Comparison of host cell gene expression in cowpox, monkeypox or vaccinia virus-infected cells reveals virus-specific regulation of immune response genes

Virology Journal

Andreas Nitsche¹  Piotr Wojtek Dabrowski²  Daniel Bourquain¹ 

[1] Centre for Biological Threats and Special Pathogens 1, Robert Koch Institute, Nordufer 20, Berlin 13353, Germany;Central Administration 4 (IT), Robert Koch Institute, Nordufer 20, Berlin 13353, Germany

关键词: Host cell response;    Gene expression;    Microarray;    Monkeypox virus;    Vaccinia virus;    Cowpox virus;    Orthopoxvirus;   

Others  :  1151675
DOI  :  10.1186/1743-422X-10-61

 received in 2012-08-15, accepted in 2013-02-08,  发布年份 2013

【 摘 要 】

Background

Animal-borne orthopoxviruses, like monkeypox, vaccinia and the closely related cowpox virus, are all capable of causing zoonotic infections in humans, representing a potential threat to human health. The disease caused by each virus differs in terms of symptoms and severity, but little is yet know about the reasons for these varying phenotypes. They may be explained by the unique repertoire of immune and host cell modulating factors encoded by each virus. In this study, we analysed the specific modulation of the host cell’s gene expression profile by cowpox, monkeypox and vaccinia virus infection. We aimed to identify mechanisms that are either common to orthopoxvirus infection or specific to certain orthopoxvirus species, allowing a more detailed description of differences in virus-host cell interactions between individual orthopoxviruses. To this end, we analysed changes in host cell gene expression of HeLa cells in response to infection with cowpox, monkeypox and vaccinia virus, using whole-genome gene expression microarrays, and compared these to each other and to non-infected cells.

Results

Despite a dominating non-responsiveness of cellular transcription towards orthopoxvirus infection, we could identify several clusters of infection-modulated genes. These clusters are either commonly regulated by orthopoxvirus infection or are uniquely regulated by infection with a specific orthopoxvirus, with major differences being observed in immune response genes. Most noticeable was an induction of genes involved in leukocyte migration and activation in cowpox and monkeypox virus-infected cells, which was not observed following vaccinia virus infection.

Conclusion

Despite their close genetic relationship, the expression profiles induced by infection with different orthopoxviruses vary significantly. It may be speculated that these differences at the cellular level contribute to the individual characteristics of cowpox, monkeypox and vaccinia virus infections in certain host species.

