Microarray analysis of MicroRNA expression in peripheral blood mononuclear cells of critically ill patients with influenza A (H1N1)

BMC Infectious Diseases

Jun Cheng¹  Deli Zhang²  Baoshun Li³  Li Dai⁴  Xuesong Gao¹  Rui Song³  Shunai Liu¹  Yang Guo⁴  Qi Wang¹  Hao Song¹ 

[1] Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, 100015, China;Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China;Department of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, 100015, China;Investigation Group of Molecular Virology, Immunology, Oncology & Systems Biology, Center for Bioinformatics, College of Life Sciences, Northwest A & F University, Yangling, Xi’an City, Shaanxi Province, 712100, China

关键词: Systems biology;    Host pathogen interaction;    miRNA;    2009 H1N1 Influenza pandemic;    Critically ill patient;   

Others  :  1147962
DOI  :  10.1186/1471-2334-13-257

 received in 2012-09-18, accepted in 2013-05-30,  发布年份 2013

【 摘 要 】

Background

With concerns about the disastrous health and economic consequences caused by the influenza pandemic, comprehensively understanding the global host response to influenza virus infection is urgent. The role of microRNA (miRNA) has recently been highlighted in pathogen-host interactions. However, the precise role of miRNAs in the pathogenesis of influenza virus infection in humans, especially in critically ill patients is still unclear.

Methods

We identified cellular miRNAs involved in the host response to influenza virus infection by performing comprehensive miRNA profiling in peripheral blood mononuclear cells (PBMCs) from critically ill patients with swine-origin influenza pandemic H1N1 (2009) virus infection via miRNA microarray and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assays. Receiver operator characteristic (ROC) curve analysis was conducted and area under the ROC curve (AUC) was calculated to evaluate the diagnostic accuracy of severe H1N1 influenza virus infection. Furthermore, an integrative network of miRNA-mediated host-influenza virus protein interactions was constructed by integrating the predicted and validated miRNA-gene interaction data with influenza virus and host-protein-protein interaction information using Cytoscape software. Moreover, several hub genes in the network were selected and validated by qRT-PCR.

Results

Forty-one significantly differentially expressed miRNAs were found by miRNA microarray; nine were selected and validated by qRT-PCR. QRT-PCR assay and ROC curve analyses revealed that miR-31, miR-29a and miR-148a all had significant potential diagnostic value for critically ill patients infected with H1N1 influenza virus, which yielded AUC of 0.9510, 0.8951 and 0.8811, respectively. We subsequently constructed an integrative network of miRNA-mediated host-influenza virus protein interactions, wherein we found that miRNAs are involved in regulating important pathways, such as mitogen-activated protein kinase signaling pathway, epidermal growth factor receptor signaling pathway, and Toll-like receptor signaling pathway, during influenza virus infection. Some of differentially expressed miRNAs via in silico analysis targeted mRNAs of several key genes in these pathways. The mRNA expression level of tumor protein T53 and transforming growth factor beta receptor 1 were found significantly reduced in critically ill patients, whereas the expression of Janus kinase 2, caspase 3 apoptosis-related cysteine peptidase, interleukin 10, and myxovirus resistance 1 were extremely increased in critically ill patients.

Conclusions

Our data suggest that the dysregulation of miRNAs in the PBMCs of H1N1 critically ill patients can regulate a number of key genes in the major signaling pathways associated with influenza virus infection. These differentially expressed miRNAs could be potential therapeutic targets or biomarkers for severe influenza virus infection.

