In vitro inhibition of monkeypox virus production and spread by Interferon-β

Virology Journal

Lisa E Hensley²  Arthur Goff²  Gordon Ruthel¹  John H Connor³  Kenny L Lin²  Sara C Johnston² 

[1] Toxicology Division, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter St. Fort Detrick, Frederick, MD 21702, USA;Virology Division, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter St. Fort Detrick, Frederick, MD 21702, USA;Microbiology Department, Boston University School of Medicine and Microbiology, 72 E.Concord St R-Bd Boston, Boston, MA 02118, USA

关键词: MxA;    IFN-β;    Type I interferon;    Monkeypox virus;    Orthopoxvirus;   

Others  :  1155311
DOI  :  10.1186/1743-422X-9-5

 received in 2011-12-07, accepted in 2012-01-06,  发布年份 2012

【 摘 要 】

Background

The Orthopoxvirus genus contains numerous virus species that are capable of causing disease in humans, including variola virus (the etiological agent of smallpox), monkeypox virus, cowpox virus, and vaccinia virus (the prototypical member of the genus). Monkeypox is a zoonotic disease that is endemic in the Democratic Republic of the Congo and is characterized by systemic lesion development and prominent lymphadenopathy. Like variola virus, monkeypox virus is a high priority pathogen for therapeutic development due to its potential to cause serious disease with significant health impacts after zoonotic, accidental, or deliberate introduction into a naïve population.

Results

The purpose of this study was to investigate the prophylactic and therapeutic potential of interferon-β (IFN-β) for use against monkeypox virus. We found that treatment with human IFN-β results in a significant decrease in monkeypox virus production and spread in vitro. IFN-β substantially inhibited monkeypox virus when introduced 6-8 h post infection, revealing its potential for use as a therapeutic. IFN-β induced the expression of the antiviral protein MxA in infected cells, and constitutive expression of MxA was shown to inhibit monkeypox virus infection.

Conclusions

Our results demonstrate the successful inhibition of monkeypox virus using human IFN-β and suggest that IFN-β could potentially serve as a novel safe therapeutic for human monkeypox disease.

