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Inhibition of Lassa virus and Ebola virus infection in host cells treated with the kinase inhibitors genistein and tyrphostin

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Abstract

Arenaviruses and filoviruses are capable of causing hemorrhagic fever syndrome in humans. Limited therapeutic and/or prophylactic options are available for humans suffering from viral hemorrhagic fever. In this report, we demonstrate that pre-treatment of host cells with the kinase inhibitors genistein and tyrphostin AG1478 leads to inhibition of infection or transduction in cells infected with Ebola virus, Marburg virus, and Lassa virus. In all, the results demonstrate that a kinase inhibitor cocktail consisting of genistein and tyrphostin AG1478 is a broad-spectrum antiviral that may be used as a therapeutic or prophylactic against arenavirus and filovirus hemorrhagic fever.

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References

  1. Towner J, Sealy T, Ksiazek TG, Nichol ST (2007) High-throughput molecular detection of hemorrhagic fever virus threats with applications for outbreak settings. J Infect Dis 196:S205–S212

    Article  PubMed  CAS  Google Scholar 

  2. Hensley LE, Mulangu S, Asiedu C, Johnson J, Honko AN, Stanley D, Fabozzi G, Nichol ST, Ksiazek TG, Rollin PE, Wahl-Jensen V, Bailey M, Jahrling PB, Roederer M, Koup RA, Sullivan NJ (2010) Demonstration of cross-protective vaccine immunity against an emerging pathogenic Ebolavirus species. PLoS Pathog 6:e1000904

    Article  PubMed  Google Scholar 

  3. McCormick JB, King I, Webb P, Johnson K, O’Sullivan R, Smith E, Tripple S, Tong T (1986) Lassa fever: effective therapy with Ribavirin. N Engl J Med 314:20–26

    Article  PubMed  CAS  Google Scholar 

  4. Akula S, Hurley D, Wixon R, Wang C, Chase C (2002) Effect of genistein on replication of bovine herpes virus type 1. Am J Veter Res 63:1124–1128

    Article  CAS  Google Scholar 

  5. Andres A, Donovan SM, Kuhlenschmidt TB, Kuhlenschmidt MS (2007) Isoflavones at concentrations present in soy infant formula inhibit Rotavirus infection in vitro. J Nutr 137(9):2068–2073

    Google Scholar 

  6. Lecot S, Belouzard S, Dubuisson J, Rouille Y (2005) Bovine viral diarrhea virus entry is dependent on clathrin-mediated endocytosis. J Virol 79:10826–10829

    Article  PubMed  CAS  Google Scholar 

  7. Yura Y, Yoshida H, Sato M (1993) Inhibition of herpes simplex virus replication by genistein, an inhibitor of protein-tyrosine kinase. Arch Virol 132:451–461

    Article  PubMed  CAS  Google Scholar 

  8. Vela EM, Colpitts T, Zhang L, Davey R, Aronson J (2008) Pichindé virus is trafficked through a dynamin 2 endocytic pathway that is dependent on cellular Rab5- and Rab7-mediated endosomes. Arch Virol 153:1391–1396

    Article  PubMed  CAS  Google Scholar 

  9. Vela EM, Knostman KA, Mott JM, Warren RL, Garver JN, Vela LJ, Stammen RL (2010) Genistein, a general kinase inhibitor, as a potential antiviral for arenaviral hemorrhagic fever as described in the Pirital virus-Syrian golden hamster model. Antivir Res 87:318–328

    Article  PubMed  CAS  Google Scholar 

  10. Sbrana E, Mateo RI, Xiao S-Y, Popov VL, Newman PC, Tesh RB (2006) Clinical laboratory, virologic, and pathologic changes in hamsters experimentally infected with Pirital virus (Arenaviridae): a rodent model of Lassa fever. Am J Trop Med Hyg 74:1096–1102

    PubMed  Google Scholar 

  11. Vela E, Knostman K, Warren R, Garver J, Stammen R (2010) The disease progression associated with Pirital virus infection in the Syrian golden hamster. J Infect Dis Immun 2:15–23

    Google Scholar 

  12. Xiao S-Y, Zhang H, Yang Y, Tesh RB (2001) Pirital virus (Arenaviridae) infection in the Syrian golden hamster, Mesocricetus auratus: a new animal model for arenaviral hemorrhagic fever. Am J Trop Med Hyg 64:111–118

    PubMed  CAS  Google Scholar 

  13. Han Y, Caday CG, Nanda A, Cavenee WK, Huang H-JS (1996) Tyrphostin AG 1478 preferentially inhibits human glioma cells expressing truncated rather than wild-type epidermal growth factor receptors. Cancer Res 56:3859–3861

    PubMed  CAS  Google Scholar 

  14. Vela EM, Bowick GC, Herzog NK, Aronson JF (2008) Genistein treatment of cells inhibits arenavirus infection. Antivir Res 77:153–156