【 授权许可】

   
2013 Song et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Butler D: Portrait of a year-old pandemic. Nature 2010, 464(7292):1112-1113.
• [2]Huarte M, Sanz-Ezquerro JJ, Roncal F, Ortin J, Nieto A: PA subunit from influenza virus polymerase complex interacts with a cellular protein with homology to a family of transcriptional activators. J Virol 2001, 75(18):8597-8604.
• [3]Hao L, Sakurai A, Watanabe T, Sorensen E, Nidom CA, Newton MA, Ahlquist P, Kawaoka Y: Drosophila RNAi screen identifies host genes important for influenza virus replication. Nature 2008, 454(7206):890-893.
• [4]Karlas A, Machuy N, Shin Y, Pleissner KP, Artarini A, Heuer D, Becker D, Khalil H, Ogilvie LA, Hess S: Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication. Nature 2010, 463(7282):818-822.
• [5]Brass AL, Huang IC, Benita Y, John SP, Krishnan MN, Feeley EM, Ryan BJ, Weyer JL, van der Weyden L, Fikrig E: The IFITM proteins mediate cellular resistance to influenza a H1N1 virus, west Nile virus, and dengue virus. Cell 2009, 139(7):1243-1254.
• [6]Konig R, Stertz S, Zhou Y, Inoue A, Hoffmann HH, Bhattacharyya S, Alamares JG, Tscherne DM, Ortigoza MB, Liang YH: Human host factors required for influenza virus replication. Nature 2010, 463(7282):813-817.
• [7]Shapira SD, Gat-Viks I, Shum BOV, Dricot A, de Grace MM, Wu LG, Gupta PB, Hao T, Silver SJ, Root DE: A physical and regulatory Map of host-influenza interactions reveals pathways in H1N1 infection. Cell 2009, 139(7):1255-1267.
• [8]O’Connell RM, Rao DS, Chaudhuri AA, Baltimore D: Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol 2010, 10(2):111-122.
• [9]Ren JQ, Jin P, Wang E, Marincola FM, Stroncek DF: MicroRNA and gene expression patterns in the differentiation of human embryonic stem cells. J Trans Med 2009, 7:20. BioMed Central Full Text
• [10]Ji JF, Shi J, Budhu A, Yu ZP, Forgues M, Roessler S, Ambs S, Chen YD, Meltzer PS, Croce CM: MicroRNA expression, survival, and response to interferon in liver cancer. N Eng J Med 2009, 361(15):1437-1447.
• [11]Lodish HF, Zhou B, Liu G, Chen CZ: Micromanagement of the immune system by microRNAs. Nat Rev Immunol 2008, 8(2):120-130.
• [12]Umbach JL, Cullen BR: The role of RNAi and microRNAs in animal virus replication and antiviral immunity. Genes Dev 2009, 23(10):1151-1164.
• [13]Ouellet DL, Provost P: Current knowledge of MicroRNAs and noncoding RNAs in virus-infected cells. Methods Mol Biol (Clifton, NJ) 2010, 623:35-65.
• [14]Cullen BR: Five questions about viruses and MicroRNAs. PLoS Pathog 2010, 6(2):e1000787.
• [15]Wang Y, Brahmakshatriya V, Zhu HF, Lupiani B, Reddy SM, Yoon BJ, Gunaratne PH, Kim JH, Chen R, Wang JJ: Identification of differentially expressed miRNAs in chicken lung and trachea with avian influenza virus infection by a deep sequencing approach. BMC Genomics 2009, 10(1):512. BioMed Central Full Text
• [16]Wang Y, Brahmakshatriya V, Lupiani B, Reddy SM, Soibam B, Benham AL, Gunaratne P, Liu HC, Trakooljul M, Ing N: Integrated analysis of microRNA expression and mRNA transcriptome in lungs of avian influenza virus infected broilers. BMC Genomics 2012, 13(1):278. BioMed Central Full Text