【 授权许可】

   
2011 Johnston et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

【 参考文献 】

• [1]Moss B: Poxviridae: the viruses and their replication. In Field's Virology. Volume 2. 4th edition. Edited by Knipe DM, Howley PM. Philadelphia: Lippincott-Raven; 2001::2849-2883.
• [2]Bahar MW, Graham SC, Chen RA, Cooray S, Smith GL, Stuart DI, Grimes JM: How vaccinia virus has evolved to subvert the host immune response. J Struct Biol 2011, 175:127-134.
• [3]Gubser C, Hue S, Kellam P, Smith GL: Poxvirus genomes: a phylogenetic analysis. J Gen Virol 2004, 85:105-117.
• [4]Jackson SS, Ilyinskii P, Philippon V, Gritz L, Yafal AG, Zinnack K, Beaudry KR, Manson KH, Lifton MA, Kuroda MJ, et al.: Role of genes that modulate host immune responses in the immunogenicity and pathogenicity of vaccinia virus. J Virol 2005, 79:6554-6559.
• [5]Altman LK: Health Workers Union Wary of Smallpox Vaccinations. The New York Times; 2002.
• [6]Henderson DA, Inglesby TV, Bartlett JG, Ascher MS, Eitzen E, Jahrling PB, Hauer J, Layton M, McDade J, Osterholm MT, et al.: Smallpox as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA 1999, 281:2127-2137.
• [7]Huhn GD, Bauer AM, Yorita K, Graham MB, Sejvar J, Likos A, Damon IK, Reynolds MG, Kuehnert MJ: Clinical characteristics of human monkeypox, and risk factors for severe disease. Clin Infect Dis 2005, 41:1742-1751.
• [8]Jezek Z, Szczeniowski M, Paluku KM, Mutombo M: Human monkeypox: clinical features of 282 patients. J Infect Dis 1987, 156:293-298.
• [9]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.
• [10]Reynolds MG, Yorita KL, Kuehnert MJ, Davidson WB, Huhn GD, Holman RC, Damon IK: Clinical manifestations of human monkeypox influenced by route of infection. J Infect Dis 2006, 194:773-780.
• [11]Weaver JR, Isaacs SN: Monkeypox virus and insights into its immunomodulatory proteins. Immunol Rev 2008, 225:96-113.
• [12]Khodakevich L, Jezek Z, Kinzanzka K: Isolation of monkeypox virus from wild squirrel infected in nature. Lancet 1986, 1:98-99.
• [13]Khodakevich L, Szczeniowski M, Manbu ma D, Jezek Z, Marennikova S, Nakano J, Messinger D: The role of squirrels in sustaining monkeypox virus transmission. Trop Geogr Med 1987, 39:115-122.
• [14]Khodakevich L, Szczeniowski M, Nambu ma D, Jezek Z, Marennikova S, Nakano J, Meier F: Monkeypox virus in relation to the ecological features surrounding human settlements in Bumba zone, Zaire. Trop Geogr Med 1987, 39:56-63.
• [15]Hutin YJ, Williams RJ, Malfait P, Pebody R, Loparev VN, Ropp SL, Rodriguez M, Knight JC, Tshioko FK, Khan AS, et al.: Outbreak of human monkeypox, Democratic Republic of Congo, 1996-1997. Emerg Infect Dis 2001, 7:434-438.
• [16]Jezek Z, Grab B, Paluku KM, Szczeniowski MV: Human monkeypox: disease pattern, incidence and attack rates in a rural area of northern Zaire. Trop Geogr Med 1988, 40:73-83.
• [17]Jezek Z, Grab B, Szczeniowski M, Paluku KM, Mutombo M: Clinico-epidemiological features of monkeypox patients with an animal or human source of infection. Bull World Health Organ 1988, 66:459-464.
• [18]Rimoin AW, Mulembakani PM, Johnston SC, Lloyd Smith JO, Kisalu NK, Kinkela TL, Blumberg S, Thomassen HA, Pike BL, Fair JN, et al.: Major increase in human monkeypox incidence 30 years after smallpox vaccination campaigns cease in the Democratic Republic of Congo. Proc Natl Acad Sci USA 2010, 107:16262-16267.
• [19]Chen N, Li G, Liszewski MK, Atkinson JP, Jahrling PB, Feng Z, Schriewer J, Buck C, Wang C, Lefkowitz EJ, et al.: Virulence differences between monkeypox virus isolates from West Africa and the Congo basin. Virology 2005, 340:46-63.
• [20]Ladnyj ID, Ziegler P, Kima E: A human infection caused by monkeypox virus in Basankusu Territory, Democratic Republic of the Congo. Bull World Health Organ 1972, 46:593-597.
• [21]Reed KD, Melski JW, Graham MB, Regnery RL, Sotir MJ, Wegner MV, Kazmierczak JJ, Stratman EJ, Li Y, Fairley JA, et al.: The detection of monkeypox in humans in the Western Hemisphere. N Engl J Med 2004, 350:342-350.
• [22]Learned LA, Reynolds MG, Wassa DW, Li Y, Olson VA, Karem K, Stempora LL, Braden ZH, Kline R, Likos A, et al.: Extended interhuman transmission of monkeypox in a hospital community in the Republic of the Congo, 2003. Am J Trop Med Hyg 2005, 73:428-434.
• [23]Biron CA: Role of early cytokines, including alpha and beta interferons (IFN-alpha/beta), in innate and adaptive immune responses to viral infections. Semin Immunol 1998, 10:383-390.