【 授权许可】

   
2013 Bourquain et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Moss B: Poxviridae: the viruses and their replication. In Fields Virology. 5th edition. Edited by Knipe DM. Philadelphia: Lippincott Williams & Wilkins; 2007:2905-2946.
• [2]King AMQ, International Committee on Taxonomy of Viruses: Virus taxonomy: classification and nomenclature of viruses: ninth report of the International Committee on Taxonomy of Viruses. London: Waltham, MA: Academic Press; 2012.
• [3]Essbauer S, Pfeffer M, Meyer H: Zoonotic poxviruses. Vet Microbiol 2010, 140:229-236.
• [4]Fenner F, Anderson DA, Arita I, Jezek Z, Ladnyi ID: Smallpox and Its Eradication. Geneva: World Health Organization; 1988.
• [5]CDC: Laboratory-acquired vaccinia exposures and infections--United States, 2005–2007. MMWR Morb Mortal Wkly Rep 2008, 57:401-404.
• [6]Mercer AA, Schmidt A, Weber OF: Poxviruses. Basel Boston: Birkhäuser; 2007.
• [7]de Souza TG, Drumond BP, Guedes MI, Leite JA, Mota BE, Campos MA, da Fonseca FG, Nogueira ML, Lobato ZI, Bonjardim CA: Zoonotic vaccinia virus infection in Brazil: clinical description and implications for health professionals. J Clin Microbiol 2007, 45:1370-1372.
• [8]Trindade GS, Emerson GL, Carroll DS, Kroon EG, Damon IK: Brazilian vaccinia viruses and their origins. Emerg Infect Dis 2007, 13:965-972.
• [9]Trindade GS, Guedes MI, Drumond BP, Mota BE, Abrahao JS, Lobato ZI, Gomes JA, Correa-Oliveira R, Nogueira ML, Kroon EG, da Fonseca FG: Zoonotic vaccinia virus: clinical and immunological characteristics in a naturally infected patient. Clin Infect Dis 2009, 48:e37-e40.
• [10]Trindade GS, Lobato ZI, Drumond BP, Leite JA, Trigueiro RC, Guedes MI, da Fonseca FG, dos Santos JR, Bonjardim CA, Ferreira PC, Kroon EG: Short report: Isolation of two vaccinia virus strains from a single bovine vaccinia outbreak in rural area from Brazil: Implications on the emergence of zoonotic orthopoxviruses. Am J Trop Med Hyg 2006, 75:486-490.
• [11]Czerny CP, Eis-Hubinger AM, Mayr A, Schneweis KE, Pfeiff B: Animal poxviruses transmitted from cat to man: current event with lethal end. Zentralbl Veterinarmed B 1991, 38:421-431.
• [12]Pelkonen PM, Tarvainen K, Hynninen A, Kallio ER, Henttonen K, Palva A, Vaheri A, Vapalahti O: Cowpox with severe generalized eruption, Finland. Emerg Infect Dis 2003, 9:1458-1461.
• [13]Vorou RM, Papavassiliou VG, Pierroutsakos IN: Cowpox virus infection: an emerging health threat. Curr Opin Infect Dis 2008, 21:153-156.
• [14]Baxby D, Bennett M, Getty B: Human cowpox 1969–93: a review based on 54 cases. Br J Dermatol 1994, 131:598-607.
• [15]Breman JG, Kalisa R, Steniowski MV, Zanotto E, Gromyko AI, Arita I: Human monkeypox, 1970–79. Bull World Health Organ 1980, 58:165-182.
• [16]Chen N, Li G, Liszewski MK, Atkinson JP, Jahrling PB, Feng Z, Schriewer J, Buck C, Wang C, Lefkowitz EJ: Virulence differences between monkeypox virus isolates from West Africa and the Congo basin. Virology 2005, 340:46-63.
• [17]Likos AM, Sammons SA, Olson VA, Frace AM, Li Y, Olsen-Rasmussen M, Davidson W, Galloway R, Khristova ML, Reynolds MG: A tale of two clades: monkeypox viruses. J Gen Virol 2005, 86:2661-2672.
• [18]Arita I, Gispen R, Kalter SS, Wah LT, Marennikova SS, Netter R, Tagaya I: Outbreaks of monkeypox and serological surveys in nonhuman primates. Bull World Health Organ 1972, 46:625-631.
• [19]Guerra S, Lopez-Fernandez LA, Conde R, Pascual-Montano A, Harshman K, Esteban M: Microarray analysis reveals characteristic changes of host cell gene expression in response to attenuated modified vaccinia virus Ankara infection of human HeLa cells. J Virol 2004, 78:5820-5834.
• [20]Ludwig H, Mages J, Staib C, Lehmann MH, Lang R, Sutter G: Role of viral factor E3L in modified vaccinia virus ankara infection of human HeLa Cells: regulation of the virus life cycle and identification of differentially expressed host genes. J Virol 2005, 79:2584-2596.
• [21]Yang Z, Bruno DP, Martens CA, Porcella SF, Moss B: Simultaneous high-resolution analysis of vaccinia virus and host cell transcriptomes by deep RNA sequencing. Proc Natl Acad Sci USA 2010, 107:11513-11518.
• [22]Brum LM, Lopez MC, Varela JC, Baker HV, Moyer RW: Microarray analysis of A549 cells infected with rabbitpox virus (RPV): a comparison of wild-type RPV and RPV deleted for the host range gene, SPI-1. Virology 2003, 315:322-334.
• [23]Guerra S, Lopez-Fernandez LA, Pascual-Montano A, Munoz M, Harshman K, Esteban M: Cellular gene expression survey of vaccinia virus infection of human HeLa cells. J Virol 2003, 77:6493-6506.
• [24]Guerra S, Najera JL, Gonzalez JM, Lopez-Fernandez LA, Climent N, Gatell JM, Gallart T, Esteban M: Distinct gene expression profiling after infection of immature human monocyte-derived dendritic cells by the attenuated poxvirus vectors MVA and NYVAC. J Virol 2007, 81:8707-8721.
• [25]Langland JO, Kash JC, Carter V, Thomas MJ, Katze MG, Jacobs BL: Suppression of proinflammatory signal transduction and gene expression by the dual nucleic acid binding domains of the vaccinia virus E3L proteins. J Virol 2006, 80:10083-10095.
• [26]Alkhalil A, Hammamieh R, Hardick J, Ichou MA, Jett M, Ibrahim S: Gene expression profiling of monkeypox virus-infected cells reveals novel interfaces for host-virus interactions. Virol J 2010, 7:173. BioMed Central Full Text