• [17]Li Y, Chan EY, Li J, Ni C, Peng X, Rosenzweig E, Tumpey TM, Katze MG: MicroRNA expression and virulence in pandemic influenza virus-infected mice. J Virol 2010, 84(6):3023-3032.
• [18]Rogers JV, Price JA, Wendling MQ, Long JP, Bresler HS: Preliminary microRNA analysis in lung tissue to identify potential therapeutic targets against H5N1 infection. Viral Immunol 2012, 25(1):3-11.
• [19]Song LP, Liu H, Gao SJ, Jiang W, Huang WL: Cellular MicroRNAs inhibit replication of the H1N1 influenza a virus in infected cells. J Virol 2010, 84(17):8849-8860.
• [20]Meliopoulos VA, Andersen LE, Brooks P, Yan X, Bakre A, Coleman JK, Tompkins SM, Tripp RA: MicroRNA regulation of human protease genes essential for influenza virus replication. PLoS One 2012, 7(5):e37169.
• [21]Loveday EK, Svinti V, Diederich S, Pasick J, Jean F: Temporal- and strain-specific host microRNA molecular signatures associated with swine-origin H1N1 and avian-origin H7N7 influenza A virus infection. J Virol 2012, 86(11):6109-6122.
• [22]Shou JY, Bull CM, Li L, Qian HR, Wei T, Luo SA, Perkins D, Solenberg PJ, Tan SL, Chen XYC: Identification of blood biomarkers of rheumatoid arthritis by transcript profiling of peripheral blood mononuclear cells from the rat collagen-induced arthritis model. Arthritis Res Ther 2006, 8(1):R28. BioMed Central Full Text
• [23]Otaegui D, Baranzini SE, Armananzas R, Calvo B, Munoz-Culla M, Khankhanian P, Inza I, Lozano JA, Castillo-Trivino T, Asensio A: Differential micro RNA expression in PBMC from multiple sclerosis patients. PLoS One 2009, 4(7):e6309.
• [24]Shao HW, Lan DM, Duan ZH, Liu ZH, Min J, Zhang LC, Huang J, Su J, Chen SW, Xu AL: Upregulation of mitochondrial gene expression in PBMC from convalescent SARS patients. J Clin Immunol 2006, 26(6):546-554.
• [25]Rollins B, Martin MV, Morgan L, Vawter MP: Analysis of whole genome biomarker expression in blood and brain. Am J Med Gen Part B-Neuropsych Gen 2010, 153B(4):919-936.
• [26]Monaco A, Marincola FM, Sabatino M, Pos Z, Tornesello ML, Stroncek DF, Wang E, Lewis GK, Buonaguro FM, Buonaguro L: Molecular immune signatures of HIV-1 vaccines in human PBMCs. FEBS Lett 2009, 583(18):3004-3008.
• [27]Li J, Yu YJ, Feng L, Cai XB, Tang HB, Sun SK, Zhang HY, Liang JJ, Luo TR: Global transcriptional profiles in peripheral blood mononuclear cell during classical swine fever virus infection. Virus Res 2010, 148(1–2):60-70.
• [28]Huang C, Chen HG, Cassidy W, Howell CD: Peripheral blood gene expression profile associated with sustained virologic response after peginterferon plus ribavirin therapy for chronic hepatitis-C genotype 1. J Nat Med Assoc 2008, 100(12):1425-1433.
• [29]Ramilo O, Allman W, Chung W, Mejias A, Ardura M, Glaser C, Wittkowski KM, Piqueras B, Banchereau J, Palucka AK: Gene expression patterns in blood leukocytes discriminate patients with acute infections. Blood 2007, 109(5):2066-2077.
• [30]Zaas AK, Chen MH, Varkey J, Veldman T, Hero AO, Lucas J, Huang YS, Tumer R, Gilbert A, Lambkin-Williams R: Gene expression signatures diagnose influenza and other symptomatic respiratory viral infections in humans. Cell Host Microbe 2009, 6(3):207-217.
• [31]Zaas AK, Aziz H, Lucas J, Perfect JR, Ginsburg GS: Blood gene expression signatures predict invasive candidiasis. Sci Trans Med 2010, 2(21):21ra17.
