Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1996 Feb;70(2):915–923. doi: 10.1128/jvi.70.2.915-923.1996

Inhibition of bunyaviruses, phleboviruses, and hantaviruses by human MxA protein.

M Frese 1, G Kochs 1, H Feldmann 1, C Hertkorn 1, O Haller 1
PMCID: PMC189895  PMID: 8551631

Abstract

Viruses of the Bunyaviridae family cause a variety of diseases ranging from uncomplicated fever to potentially lethal encephalitis and hemorrhagic fever. Little is known about the factors determining pathogenicity in the vertebrate host. Interferons have been reported to be inhibitory, but their mode of action against members of the Bunyaviridae has not yet been elucidated. The interferon-induced MxA protein encoded on human chromosome 21 is a large GTPase with antiviral activity against distinct negative-strand RNA viruses, notably influenza viruses. Here we show that MxA inhibits representative members of the Bunyaviridae family by interacting with an early step of virus replication. When constitutively expressed in stably transfected Vero cells, MxA prevented the accumulation of viral transcripts and proteins of Hantaan virus (genus Hantavirus). Other members of the family such as La Crosse virus (genus Bunyavirus) and Rift Valley fever virus and sandfly fever virus (both genus Phlebovirus) were likewise inhibited, and virus titers were reduced up to 10(4)-fold. Our data indicate that humans have evolved a mechanism of controlling these viruses irrespective of differences in viral coding strategies.