    Article  PubMed  CAS  Google Scholar 

  15. Smit JM, Bittman R, Wilschut J (1999) Low-pH-dependent fusion of Sindbis virus with receptor-free cholesterol- and sphingolipid-containing liposomes. J Virol 73:8476–8484

    PubMed  CAS  Google Scholar 

  16. Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:2002–2007

    Article  Google Scholar 

  17. Bowick G, Fennewald S, Scott E, Zhang L, Elsom B, Aronson J, Spratt H, Luxon B, Gorenstein D, Herzog N (2007) Identification of differentially activated cell-signalling networks associated with Pichinde virus pathogenesis by using systems kinomics. J Virol 81:1923–1933

    Article  PubMed  CAS  Google Scholar 

  18. Radoshitzky S, Abraham J, Spiropoulou C, Kuhn J, Nguyen D, Wenhui L, Nagel J, Schmidt P, Nunberg J, Andrews N, Farzan M, Choe H (2007) Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenaviruses. Nature 446:92–96

    Article  PubMed  CAS  Google Scholar 

  19. Martinez M, Cordo S, Candurra N (2007) Characterization of Junin arenavirus cell entry. J Gen Virol 88:1776–1784

    Article  PubMed  CAS  Google Scholar 

  20. Vela E, Zhang L, Colpitts T, Davey R, Aronson J (2007) Arenavirus entry occurs through a cholesterol-dependent, non-caveolar, clathrin-mediated endocytic mechanism. Virology 369:1–11

    Article  PubMed  CAS  Google Scholar 

  21. Castilla V, Merisch S (1996) Low pH-induced fusion of Vero cells infected with Junin virus. Arch Virol 141:1307–1317

    Article  PubMed  CAS  Google Scholar 

  22. Di Simone C, Zandonatti M, Buchmeier M (1994) Acidic pH triggers LCMV membrane fusion activity and conformational change in the glycoprotein spike. Virology 198:455–465

    Article  PubMed  CAS  Google Scholar 

  23. Di Simone C, Buchmeier M (1995) Kinetics and pH dependence of acid-induced structural changes in the lymphoytic choriomeningitis virus glycoprotein complex. Virology 209:3–9

    Article  PubMed  CAS  Google Scholar 

  24. Benmerah A, Bayrou M, Cerf-Bensussan N, Dautry-Varsat A (1999) Inhibition of clathrin-coated pit assembly by an Eps15 mutant. J Cell Sci 112:1303–1311

    PubMed  CAS  Google Scholar 

  25. Conner S, Schmid S (2003) Regulated portasl of entry into the cell. Nature 422:37–44

    Article  PubMed  CAS  Google Scholar 

  26. McNiven M, Cao H, Pitts K, Yoon Y (2000) The dynamin family of mechanoenzymes: pinching in new places. TRENDS Biochem Sci 25:115–120

    Article  PubMed  CAS  Google Scholar 

  27. Ang F, Wong A, Ng M, Chu J (2010) Small interference RNA profiling reveals the essential role of human membrane trafficking genes in mediating the infectious entry of dengue virus. Virol J 7:24

    Article  PubMed  Google Scholar 

  28. Bhattacharyya S, Warfield KL, Ruthel G, Bavari S, Aman MJ, Hope TJ (2010) Ebola virus uses clathrin-mediated endocytosis as an entry pathway. Virology 401:18–28

    Article  PubMed  CAS  Google Scholar 

  29. Jin M, Park J, Lee S, Park B, Shin J, Song KJ, Ahn TI, Hwang SY, Ahn BY, Ahn K (2002) Hantaan virus enters cells by clathrin-dependent receptor-mediated endocytosis. Virology 294:60–69

    Article  PubMed  CAS  Google Scholar 

  30. Simmons G, Rennekamp AJ, Chai N, Vandenberghe LH, Riley JL, Bates P (2003) Folate receptor alpha and Caveolae are not required for Ebola virus glycoprotein-mediated viral infection. J Virol 77:13433–13438

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors would like to acknowledge Drs. James Blank, Herbert Bresler, and Catherine Smith for providing their support and technical assistance. This work was funded through the Battelle Health and Life Sciences Independent Research and Development Program.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX, 77555, USA

    Andrey A. Kolokoltsov, Shramika Adhikary & Robert A. Davey

  2. Battelle Memorial Institute, 505 King Ave, Columbus, OH, 43201, USA

    Jennifer Garver, Lela Johnson & Eric M. Vela

Authors
  1. Andrey A. Kolokoltsov
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  2. Shramika Adhikary
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  3. Jennifer Garver
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  4. Lela Johnson
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  5. Robert A. Davey
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  6. Eric M. Vela
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Correspondence to Eric M. Vela.

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Kolokoltsov, A.A., Adhikary, S., Garver, J. et al. Inhibition of Lassa virus and Ebola virus infection in host cells treated with the kinase inhibitors genistein and tyrphostin. Arch Virol 157, 121–127 (2012). https://doi.org/10.1007/s00705-011-1115-8

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  • DOI: https://doi.org/10.1007/s00705-011-1115-8

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