• [32]Aziz H, Zaas A, Ginsburg GS: Peripheral blood gene expression profiling for cardiovascular disease assessment. Genomic Med 2007, 1:105-112.
• [33]Taurino C, Miller WH, McBride MW, McClure JD, Khanin R, Moreno MU, Dymott JA, Delles C, Dominiczak AF: Gene expression profiling in whole blood of patients with coronary artery disease. Clin Sci 2010, 119(7–8):335-343.
• [34]Osterlund P, Pirhonen J, Ikonen N, Ronkko E, Strengell M, Makela SM, Broman M, Hamming OJ, Hartmann R, Ziegler T: Pandemic H1N1 2009 influenza a virus induces weak cytokine responses in human macrophages and dendritic cells and is highly sensitive to the antiviral actions of interferons. J Virol 2010, 84(3):1414-1422.
• [35]Peiris JSM, Cheung CY, Leung CYH, Nicholls JM: Innate immune responses to influenza A H5N1: friend or foe? Trends Immunol 2009, 30(12):574-584.
• [36]Arankalle VA, Lole KS, Arya RP, Tripathy AS, Ramdasi AY, Chadha MS, Sangle SA, Kadam DB: Role of host immune response and viral load in the differential outcome of pandemic H1N1 (2009) influenza virus infection in Indian patients. PLoS One 2010, 5(10):e13099.
• [37]Liu L, Zhang RF, Lu HZ, Lu SH, Huang Q, Xiong YY, Xi XH, Zhang ZY: Sixty-two severe and critical patients with 2009 influenza A (H1N1) in Shanghai. China. Chin Med J 2011, 124(11):1662-1666.
• [38]WHO website: CDC protocol of real time RT-PCR for influenza A (H1N1). 2009. http://www.who.int/csr/resources/publications/swineflu/realtimeptpcr/en/index.html webcite
• [39]Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ: miRBase: tools for microRNA genomics. Nucleic Acids Res 2008, 36:D154-D158.
• [40]Tusher VG, Tibshirani R, Chu G: Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 2001, 98(9):5116-5121.
• [41]de Hoon MJL, Imoto S, Nolan J, Miyano S: Open source clustering software. Bioinformatics 2004, 20(9):1453-1454.
• [42]Saldanha AJ: Java Treeview-extensible visualization of microarray data. Bioinformatics 2004, 20(17):3246-3248.
• [43]Barrett T, Troup DB, Wilhite SE, Ledoux P, Rudnev D, Evangelista C, Kim IF, Soboleva A, Tomashevsky M, Marshall KA: NCBI GEO: archive for high-throughput functional genomic data. Nucleic Acids Res 2009, 37(Database issue):D885-890.
• [44]John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS: Human MicroRNA targets. PLoS Biol 2004, 2(11):1862-1879.
• [45]Friedman RC, Farh KK-H, Burge CB, Bartel DP: Most mammalian mRNAs are conserved targets of microRNAs. Gen Res 2009, 19(1):92-105.
• [46]Wang XW: miRDB: A microRNA target prediction and functional annotation database with a wiki interface. RNA-Publ RNA Soc 2008, 14(6):1012-1017.
• [47]Miranda KC, Huynh T, Tay Y, Ang YS, Tam WL, Thomson AM, Lim B, Rigoutsos I: A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes. Cell 2006, 126(6):1203-1217.
• [48]Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, MacMenamin P, da Piedade I, Gunsalus KC, Stoffel M: Combinatorial microRNA target predictions. Nat Genet 2005, 37(5):495-500.
• [49]Dweep H, Sticht C, Pandey P, Gretz N: MiRWalk - database: prediction of possible miRNA binding sites by “walking” the genes of three genomes. J Biomed Info 2011, 44(5):839-847.