• [24]Randall RE, Goodbourn S: Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures. J Gen Virol 2008, 89:1-47.
• [25]Samuel CE: Antiviral actions of interferon. Interferon-regulated cellular proteins and their surprisingly selective antiviral activities. Virology 1991, 183:1-11.
• [26]Perdiguero B, Esteban M: The interferon system and vaccinia virus evasion mechanisms. J Interferon Cytokine Res 2009, 29:581-598.
• [27]Mohamed MR, Rahman MM, Lanchbury JS, Shattuck D, Neff C, Dufford M, van Buuren N, Fagan K, Barry M, Smith S, et al.: Proteomic screening of variola virus reveals a unique NF-kappaB inhibitor that is highly conserved among pathogenic orthopoxviruses. Proc Natl Acad Sci USA 2009, 106:9045-9050.
• [28]Chang HW, Jacobs BL: Identification of a conserved motif that is necessary for binding of the vaccinia virus E3L gene products to double-stranded RNA. Virology 1993, 194:537-547.
• [29]Chang HW, Watson JC, Jacobs BL: The E3L gene of vaccinia virus encodes an inhibitor of the interferon-induced, double-stranded RNA-dependent protein kinase. Proc Natl Acad Sci USA 1992, 89:4825-4829.
• [30]Kim YG, Muralinath M, Brandt T, Pearcy M, Hauns K, Lowenhaupt K, Jacobs BL, Rich A: A role for Z-DNA binding in vaccinia virus pathogenesis. Proc Natl Acad Sci USA 2003, 100:6974-6979.
• [31]Kim YG, Lowenhaupt K, Oh DB, Kim KK, Rich A: Evidence that vaccinia virulence factor E3L binds to Z-DNA in vivo: Implications for development of a therapy for poxvirus infection. Proc Natl Acad Sci USA 2004, 101:1514-1518.
• [32]Brandt TA, Jacobs BL: Both carboxy--and amino-terminal domains of the vaccinia virus interferon resistance gene, E3L, are required for pathogenesis in a mouse model. J Virol 2001, 75:850-856.
• [33]Carroll K, Elroy-Stein O, Moss B, Jagus R: Recombinant vaccinia virus K3L gene product prevents activation of double-stranded RNA-dependent, initiation factor 2 alpha-specific protein kinase. J Biol Chem 1993, 268:12837-12842.
• [34]Davies MV, Elroy-Stein O, Jagus R, Moss B, Kaufman RJ: The vaccinia virus K3L gene product potentiates translation by inhibiting double-stranded-RNA-activated protein kinase and phosphorylation of the alpha subunit of eukaryotic initiation factor 2. J Virol 1992, 66:1943-1950.
• [35]Sharp TV, Witzel JE, Jagus R: Homologous regions of the alpha subunit of eukaryotic translational initiation factor 2 (eIF2alpha) and the vaccinia virus K3L gene product interact with the same domain within the dsRNA-activated protein kinase (PKR). Eur J Biochem 1997, 250:85-91.
• [36]Langland JO, Jacobs BL: The role of the PKR-inhibitory genes, E3L and K3L, in determining vaccinia virus host range. Virology 2002, 299:133-141.
• [37]Meng X, Jiang C, Arsenio J, Dick K, Cao J, Xiang Y: Vaccinia virus K1L and C7L inhibit antiviral activities induced by type I interferons. J Virol 2009, 83:10627-10636.
• [38]Oguiura N, Spehner D, Drillien R: Detection of a protein encoded by the vaccinia virus C7L open reading frame and study of its effect on virus multiplication in different cell lines. J Gen Virol 1993, 74(Pt 7):1409-1413.
• [39]Perkus ME, Goebel SJ, Davis SW, Johnson GP, Limbach K, Norton EK, Paoletti E: Vaccinia virus host range genes. Virology 1990, 179:276-286.
• [40]Shisler JL, Jin XL: The vaccinia virus K1L gene product inhibits host NF-kappaB activation by preventing IkappaBalpha degradation. J Virol 2004, 78:3553-3560.
• [41]Backes S, Sperling KM, Zwilling J, Gasteiger G, Ludwig H, Kremmer E, Schwantes A, Staib C, Sutter G: Viral host-range factor C7 or K1 is essential for modified vaccinia virus Ankara late gene expression in human and murine cells, irrespective of their capacity to inhibit protein kinase R-mediated phosphorylation of eukaryotic translation initiation factor 2alpha. J Gen Virol 2010, 91:470-482.
• [42]Fernandez de Marco Mdel M, Alejo A, Hudson P, Damon IK, Alcami A: The highly virulent variola and monkeypox viruses express secreted inhibitors of type I interferon. FASEB J 2010, 24:1479-1488.
• [43]Day SL, Ramshaw IA, Ramsay AJ, Ranasinghe C: Differential effects of the type I interferons alpha4, beta, and epsilon on antiviral activity and vaccine efficacy. J Immunol 2008, 180:7158-7166.
• [44]Weimar W, Stitz L, Billiau A, Cantell K, Schellekens H: Prevention of vaccinia lesions in Rhesus monkeys by human leucocyte and fibroblast interferon. J Gen Virol 1980, 48:25-30.