Full Text

The Full Text of this article is available as a PDF (821.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aebi M., Fäh J., Hurt N., Samuel C. E., Thomis D., Bazzigher L., Pavlovic J., Haller O., Staeheli P. cDNA structures and regulation of two interferon-induced human Mx proteins. Mol Cell Biol. 1989 Nov;9(11):5062–5072. doi: 10.1128/mcb.9.11.5062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Caplen H., Peters C. J., Bishop D. H. Mutagen-directed attenuation of Rift Valley fever virus as a method for vaccine development. J Gen Virol. 1985 Oct;66(Pt 10):2271–2277. doi: 10.1099/0022-1317-66-10-2271. [DOI] [PubMed] [Google Scholar]
  3. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  4. Diaz M. O., Ziemin S., Le Beau M. M., Pitha P., Smith S. D., Chilcote R. R., Rowley J. D. Homozygous deletion of the alpha- and beta 1-interferon genes in human leukemia and derived cell lines. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5259–5263. doi: 10.1073/pnas.85.14.5259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. 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 Jun;69(6):3904–3909. doi: 10.1128/jvi.69.6.3904-3909.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Gonzalez-Scarano F., Shope R. E., Calisher C. E., Nathanson N. Characterization of monoclonal antibodies against the G1 and N proteins of LaCrosse and Tahyna, two California serogroup bunyaviruses. Virology. 1982 Jul 15;120(1):42–53. doi: 10.1016/0042-6822(82)90005-8. [DOI] [PubMed] [Google Scholar]
  7. Griot C., Gonzalez-Scarano F., Nathanson N. Molecular determinants of the virulence and infectivity of California serogroup bunyaviruses. Annu Rev Microbiol. 1993;47:117–138. doi: 10.1146/annurev.mi.47.100193.001001. [DOI] [PubMed] [Google Scholar]
  8. Gui X. E., Ho M., Cohen M. S., Wang Q. L., Huang H. P., Xie Q. X. Hemorrhagic fever with renal syndrome: treatment with recombinant alpha interferon. J Infect Dis. 1987 May;155(5):1047–1051. doi: 10.1093/infdis/155.5.1047. [DOI] [PubMed] [Google Scholar]
  9. Gunning P., Ponte P., Okayama H., Engel J., Blau H., Kedes L. Isolation and characterization of full-length cDNA clones for human alpha-, beta-, and gamma-actin mRNAs: skeletal but not cytoplasmic actins have an amino-terminal cysteine that is subsequently removed. Mol Cell Biol. 1983 May;3(5):787–795. doi: 10.1128/mcb.3.5.787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Huang T., Pavlovic J., Staeheli P., Krystal M. Overexpression of the influenza virus polymerase can titrate out inhibition by the murine Mx1 protein. J Virol. 1992 Jul;66(7):4154–4160. doi: 10.1128/jvi.66.7.4154-4160.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. ISAACS A., PORTERFIELD J. S., BARON S. The influence of oxygenation on virus growth. II. Effect on the antiviral action of interferon. Virology. 1961 Aug;14:450–455. doi: 10.1016/0042-6822(61)90337-3. [DOI] [PubMed] [Google Scholar]
  12. Israël A. Preliminary characterization of the particles from productive and abortive infections of L cells by fowl plague virus. Ann Microbiol (Paris) 1979 Jul;130B(1):85–100. [PubMed] [Google Scholar]
  13. Jacoby D. R., Cooke C., Prabakaran I., Boland J., Nathanson N., Gonzalez-Scarano F. Expression of the La Crosse M segment proteins in a recombinant vaccinia expression system mediates pH-dependent cellular fusion. Virology. 1993 Apr;193(2):993–996. doi: 10.1006/viro.1993.1213. [DOI] [PubMed] [Google Scholar]
  14. Knuth T., Liebermann H., Urbaneck D. Für die DDR neuartige Virusinfektionen der Haustiere. 4. Mitteilung: Die Tahyna-Virusinfektion--ein Uberblick. Arch Exp Veterinarmed. 1990;44(2):265–277. [PubMed] [Google Scholar]
  15. Krug R. M., Shaw M., Broni B., Shapiro G., Haller O. Inhibition of influenza viral mRNA synthesis in cells expressing the interferon-induced Mx gene product. J Virol. 1985 Oct;56(1):201–206. doi: 10.1128/jvi.56.1.201-206.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  17. Laughlin L. W., Meegan J. M., Strausbaugh L. J., Morens D. M., Watten R. H. Epidemic Rift Valley fever in Egypt: observations of the spectrum of human illness. Trans R Soc Trop Med Hyg. 1979;73(6):630–633. doi: 10.1016/0035-9203(79)90006-3. [DOI] [PubMed] [Google Scholar]
  18. Nichol S. T., Spiropoulou C. F., Morzunov S., Rollin P. E., Ksiazek T. G., Feldmann H., Sanchez A., Childs J., Zaki S., Peters C. J. Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness. Science. 1993 Nov 5;262(5135):914–917. doi: 10.1126/science.8235615. [DOI] [PubMed] [Google Scholar]