• [50]Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P, Doerks T, Stark M, Muller J, Bork P: The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res 2011, 39(Database issue):D561-568.
• [51]von Mering C, Jensen LJ, Snel B, Hooper SD, Krupp M, Foglierini M, Jouffre N, Huynen MA, Bork P: STRING: known and predicted protein-protein associations, integrated and transferred across organisms. Nucleic Acids Res 2005, 33:D433-D437.
• [52]Dennis G, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC, Lempicki RA: DAVID: Database for annotation, visualization, and integrated discovery. Genome Biol 2003, 4(5):P3. BioMed Central Full Text
• [53]Kanehisa M, Goto S, Furumichi M, Tanabe M, Hirakawa M: KEGG for representation and analysis of molecular networks involving diseases and drugs. Nucleic Acids Res 2010, 38(Database issue):D355-360.
• [54]D’Eustachio P: Reactome knowledgebase of human biological pathways and processes. Methods Mol Biol 2011, 694:49-61.
• [55]Cline MS, Smoot M, Cerami E, Kuchinsky A, Landys N, Workman C, Christmas R, Avila-Campilo I, Creech M, Gross B: Integration of biological networks and gene expression data using Cytoscape. Nat Protoc 2007, 2(10):2366-2382.
• [56]Wang X: miRDB: a microRNA target prediction and functional annotation database with a wiki interface. RNA 2008, 14(6):1012-1017.
• [57]Watanabe T, Watanabe S, Kawaoka Y: Cellular networks involved in the influenza virus life cycle. Cell Host Microbe 2010, 7(6):427-439.
• [58]Nathans R, Chu CY, Serquina AK, Lu CC, Cao H, Rana TM: Cellular MicroRNA and P bodies modulate host-HIV-1 interactions. Mol Cell 2009, 34(6):696-709.
• [59]Lecellier CH, Dunoyer P, Arar K, Lehmann-Che J, Eyquem S, Himber C, Saib A, Voinnet O: A cellular microRNA mediates antiviral defense in human cells. Science 2005, 308(5721):557-560.
• [60]Jopling CL, Schuetz S, Sarnow P: Position-dependent function for a tandem microRNA miR-122-binding site located in the hepatitis C virus RNA genome. Cell Host Microbe 2008, 4(1):77-85.
• [61]Jangra RK, Yi M, Lemon SM: Regulation of hepatitis C virus translation and infectious virus production by the MicroRNA miR-122. J Virol 2010, 84(13):6615-6625.
• [62]Chang JH, Cruo JT, Jiang D, Guo HT, Taylor JM, Block TM: Liver-specific MicroRNA miR-122 enhances the replication of hepatitis C virus in nonhepatic cells. J Virol 2008, 82(16):8215-8223.
• [63]Steiner DF, Thomas MF, Hu JK, Yang Z, Babiarz JE, Allen CDC, Matloubian M, Blelloch R, Ansel KM: MicroRNA-29 regulates T-Box transcription factors and interferon-gamma production in helper T cells. Immunity 2011, 35(2):169-181.
• [64]Ding Z, Wang X, Khaidakov M, Liu S, Mehta JL: MicroRNA hsa-let-7g targets lectin-like oxidized low-density lipoprotein receptor-1 expression and inhibits apoptosis in human smooth muscle cells. Exp Biol Med 2012, 237(9):1093-1100.
• [65]Kumar M, Ahmad T, Sharma A, Mabalirajan U, Kulshreshtha A, Agrawal A, Ghosh B: Let-7 microRNA-mediated regulation of IL-13 and allergic airway inflammation. J Allergy Clin Immunol 2011, 128(5):1077-1085.
• [66]Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, Zhang Y, Elias JA: Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest 1999, 103(6):779-788.