• [45]Haller O, Gao S, von der Malsburg A, Daumke O, Kochs G: Dynamin-like MxA GTPase: structural insights into oligomerization and implications for antiviral activity. J Biol Chem 2010, 285:28419-28424.
• [46]Haller O, Kochs G: Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity. J Interferon Cytokine Res 2010, 31:79-87.
• [47]Haller O, Stertz S, Kochs G: The Mx GTPase family of interferon-induced antiviral proteins. Microbes Infect 2007, 9:1636-1643.
• [48]Haller O, Weber F: The interferon response circuit in antiviral host defense. Verh K Acad Geneeskd Belg 2009, 71:73-86.
• [49]Netherton CL, Simpson J, Haller O, Wileman TE, Takamatsu HH, Monaghan P, Taylor G: Inhibition of a large double-stranded DNA virus by MxA protein. J Virol 2009, 83:2310-2320.
• [50]Pavlovic J, Zurcher T, Haller O, Staeheli P: Resistance to influenza virus and vesicular stomatitis virus conferred by expression of human MxA protein. J Virol 1990, 64:3370-3375.
• [51]Staeheli P, Pravtcheva D, Lundin LG, Acklin M, Ruddle F, Lindenmann J, Haller O: Interferon-regulated influenza virus resistance gene Mx is localized on mouse chromosome 16. J Virol 1986, 58:967-969.
• [52]Stertz S, Reichelt M, Krijnse-Locker J, Mackenzie J, Simpson JC, Haller O, Kochs G: Interferon-induced, antiviral human MxA protein localizes to a distinct subcompartment of the smooth endoplasmic reticulum. J Interferon Cytokine Res 2006, 26:650-660.
• [53]Frese M, Kochs G, Meier-Dieter U, Siebler J, Haller O: Human MxA protein inhibits tick-borne Thogoto virus but not Dhori virus. J Virol 1995, 69:3904-3909.
• [54]Zurcher T, Pavlovic J, Staeheli P: Mechanism of human MxA protein action: variants with changed antiviral properties. EMBO J 1992, 11:1657-1661.
• [55]Huggins J, Goff A, Hensley L, Mucker E, Shamblin J, Wlazlowski C, Johnson W, Chapman J, Larsen T, Twenhafel N, et al.: Nonhuman primates are protected from smallpox virus or monkeypox virus challenges by the antiviral drug ST-246. Antimicrob Agents Chemother 2009, 53:2620-2625.
• [56]Kennedy RB, Ovsyannikova I, Poland GA: Smallpox vaccines for biodefense. Vaccine 2009, 27(Suppl 4):D73-79.
• [57]Wiser I, Balicer RD, Cohen D: An update on smallpox vaccine candidates and their role in bioterrorism related vaccination strategies. Vaccine 2007, 25:976-984.
• [58]Everett WW, Coffin SE, Zaoutis T, Halpern SD, Strom BL: Smallpox vaccination: a national survey of emergency health care providers. Acad Emerg Med 2003, 10:606-611.
• [59]McNeil D: When parents say no to child vaccinations. The New York Times; 2002.
• [60]Dropulic LK, Cohen JI: Update on new antivirals under development for the treatment of double-stranded DNA virus infections. Clin Pharmacol Ther 2010, 88:610-619.
• [61]Baker RO, Bray M, Huggins JW: Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections. Antiviral Res 2003, 57:13-23.
• [62]Smee DF, Bailey KW, Wong MH, Sidwell RW: Effects of cidofovir on the pathogenesis of a lethal vaccinia virus respiratory infection in mice. Antiviral Res 2001, 52:55-62.
• [63]Stittelaar KJ, Neyts J, Naesens L, van Amerongen G, van Lavieren RF, Holy A, De Clercq E, Niesters HG, Fries E, Maas C, et al.: Antiviral treatment is more effective than smallpox vaccination upon lethal monkeypox virus infection. Nature 2006, 439:745-748.
• [64]Jahrling PB, Fritz EA, Hensley LE: Countermeasures to the bioterrorist threat of smallpox. Curr Mol Med 2005, 5:817-826.
• [65]Reeves PM, Bommarius B, Lebeis S, McNulty S, Christensen J, Swimm A, Chahroudi A, Chavan R, Feinberg MB, Veach D, et al.: Disabling poxvirus pathogenesis by inhibition of Abl-family tyrosine kinases. Nat Med 2005, 11:731-739.
• [66]Bolken TC, Hruby DE: Tecovirimat for smallpox infections. Drugs Today (Barc) 2010, 46:109-117.
• [67]Goff AJ, Chapman J, Foster C, Wlazlowski C, Shamblin J, Lin K, Kreiselmeier N, Mucker E, Paragas J, Lawler J, Hensley L: A novel respiratory model of infection with monkeypox virus in cynomolgus macaques. J Virol 2011, 85:4898-4909.
• [68]Jordan R, Goff A, Frimm A, Corrado ML, Hensley LE, Byrd CM, Mucker E, Shamblin J, Bolken TC, Wlazlowski C, et al.: ST-246 antiviral efficacy in a nonhuman primate monkeypox model: determination of the minimal effective dose and human dose justification. Antimicrob Agents Chemother 2009, 53:1817-1822.
• [69]Ward BM, Moss B: Visualization of intracellular movement of vaccinia virus virions containing a green fluorescent protein-B5R membrane protein chimera. J Virol 2001, 75:4802-4813.