• [27]Rubins KH, Hensley LE, Relman DA, Brown PO: Stunned silence: gene expression programs in human cells infected with monkeypox or vaccinia virus. PLoS One 2011, 6:e15615.
• [28]Meyer H, Perrichot M, Stemmler M, Emmerich P, Schmitz H, Varaine F, Shungu R, Tshioko F, Formenty P: Outbreaks of disease suspected of being due to human monkeypox virus infection in the Democratic Republic of Congo in 2001. J Clin Microbiol 2002, 40:2919-2921.
• [29]Chang PY, Pogo BG: Reintroduction of gene(s) into an attenuated deletion mutant of vaccinia virus strain IHD-W. Microb Pathog 1993, 15:347-357.
• [30]Rubins KH, Hensley LE, Bell GW, Wang C, Lefkowitz EJ, Brown PO, Relman DA: Comparative analysis of viral gene expression programs during poxvirus infection: a transcriptional map of the vaccinia and monkeypox genomes. PLoS One 2008, 3:e2628.
• [31]Hanafusa H, Torii S, Yasunaga T, Nishida E: Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nat Cell Biol 2002, 4:850-858.
• [32]Impagnatiello MA, Weitzer S, Gannon G, Compagni A, Cotten M, Christofori G: Mammalian sprouty-1 and −2 are membrane-anchored phosphoprotein inhibitors of growth factor signaling in endothelial cells. J Cell Biol 2001, 152:1087-1098.
• [33]Wakioka T, Sasaki A, Kato R, Shouda T, Matsumoto A, Miyoshi K, Tsuneoka M, Komiya S, Baron R, Yoshimura A: Spred is a Sprouty-related suppressor of Ras signalling. Nature 2001, 412:647-651.
• [34]Zhang Z, Kobayashi S, Borczuk AC, Leidner RS, Laframboise T, Levine AD, Halmos B: Dual specificity phosphatase 6 (DUSP6) is an ETS-regulated negative feedback mediator of oncogenic ERK signaling in lung cancer cells. Carcinogenesis 2010, 31:577-586.
• [35]Kovanen PE, Rosenwald A, Fu J, Hurt EM, Lam LT, Giltnane JM, Wright G, Staudt LM, Leonard WJ: Analysis of gamma c-family cytokine target genes. Identification of dual-specificity phosphatase 5 (DUSP5) as a regulator of mitogen-activated protein kinase activity in interleukin-2 signaling. J Biol Chem 2003, 278:5205-5213.
• [36]Silva PN, Soares JA, Brasil BS, Nogueira SV, Andrade AA, de Magalhaes JC, Bonjardim MB, Ferreira PC, Kroon EG, Bruna-Romero O, Bonjardim CA: Differential role played by the MEK/ERK/EGR-1 pathway in orthopoxviruses vaccinia and cowpox biology. Biochem J 2006, 398:83-95.
• [37]Centers for Disease C, Prevention: Update: multistate outbreak of monkeypox--Illinois, Indiana, Kansas, Missouri, Ohio, and Wisconsin, 2003. MMWR Morb Mortal Wkly Rep 2003, 52:642-646.
• [38]Reynolds MG, Damon IK: Outbreaks of human monkeypox after cessation of smallpox vaccination. Trends Microbiol 2012, 20(2):80-87.
• [39]de Freitas MH, de Oliveira LC, Mugge FL, Ferreira PC, Trindade Gde S, Kroon EG, Bonjardim CA: The interplay between Aracatuba virus and host signaling pathways: role of PI3K/Akt in viral replication. Arch Virol 2011, 156:1775-1785.
• [40]Soares JA, Leite FG, Andrade LG, Torres AA, De Sousa LP, Barcelos LS, Teixeira MM, Ferreira PC, Kroon EG, Souto-Padron T, Bonjardim CA: Activation of the PI3K/Akt pathway early during vaccinia and cowpox virus infections is required for both host survival and viral replication. J Virol 2009, 83:6883-6899.
• [41]Johnson RF, Dyall J, Ragland DR, Huzella L, Byrum R, Jett C, St Claire M, Smith AL, Paragas J, Blaney JE, Jahrling PB: Comparative analysis of monkeypox virus infection of cynomolgus macaques by the intravenous or intrabronchial inoculation route. J Virol 2011, 85:2112-2125.
• [42]Johnson RF, Yellayi S, Cann JA, Johnson A, Smith AL, Paragas J, Jahrling PB, Blaney JE: Cowpox virus infection of cynomolgus macaques as a model of hemorrhagic smallpox. Virology 2011, 418:102-112.
• [43]Smith AL, St Claire M, Yellayi S, Bollinger L, Jahrling PB, Paragas J, Blaney JE, Johnson RF: Intrabronchial inoculation of cynomolgus macaques with cowpox virus. J Gen Virol 2012, 93:159-164.
• [44]Wahl-Jensen V, Cann JA, Rubins KH, Huggins JW, Fisher RW, Johnson AJ, de Kok-Mercado F, Larsen T, Raymond JL, Hensley LE, Jahrling PB: Progression of pathogenic events in cynomolgus macaques infected with variola virus. PLoS One 2011, 6:e24832.
• [45]Tsuchiya Y, Tagaya I: Plaque assay of variola virus in a cynomolgus monkey kidney cell line. Arch Gesamte Virusforsch 1970, 32:73-81.
• [46]Witkowski PT, Schuenadel L, Wiethaus J, Bourquain DR, Kurth A, Nitsche A: Cellular impedance measurement as a new tool for poxvirus titration, antibody neutralization testing and evaluation of antiviral substances. Biochem Biophys Res Commun 2010, 401:37-41.
• [47]Weng L, Dai H, Zhan Y, He Y, Stepaniants SB, Bassett DE: Rosetta error model for gene expression analysis. Bioinformatics 2006, 22:1111-1121.
• [48]Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, Fridman WH, Pages F, Trajanoski Z, Galon J: ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 2009, 25:1091-1093.
• [49]Smoot ME, Ono K, Ruscheinski J, Wang PL, Ideker T: Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics 2011, 27:431-432.
• [50]Kanehisa M, Goto S: KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 2000, 28:27-30.
• [51]Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT: Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 2000, 25:25-29.