Green DR.Infection and the origins of apoptosis[J].Cell Death Differ,2002,9(4):355-357.
[27]Mohebbi S,Erfurth F,Hennersdorf P,Brakhage AA,Saluz HP.Hyperspectral imaging using intracellular spies:quantitative real-time measurement of intracellular parameters in vivo during interaction of the pathogenic fungus Aspergillus fumigatus with human monocytes[J].PLoS One,2016,11(10):e0163505.
[28]Amin S,Thywissen A,Heinekamp T,Saluz HP,Brakhage AA.Melanin dependent survival of Apergillus fumigatus conidia in lung epithelial cells[J].Int J Med Microbiol,2014,304(5-6):626-636.
[29]Pastor A,Gafa V,Boutonnat J,Grillot R,AmbroiseThomas P,Aldebert D.Intracellular oxidative response of human monocytes and granulocytes to different strains of Aspergillus fumigatus[J].Mycoses,2006,49(2):73-79.
[30]Chandorkar P,Posch W,Zaderer V,Blatzer M,Steger M,Ammann CG,Binder U,Hermann M,H9rtnagl P,LassFl9rl C,Wilflingseder D.Fast-track development of an in vitro 3D lung/immune cell model to study Aspergillus infections[J].Sci Rep,2017,7(1):11644.doi:10.1038/s41598-017-11271-4.
[31]Underhill DM,Pearlman E.Immune interactions with pathogenic and commensal fungi:a two-way street[J].Immunity,2015,43(5):845-858.
[32]Caffrey AK,Lehmann MM,Zickovich JM,Espinosa V,Shepardson KM,Watschke CP,Hilmer KM,Thammahong A,Barker BM,Rivera A,Cramer RA,Obar JJ.IL-1αsignaling is critical for leukocyte recruitment after pulmonary Aspergillus fumigatus challenge[J].PLoSPathog,2015,11(1):e1004625.
[33]Serbina NV,Jia T,Hohl TM,Pamer EG.Monocytemediated defense against microbial pathogens[J].Annu Rev Immunol,2008,26:421-452.
[2]Kizhakedathil MPJ,Koppula AR,Subathra Devi C.A brief review on invasive aspergillosis and the host immune response and the target drugs[J]Immun Endoc Metab Agents Med Chem,2017,17(1):4-14.doi:10.2174/1871522217666170706151211.
[3]Kwon-Chung KJ,Sugui JA.Aspergillus fumigatus-what makes the species a ubiquitous human fungal pathogen?[J].PLoS Pathog,2013,9(12):e1003743.
[4]Espinosa V,Jhingran A,Dutta O,Kasahara S,Donnelly R,Du P,Rosenfeld J,Leiner I,Chen CC,Ron Y,Hohl TM,Rivera A.Inflammatory monocytes orchestrate innate antifungal immunity in the lung[J].PLoS Pathog,2014,10(2):e1003940.
[5]Jhingran A,Mar KB,Kumasaka DK,Knoblaugh SE,Ngo LY,Segal BH,Iwakura Y,Lowell CA,Hamerman JA,Lin X,Hohl TM.Tracing conidial fate and measuring host cell antifungal activity using a reporter of microbial viability in the lung[J].Cell Rep,2012,2(6):1762-1773.
[6]Albrecht D,Guthke R,Brakhage AA,Kniemeyer O.Integrative analysis of the heat shock response in Aspergillus fumigatus[J].BMC Genomics,2010,11:32.doi:10.1186/1471-2164-11-32.
[7]Paris S,Debeaupuis JP,Crameri R,Carey M,Charlès F,Prévost MC,Schmitt C,Philippe B,LatgéJP.Conidial hydrophobins of Aspergillus fumigatus[J].Appl Environ Microbiol,2003,69(3):1581-1588.
[8]Wasylnka JA,Simmer MI,Moore MM.Differences in sialic acid density in pathogenic and non-pathogenic Aspergillus species[J].Microbiology,2001,147(Pt 4):869-877.
[9]Aimanianda V,Bayry J,Bozza S,Kniemeyer O,Perruccio K,Elluru SR,Clavaud C,Paris S,Brakhage AA,Kaveri SV,Romani L,LatgéJP.Surface hydrophobin prevents immune recognition of airborne fungal spores[J].Nature,2009,460(7259):1117-1121.
[10]Shibuya K,Takaoka M,Uchida K,Wakayama M,Yamaguchi H,Takahashi K,Paris S,Latge JP,Naoe S.Histopathology of experimental invasive pulmonary aspergillosis in rats:pathological comparison of pulmonary lesions induced by specific virulent factor deficient mutants[J].Microb Pathog,1999,27(3):123-131.
[11]Brakhage AA,Liebmann B.Aspergillus fumigatus conidial pigment and cAMP signal transduction:significance for virulence[J].Med Mycol,2005,43(Suppl 1):S75-S82.
[12]Stanzani M,Orciuolo E,Lewis R,Kontoyiannis DP,Martins SL,St John LS,Komanduri KV.Aspergillus fumigatus suppresses the human cellular immune response via gliotoxin-mediated apoptosis of monocytes[J].Blood,2005,105(6):2258-2265.
[13]McDonagh A,Fedorova ND,Crabtree J,Yu Y,Kim S,Chen D,Loss O,Cairns T,Goldman G,Armstrong-James D,Haynes K,Haas H,Schrettl M,May G,Nierman WC,Bignell E.Sub-telomere directed gene expression during initiation of invasive aspergillosis[J].PLoS Pathog,2008,4(9):e1000154.