  19. Pavlovic J., Arzet H. A., Hefti H. P., Frese M., Rost D., Ernst B., Kolb E., Staeheli P., Haller O. Enhanced virus resistance of transgenic mice expressing the human MxA protein. J Virol. 1995 Jul;69(7):4506–4510. doi: 10.1128/jvi.69.7.4506-4510.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Pavlovic J., Haller O., Staeheli P. Human and mouse Mx proteins inhibit different steps of the influenza virus multiplication cycle. J Virol. 1992 Apr;66(4):2564–2569. doi: 10.1128/jvi.66.4.2564-2569.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Pavlovic J., Zürcher T., Haller O., Staeheli P. Resistance to influenza virus and vesicular stomatitis virus conferred by expression of human MxA protein. J Virol. 1990 Jul;64(7):3370–3375. doi: 10.1128/jvi.64.7.3370-3375.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Pensiero M. N., Sharefkin J. B., Dieffenbach C. W., Hay J. Hantaan virus infection of human endothelial cells. J Virol. 1992 Oct;66(10):5929–5936. doi: 10.1128/jvi.66.10.5929-5936.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Peters C. J., Reynolds J. A., Slone T. W., Jones D. E., Stephen E. L. Prophylaxis of Rift Valley fever with antiviral drugs, immune serum, an interferon inducer, and a macrophage activator. Antiviral Res. 1986 Aug;6(5):285–297. doi: 10.1016/0166-3542(86)90024-0. [DOI] [PubMed] [Google Scholar]
  24. Rossier C., Patterson J., Kolakofsky D. La Crosse virus small genome mRNA is made in the cytoplasm. J Virol. 1986 May;58(2):647–650. doi: 10.1128/jvi.58.2.647-650.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ruo S. L., Sanchez A., Elliott L. H., Brammer L. S., McCormick J. B., Fisher-Hoch S. P. Monoclonal antibodies to three strains of hantaviruses: Hantaan, R22, and Puumala. Arch Virol. 1991;119(1-2):1–11. doi: 10.1007/BF01314318. [DOI] [PubMed] [Google Scholar]
  26. Samuel C. E. Antiviral actions of interferon. Interferon-regulated cellular proteins and their surprisingly selective antiviral activities. Virology. 1991 Jul;183(1):1–11. doi: 10.1016/0042-6822(91)90112-o. [DOI] [PubMed] [Google Scholar]
  27. Schneider-Schaulies S., Schneider-Schaulies J., Schuster A., Bayer M., Pavlovic J., ter Meulen V. Cell type-specific MxA-mediated inhibition of measles virus transcription in human brain cells. J Virol. 1994 Nov;68(11):6910–6917. doi: 10.1128/jvi.68.11.6910-6917.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Schnorr J. J., Schneider-Schaulies S., Simon-Jödicke A., Pavlovic J., Horisberger M. A., ter Meulen V. MxA-dependent inhibition of measles virus glycoprotein synthesis in a stably transfected human monocytic cell line. J Virol. 1993 Aug;67(8):4760–4768. doi: 10.1128/jvi.67.8.4760-4768.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Schwemmle M., Weining K. C., Richter M. F., Schumacher B., Staeheli P. Vesicular stomatitis virus transcription inhibited by purified MxA protein. Virology. 1995 Jan 10;206(1):545–554. doi: 10.1016/s0042-6822(95)80071-9. [DOI] [PubMed] [Google Scholar]
  30. Staeheli P., Haller O. Interferon-induced Mx protein: a mediator of cellular resistance to influenza virus. Interferon. 1987;8:1–23. [PubMed] [Google Scholar]
  31. Staeheli P., Haller O. Interferon-induced human protein with homology to protein Mx of influenza virus-resistant mice. Mol Cell Biol. 1985 Aug;5(8):2150–2153. doi: 10.1128/mcb.5.8.2150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Staeheli P. Interferon-induced proteins and the antiviral state. Adv Virus Res. 1990;38:147–200. doi: 10.1016/s0065-3527(08)60862-3. [DOI] [PubMed] [Google Scholar]
  33. Staeheli P., Pavlovic J. Inhibition of vesicular stomatitis virus mRNA synthesis by human MxA protein. J Virol. 1991 Aug;65(8):4498–4501. doi: 10.1128/jvi.65.8.4498-4501.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Staeheli P., Pitossi F., Pavlovic J. Mx proteins: GTPases with antiviral activity. Trends Cell Biol. 1993 Aug;3(8):268–272. doi: 10.1016/0962-8924(93)90055-6. [DOI] [PubMed] [Google Scholar]
  35. Stranden A. M., Staeheli P., Pavlovic J. Function of the mouse Mx1 protein is inhibited by overexpression of the PB2 protein of influenza virus. Virology. 1993 Dec;197(2):642–651. doi: 10.1006/viro.1993.1639. [DOI] [PubMed] [Google Scholar]
  36. THOMPSON W. H., KALFAYAN B., ANSLOW R. O. ISOLATION OF CALIFORNIA ENCEPHALITIS GROUP VIRUS FROM A FATAL HUMAN ILLNESS. Am J Epidemiol. 1965 Mar;81:245–253. doi: 10.1093/oxfordjournals.aje.a120512. [DOI] [PubMed] [Google Scholar]
  37. Tamura M., Asada H., Kondo K., Takahashi M., Yamanishi K. Effects of human and murine interferons against hemorrhagic fever with renal syndrome (HFRS) virus (Hantaan virus). Antiviral Res. 1987 Nov;8(4):171–178. doi: 10.1016/0166-3542(87)90071-4. [DOI] [PubMed] [Google Scholar]
  38. Temonen M., Lankinen H., Vapalahti O., Ronni T., Julkunen I., Vaheri A. Effect of interferon-alpha and cell differentiation on Puumala virus infection in human monocyte/macrophages. Virology. 1995 Jan 10;206(1):8–15. doi: 10.1016/s0042-6822(95)80014-x. [DOI] [PubMed] [Google Scholar]
  39. Thimme R., Frese M., Kochs G., Haller O. Mx1 but not MxA confers resistance against tick-borne Dhori virus in mice. Virology. 1995 Aug 1;211(1):296–301. doi: 10.1006/viro.1995.1404. [DOI] [PubMed] [Google Scholar]
  40. Zürcher T., Pavlovic J., Staeheli P. Mechanism of human MxA protein action: variants with changed antiviral properties. EMBO J. 1992 Apr;11(4):1657–1661. doi: 10.1002/j.1460-2075.1992.tb05212.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES