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Archives of Virology

, Volume 157, Issue 1, pp 121–127 | Cite as

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

  • Andrey A. Kolokoltsov
  • Shramika Adhikary
  • Jennifer Garver
  • Lela Johnson
  • Robert A. Davey
  • Eric M. Vela
Brief Report

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.

Keywords

Arenavirus Filovirus Lassa virus Ebola virus Kinase inhibitors 

Notes

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.

References

  1. 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–S212PubMedCrossRefGoogle Scholar
  2. 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:e1000904PubMedCrossRefGoogle Scholar
  3. 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 314:20–26PubMedCrossRefGoogle Scholar
  4. 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 63:1124–1128CrossRefGoogle Scholar
  5. 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):2068–2073Google Scholar
  6. 6.
    Lecot S, Belouzard S, Dubuisson J, Rouille Y (2005) Bovine viral diarrhea virus entry is dependent on clathrin-mediated endocytosis. J Virol 79:10826–10829PubMedCrossRefGoogle Scholar
  7. 7.
    Yura Y, Yoshida H, Sato M (1993) Inhibition of herpes simplex virus replication by genistein, an inhibitor of protein-tyrosine kinase. Arch Virol 132:451–461PubMedCrossRefGoogle Scholar
  8. 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 153:1391–1396PubMedCrossRefGoogle Scholar
  9. 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 87:318–328PubMedCrossRefGoogle Scholar
  10. 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 74:1096–1102PubMedGoogle Scholar
  11. 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 2:15–23Google Scholar
  12. 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 64:111–118PubMedGoogle Scholar
  13. 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 56:3859–3861PubMedGoogle Scholar
  14. 14.
    Vela EM, Bowick GC, Herzog NK, Aronson JF (2008) Genistein treatment of cells inhibits arenavirus infection. Antivir Res 77:153–156PubMedCrossRefGoogle Scholar
  15. 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 73:8476–8484PubMedGoogle Scholar
  16. 16.
    Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29:2002–2007CrossRefGoogle Scholar
  17. 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 81:1923–1933PubMedCrossRefGoogle Scholar
  18. 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 446:92–96PubMedCrossRefGoogle Scholar
  19. 19.
    Martinez M, Cordo S, Candurra N (2007) Characterization of Junin arenavirus cell entry. J Gen Virol 88:1776–1784PubMedCrossRefGoogle Scholar
  20. 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 369:1–11PubMedCrossRefGoogle Scholar
  21. 21.
    Castilla V, Merisch S (1996) Low pH-induced fusion of Vero cells infected with Junin virus. Arch Virol 141:1307–1317PubMedCrossRefGoogle Scholar
  22. 22.
    Di Simone C, Zandonatti M, Buchmeier M (1994) Acidic pH triggers LCMV membrane fusion activity and conformational change in the glycoprotein spike. Virology 198:455–465PubMedCrossRefGoogle Scholar
  23. 23.
    Di Simone C, Buchmeier M (1995) Kinetics and pH dependence of acid-induced structural changes in the lymphoytic choriomeningitis virus glycoprotein complex. Virology 209:3–9PubMedCrossRefGoogle Scholar
  24. 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 112:1303–1311PubMedGoogle Scholar
  25. 25.
    Conner S, Schmid S (2003) Regulated portasl of entry into the cell. Nature 422:37–44PubMedCrossRefGoogle Scholar
  26. 26.
    McNiven M, Cao H, Pitts K, Yoon Y (2000) The dynamin family of mechanoenzymes: pinching in new places. TRENDS Biochem Sci 25:115–120PubMedCrossRefGoogle Scholar
  27. 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 7:24PubMedCrossRefGoogle Scholar
  28. 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 401:18–28PubMedCrossRefGoogle Scholar
  29. 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 294:60–69PubMedCrossRefGoogle Scholar
  30. 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 77:13433–13438PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Andrey A. Kolokoltsov
    • 1
  • Shramika Adhikary
    • 1
  • Jennifer Garver
    • 2
  • Lela Johnson
    • 2
  • Robert A. Davey
    • 1
  • Eric M. Vela
    • 2
  1. 1.Department of Microbiology and ImmunologyThe University of Texas Medical BranchGalvestonUSA
  2. 2.Battelle Memorial InstituteColumbusUSA

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