[14]Calera JA,Paris S,Monod M,Hamilton AJ,Debeaupuis JP,Diaquin M,López-Medrano R,Leal F,LatgéJP.Cloning and disruption of the antigenic catalase gene of Aspergillus fumigatus[J].Infect Immun,1997,65(11):4718-4724.
[15]Murray PJ.Immune regulation by monocytes[J].Semin Immunol,2018,35:12-18.
[16]Paul F,Arkin Y,Giladi A,Jaitin DA,Kenigsberg E,Keren-Shaul H,Winter D,Lara-Astiaso D,Gury M,Weiner A,David E,Cohen N,Lauridsen FK,Haas S,Schlitzer A,Mildner A,Ginhoux F,Jung S,Trumpp A,Porse BT,Tanay A,Amit I.Transcriptional heterogeneity and lineage commitment in myeloid progenitors[J].Cell,2015,163(7):1663-1677.
[17]Serbina NV,Cherny M,Shi C,Bleau SA,Collins NH,Young JW,Pamer EG.Distinct responses of human monocyte subsets to Aspergillus fumigatus conidia[J].JImmunol,2009,183(4):2678-2687.
[18]唐康,金伯泉.单核细胞亚群的研究进展[J].细胞与分子免疫学杂志,2016,32(6):840-844.
[19]Cros J,Cagnard N,Woollard K,Patey N,Zhang SY,Senechal B,Puel A,Biswas SK,Moshous D,Picard C,Jais JP,D’Cruz D,Casanova JL,Trouillet C,Geissmann F.Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7and TLR8receptors[J].Immunity,2010,33(3):375-386.
[20]Schmidl C,Renner K,Peter K,Eder R,Lassmann T,Balwierz PJ,Itoh M,Nagao-Sato S,Kawaji H,Carninci P,Suzuki H,Hayashizaki Y,Andreesen R,Hume DA,Hoffmann P,Forrest AR,Kreutz MP,Edinger M,Rehli M;FANTOM consortium.Transcription and enhancer profiling in human monocyte subsets[J].Blood,2014,123(17):e90-e99.
[21]Cortez KJ,Lyman CA,Kottilil S,Kim HS,Roilides E,Yang J,Fullmer B,Lempicki R,Walsh TJ.Functional genomics of innate host defense molecules in normal human monocytes in response to Aspergillus fumigatus[J].Infect Immun,2006,74(4):2353-2365.
[22]Rdland EK,Mattingsdal M,Olstad OK,OvstebR,Kierulf P,Muller F,Frland SS.Expression of genes in normal human monocytes in response to Aspergillus fumigatus[J].Med Mycol,2008,46(4):327-336.
[23]Loeffler J,Haddad Z,Bonin M,Romeike N,Mezger M,Schumacher U,Kapp M,Gebhardt F,Grigoleit GU,Stevanovic S,Einsele H,Hebart H.Interaction analyses of human monocytes co-cultured with different forms of Aspergillus fumigatus[J].J Med Microbiol,2009,58(Pt1):49-58.
[24]Wang JE,Warris A,Ellingsen EA,Jrgensen PF,Flo TH,Espevik T,Solberg R,Verweij PE,Aasen AO.Involvement of CD14and Toll-like receptors in activation of human monocytes by Aspergillus fumigatus hyphae[J].Infect Immun,2001,69(4):2402-2406.
[25]Smith NL,Hankinson J,Simpson A,Bowyer P,Denning DW.A prominent role for the IL1pathway and IL15in susceptibility to chronic cavitary pulmonary aspergillosis[J].Clin Microbiol Infect,2014,20(8):O480-O488.
[26]James ER,Green DR.Infection and the origins of apoptosis[J].Cell Death Differ,2002,9(4):355-357.
[27]Mohebbi S,Erfurth F,Hennersdorf P,Brakhage AA,Saluz HP.Hyperspectral imaging using intracellular spies:quantitative real-time measurement of intracellular parameters in vivo during interaction of the pathogenic fungus Aspergillus fumigatus with human monocytes[J].PLoS One,2016,11(10):e0163505.
[28]Amin S,Thywissen A,Heinekamp T,Saluz HP,Brakhage AA.Melanin dependent survival of Apergillus fumigatus conidia in lung epithelial cells[J].Int J Med Microbiol,2014,304(5-6):626-636.
[29]Pastor A,Gafa V,Boutonnat J,Grillot R,AmbroiseThomas P,Aldebert D.Intracellular oxidative response of human monocytes and granulocytes to different strains of Aspergillus fumigatus[J].Mycoses,2006,49(2):73-79.
[30]Chandorkar P,Posch W,Zaderer V,Blatzer M,Steger M,Ammann CG,Binder U,Hermann M,H9rtnagl P,LassFl9rl C,Wilflingseder D.Fast-track development of an in vitro 3D lung/immune cell model to study Aspergillus infections[J].Sci Rep,2017,7(1):11644.doi:10.1038/s41598-017-11271-4.
[31]Underhill DM,Pearlman E.Immune interactions with pathogenic and commensal fungi:a two-way street[J].Immunity,2015,43(5):845-858.
[32]Caffrey AK,Lehmann MM,Zickovich JM,Espinosa V,Shepardson KM,Watschke CP,Hilmer KM,Thammahong A,Barker BM,Rivera A,Cramer RA,Obar JJ.IL-1αsignaling is critical for leukocyte recruitment after pulmonary Aspergillus fumigatus challenge[J].PLoSPathog,2015,11(1):e1004625.
[33]Serbina NV,Jia T,Hohl TM,Pamer EG.Monocytemediated defense against microbial pathogens[J].Annu Rev Immunol,2008,26:421-452.