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Thromb Haemost 2003; 89(06): 967-972
DOI: 10.1055/s-0037-1613397
Review Article
Schattauer GmbH

Viral hemorrhagic fever – a vascular disease?

Hans J. Schnittler
1   Institute of Physiology, Medical Faculty Carl Gustav Carus of the Technical University Dresden, Dresden, Germany
,
Heinz Feldmann
2   Canadian Science Centre for Human and Animal Health, National Microbiology Laboratory, Special Pathogens Program, Winnipeg, Canada
3   Department of Medical Microbiology, University of Manitoba, Winnipeg, Canada
› Author AffiliationsFinancial support: The above review was based on data that were generated through projects financed by the Deutsche Forschungsgemeinschaft (SPP 1130 project SCHN 430/3-1, SCHN 430/1-2, Fe 286/4-1, SFB 286, SFB 535, SFB 355), the Kempkes-Stiftung (21/95), the Canadian Institutes of Health Research (MOP – 43921), the European Community (INCO-grant ERBIC 18 CT9803832) and “Med Drive Program” of the Medical faculty of Dresden.
Further Information

Publication History

Received 14 January 2003

Accepted after revision 07 March 2003

Publication Date:
08 December 2017 (online)

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Summary

The syndrome of “viral hemorrhagic fever” in man caused by certain viruses, such as Ebola, Lassa, Dengue, and Crimean-Congo hemorrhagic fever viruses, is often associated with a shock syndrome of undetermined pathogenesis. However, the vascular system, particularly the vascular endothelium, seems to be directly and indirectly targeted by all these viruses. Here we briefly summarize the current knowledge on Marburg and Ebola virus infections, the prototype viral hemorrhagic fever agents, and formulate a working hypothesis for the pathogenesis of viral hemorrhagic fever. Infections with filoviruses show lethality up to 89% and in severe cases lead to a shock syndrome associated with hypotension, coagulation disorders and an imbalance of fluid distribution between the intravascular and extravascular tissue space. The primary target cells for filovi-ruses are mononuclear phagocytotic cells which are activated upon infection and release certain cytokines and chemokines. These mediators indirectly target the endothelium and are thought to play a key role in the pathogenesis of filoviral hemorrhagic fever. In addition, direct infection and subsequent destruction of endothelial cells might contribute to the pathogenesis. Filoviruses, particularly Ebola virus, encode nonstructural glycoproteins which are released from infected host cells. Their function as potential determinants in pathogenicity remains to be investigated.

Keywords

Filoviruses - influenza virus - endothelium - cytokines
 

  • References

  • 1 Schnittler HJ, Feldmann H. Molecular pathogenesis of filovirus infections: role of macrophages and endothelial cells. Curr Top Microbiol Immunol 1999; 235: 175-204.
    PubMedGoogle Scholar
  • 2 Sanchez A, Khan AS, Zaki SR, Nabel GJ, Ksiazek TG, Peters CJ. Filoviridae : Marburg and Ebola viruses. In Fields BN, Knipe DM, al e. eds Virology. (ed 4th) Philadelphia: Raven Press; 2001: 1279-304.
    Google Scholar
  • 3 Feldmann H, Saches A, Klenk HD. Filoviruses. In Collier LH. ed Topley and Wilosn’s Microbiology and Microbial Infections (ed 9th). London: Edward Arnold; 1998: 651-64.
    Google Scholar
  • 4 Feldmann A, Schafer MK, Garten W, Klenk HD. Targeted infection of endothelial cells by avian influenza virus A/FPV/Rostock/34 (H7N1) in chicken embryos. J Virol 2000; 74: 8018-27.
    CrossrefPubMedGoogle Scholar
  • 5 Feldmann H, Volchkov VE, Volchkova VA, Stroher U, Klenk HD. Biosynthesis and role of filoviral glycoproteins. J Gen Virol 2001; 82: 2839-48.
    CrossrefPubMedGoogle Scholar
  • 6 Geisbert TW, Jahrling PB, Hanes MA, Zack PM. Association of Ebola-related Reston virus particles and antigen with tissue lesions of monkeys imported to the United States. J Comp Pathol 1992; 106: 137-52.
    CrossrefPubMedGoogle Scholar
  • 7 Feldmann H, Bugany H, Mahner F, Klenk HD, Drenckhahn D, Schnittler HJ. Filovirus-induced endothelial leakage triggered by infected monocytes/macrophages. J Virol 1996; 70: 2208-14.
    PubMedGoogle Scholar
  • 8 Schnittler HJ, Feldmann H. Marburg and Ebola hemorrhagic fevers: does the primary course of infection depend on the accessibility of organ-specific macrophages?. Clin Infect Dis 1998; 27: 404-6.
    CrossrefPubMedGoogle Scholar
  • 9 Stroeher U, West E, Bugany H, Klenk HD, Schnittler HJ, Feldmann H. Infection and activation of monocytes by marburg and ebola viruses. J Virol 2001; 75: 11025-33.
    CrossrefPubMedGoogle Scholar
  • 10 Gupta M, Mahanty S, Ahmed R, Rollin PE. Monocyte-derived human macrophages and peripheral blood mononuclear cells infected with ebola virus secrete MIP-1alpha and TNF-alpha and inhibit poly-IC-induced IFN-alpha in vitro. Virology 2001; 284: 20-5.
    CrossrefPubMedGoogle Scholar
  • 11 Villinger F, Rollin PE, Brar SS. et al. Markedly elevated levels of interferon (IFN)-gamma, IFN-alpha, interleukin (IL)-2, IL-10, and tumor necrosis factor-alpha associated with fatal Ebola virus infection. J Infect Dis 1999; 179 (Suppl. 01) S188-91.
    CrossrefPubMedGoogle Scholar
  • 12 Ryabchikova EI, Kolesnikova LV, Luchko SV. An analysis of features of pathogenesis in two animal models of Ebola virus infection. J Infect Dis 1999; 179 (Suppl. 01) S199-202.
    CrossrefPubMedGoogle Scholar
  • 13 Stroeher U, Bevec D, Feldmann H, Klenk HD. TNF-alpha production follows a distinct signal cascade pathway. XIIth International Congress of Virology. Paris, France 2002; V: 539
    PubMedGoogle Scholar
  • 14 Chen JP, Cosgriff TM. Hemorrhagic fever virus-induced changes in hemostasis and vascular biology. Blood Coagul Fibrinolysis 2000; 11: 461-83.
    CrossrefPubMedGoogle Scholar
  • 15 Fisher-Hoch SP, Platt GS, Neild GH. et al. Pathophysiology of shock and hemorrhage in a fulminating viral infcetions (Ebola). J Infect Dis 1985; 152: 887-94.
    CrossrefPubMedGoogle Scholar
  • 16 Formenty P, Hatz C, LeGuenno B, Stoll A, Rogenmoser P, Widmer A. Human infection due to Ebola virus, subtype Cote d´Ivoire: clinical and biological presentation. J Infect Dis 1999; 179: S48-S53.
    CrossrefPubMedGoogle Scholar
  • 17 Bray M, Hatfill S, Hensley L, Huggins JW. Haematological, biochemical, and coagulation changes in mice, guinea pigs and monkeys infected with a mouse-adapted variant of ebola zaire virus. J Comp Pathol 2001; 125: 243-53.
    CrossrefPubMedGoogle Scholar
  • 18 Geisbert T, Hensley L, Young H, Davis K, Jahrling PB. Investigation of the role of the endothelium in Ebola virus hemorrhagic fever. XIIth International Congress of Virology. Paris, France 2002; V: 293
    PubMedGoogle Scholar
  • 19 Schnittler HJ, Mahner F, Drenckhahn D, Klenk HD, Feldmann H. Replication of Marburg virus in human endothelial cells. A possible mechanism for the development of viral hemorrhagic disease. J Clin Invest 1993; 91: 1301-9.
    CrossrefPubMedGoogle Scholar
  • 20 Yang ZY, Duckers HJ, Sullivan NJ, Sanchez A, Nabel EG, Nabel GJ. Identification of the Ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury. Nat Med 2000; 6: 886-9.
    CrossrefPubMedGoogle Scholar
  • 21 Chan SY, Ma MC, Goldsmith MA. Differential induction of cellular detachment by envelope glycoproteins of marburg and ebola (Zaire) viruses. J Gen Virol 2000; 81 Pt 9 2155-9.
    CrossrefPubMedGoogle Scholar
  • 22 Volchkov VE, Volchkova VA, Muhlberger E, Kolesnikova LV, Weik M, Dolnik O, Klenk HD. Recovery of infectious Ebola virus from complementary DNA: RNA editing of the GP gene and viral cytotoxicity. Science 2001; 291: 1965 9
    PubMedGoogle Scholar
  • 23 Narayan O, Thorsen J, Hulland TJ, Ankeli G, Joseph PG. Pathogenesis of lethal influenza virus infection in turkeys. I. Extraneural phase of infection. J Comp Pathol 1972; 82: 129-37.
    CrossrefPubMedGoogle Scholar
  • 24 Rogers GN, Paulson JC. Receptor determinants of human and animal influenza virus isolates: differences in receptor specificity of the H3 hemagglutinin based on species of origin. Virology 1983; 127: 361-73.
    CrossrefPubMedGoogle Scholar
  • 25 Geyer H, Geyer R, Odenthal-Schnittler M, Schnittler HJ. Characterization of human vascular endothelial cadherin glycans [In Process Citation]. Glycobiology 1999; 9: 915-25.
    CrossrefPubMedGoogle Scholar