• [67]Fezeu L, Julia C, Henegar A, Bitu J, Hu FB, Grobbee DE, Kengne AP, Hercberg S, Czernichow S: Obesity is associated with higher risk of intensive care unit admission and death in influenza A (H1N1) patients: a systematic review and meta-analysis. Obes Rev 2011, 12(8):653-659.
• [68]Louie JK, Acosta M, Samuel MC, Schechter R, Vugia DJ, Harriman K, Matyas BT, Calif Pandem HNWG: A novel risk factor for a novel virus: obesity and 2009 pandemic influenza a (H1N1). Clin Infect Diseases 2011, 52(3):301-312.
• [69]Jain S, Chaves SS: Obesity and influenza. Clin Infect Diseases 2011, 53(5):422-424.
• [70]Kornum JB, Norgaard M, Dethlefsen C, Due KM, Thomsen RW, Tjonneland A, Sorensen HT, Overvad K: Obesity and risk of subsequent hospitalisation with pneumonia. Eur Res J 2010, 36(6):1330-1336.
• [71]Hingston CD, Holmes TW, Saayman AG, Wise MP: Obesity and risk of pneumonia in patients with influenza. Eur Res J 2011, 37(5):1299-1299.
• [72]Kok J, Blyth CC, Foo H, Bailey MJ, Pilcher DV, Webb SA, Seppelt IM, Dwyer DE, Iredell JR: Viral pneumonitis is increased in obese patients during the first wave of pandemic a(H1N1) 2009 virus. PLoS One 2013, 8(2):e55631.
• [73]Smith AG, Sheridan PA, Tseng RJ, Sheridan JF, Beck MA: Selective impairment in dendritic cell function and altered antigen-specific CD8(+) T-cell responses in diet-induced obese mice infected with influenza virus. Immunology 2009, 126(2):268-279.
• [74]Smith AG, Sheridan PA, Harp JB, Beck MA: Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus. J Nutr 2007, 137(5):1236-1243.
• [75]Karlsson EA, Sheridan PA, Beck MA: Diet-induced obesity impairs the T cell memory response to influenza virus infection. J Immunol 2010, 184(6):3127-3133.
• [76]Hulsmans M, Van Dooren E, Mathieu C, Holvoet P: Decrease of miR-146b-5p in monocytes during obesity is associated with loss of the anti-inflammatory but not insulin signaling action of adiponectin. PLoS One 2012, 7(2):e32794.
• [77]Yan X, Huang Y, Zhao JX, Rogers CJ, Zhu MJ, Ford SP, Nathanielsz PW, Du M: Maternal obesity downregulates microRNA let-7g expression, a possible mechanism for enhanced adipogenesis during ovine fetal skeletal muscle development. Int J Obes 2013, 37(4):568-575.
• [78]Schmidt WM, Spiel AO, Jilma B, Wolzt M, Wuller M: In vivo profile of the human leukocyte microRNA response to endotoxemia. Biochem Biophysic Res Comm 2009, 380(3):437-441.
• [79]Giamarellos-Bourboulis EJ, Raftogiannis M, Antonopoulou A, Baziaka F, Koutoukas P, Savva A, Kanni T, Georgitsi M, Pistiki A, Tsaganos T: Effect of the Novel Influenza A (H1N1) Virus in the Human Immune System. PLoS One 2009, 4(12):e8393.
• [80]Palacios G, Hornig M, Cisterna D, Savji N, Bussetti AV, Kapoor V, Hui J, Tokarz R, Briese T, Baumeister E: Streptococcus pneumoniae coinfection is correlated with the severity of H1N1 pandemic influenza. PLoS One 2009, 4(12):e8540.
• [81]Cuadrado A, Nebreda AR: Mechanisms and functions of p38 MAPK signalling. Biochem J 2010, 429:403-417.
• [82]Xing Z, Cardona CJ, Anunciacion J, Adams S, Dao N: Roles of the ERK MAPK in the regulation of proinflammatory and apoptotic responses in chicken macrophages infected with H9N2 avian influenza virus. J Gen Virol 2010, 91:343-351.
• [83]Marchant D, Singhera GK, Utokaparch S, Hackett TL, Boyd JH, Luo ZS, Si XN, Dorscheid DR, McManus BM, Hegele RG: Toll-like receptor 4-mediated activation of p38 mitogen-activated protein kinase is a determinant of respiratory virus entry and tropism. J Virol 2010, 84(21):11359-11373.
• [84]Eierhoff T, Hrincius ER, Rescher U, Ludwig S, Ehrhardt C: The epidermal growth factor receptor (EGFR) promotes uptake of influenza a viruses (IAV) into host cells. PLoS Pathog 2010, 6(9):e1001099.
• [85]Wurzer WJ, Planz O, Ehrhardt C, Giner M, Silberzahn T, Pleschka S, Ludwig S: Caspase 3 activation is essential for efficient influenza virus propagation. EMBO J 2003, 22(11):2717-2728.
• [86]SchultzCherry S, Hinshaw VS: Influenza virus neuraminidase activates latent transforming growth factor beta. J Virol 1996, 70(12):8624-8629.
• [87]Bloomston M, Frankel WL, Petrocca F, Volinia S, Alder H, Hagan JP, Liu CG, Bhatt D, Taccioli C, Croce CM: MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 2007, 297(17):1901-1908.
• [88]Lehmann U, Hasemeier B, Romermann D, Muller M, Langer F, Kreipe H: Epigenetic inactivation of microRNA genes in mammary carcinoma. Verh Dtsch Ges Pathol 2007, 91:214-220.
• [89]Tan Z, Randall G, Fan J, Camoretti-Mercado B, Brockman-Schneider R, Pan L, Solway J, Gern JE, Lemanske RF, Nicolae D: Allele-specific targeting of microRNAs to HLA-G and risk of asthma. Am J Human Gen 2007, 81(4):829-834.
• [90]Pan W, Zhu S, Yuan M, Cui HJ, Wang LJ, Luo XB, Li J, Zhou HB, Tang YJ, Shen N: MicroRNA-21 and MicroRNA-148a contribute to DNA hypomethylation in lupus CD4(+) T cells by directly and indirectly targeting DNA methyltransferase 1. J Immunol 2010, 184(12):6773-6781.
• [91]Liu X, Zhan Z, Xu L, Ma F, Li D, Guo Z, Li N, Cao X: MicroRNA-148/152 impair innate response and antigen presentation of TLR-triggered dendritic cells by targeting CaMKII alpha. J Immunol 2010, 185(12):7244-7251.
• [92]Rouas R, Fawad-Kazan H, El Zein N, Lewalle P, Rothe F, Simion A, Akl H, Mourtada M, El Rifai M, Burny A: Human natural Treg microRNA signature: Role of microRNA-31 and microRNA-21 in FOXP3 expression. Eur J Immunol 2009, 39(6):1608-1618.
• [93]Wieckiewicz J, Goto R, Wood KJ: T regulatory cells and the control of alloimmunity: from characterisation to clinical application. Curr Opinion Immunol 2010, 22(5):662-668.
• [94]Chen HX, Chen BG, Shi WW, Zhen R, Xu DP, Lin AF, Yan WH: Induction of cell surface human leukocyte antigen-G expression in pandemic H1N1 2009 and seasonal H1N1 influenza virus-infected patients. Human Immunol 2011, 72(2):159-165.
• [95]Pavlovic J, Haller O, Staeheli P: Human and mouse Mx-proteins inhibit different steps of the influenza-virus multiplication cycle. J Virol 1992, 66(4):2564-2569.
• [96]Haller O, Staeheli P, Kochs G: Interferon-induced Mx proteins in antiviral host defense. Biochimie 2007, 89(6–7):812-818.
• [97]Tumpey TM, Szretter KJ, Van Hoeven N, Katz JM, Kochs G, Haller O, Garcia-Sastre A, Staeheli P: The Mx1 gene protects mice against the pandemic 1918 and highly lethal human H5N1 influenza viruses. J Virol 2007, 81(19):10818-10821.
• [98]Cilloniz C, Pantin-Jackwood MJ, Ni C, Carter VS, Korth MJ, Swayne DE, Tumpey TM, Katze MG: Molecular signatures associated with Mx1-mediated resistance to highly pathogenic influenza virus infection: mechanisms of survival. J Virol 2012, 86(5):2437-2446.