Download PDF
Hamostaseologie 2008; 28(01/02): 77-84
DOI: 10.1055/s-0037-1616926
Original Article
Schattauer GmbH

Viral haemorrhagic fever and vascular alterations

Die Bedeutung des Gefäßsystems für die Pathogenese des Virus-induzierten hämorrhagischen Fiebers
P. Aleksandrowicz
1   Institute of Physiology, Technical University, Dresden, Germany
,
K. Wolf
1   Institute of Physiology, Technical University, Dresden, Germany
,
D. Falzarano
2   Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, and Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada
,
H. Feldmann
2   Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, and Department of Medical Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada
,
J. Seebach
1   Institute of Physiology, Technical University, Dresden, Germany
,
H. Schnittler
1   Institute of Physiology, Technical University, Dresden, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
29 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Pathogenesis of viral haemorrhagic fever (VHF) is closely associated with alterations of the vascular system. Among the virus families causing VHF, filoviruses (Marburg and Ebola) are the most fatal, and will be focused on here. After entering the body, Ebola primarily targets monocytes/ macrophages and dendritic cells. Infected dendritic cells are largely impaired in their activation potency, likely contributing to the immune suppression that occurs during filovirus infection. Monocytes/macrophages, however, immediately activate after viral contact and release reasonable amounts of cytokines that target the vascular system, particularly the endothelial cells.

Some underlying molecular mechanisms such as alteration of the vascular endothelial cadherin/catenin complex, tyrosine phosphorylation, expression of cell adhesion molecules, tissue factor and the effect of soluble viral proteins released from infected cells to the blood stream will be discussed.

Zusammenfassung

Die Pathogenese Virus-induzierter hämorrhagischer Fiebererkrankungen ist mit Gefäßstörungen verbunden. Die schwersten Virus-induzierten hämorrhagischen Fieber werden durch Filoviren (Marburg- und Ebola-Virus) ausgelöst und sollen hier im Vordergrund stehen. Monozyten/Makrophagen und dendritische Zellen werden nach Eintritt des Virus in den Körper primär infiziert. Während infizierte dendritische Zellen erheblich in ihrer immunmodulatorischen Funktion gestört werden und zu der bei Filovirusinfektionen beobachteten Immunsuppression beitragen, kann es nach Infektion von Monozyten/Makrophagen zu einer Überaktivierung kommen, die mit einer überschießenden Ausschüttung von Zytokinen und proinflammatorischen Mediatoren einhergeht. Diese freigesetzten Mediatoren führen zu pathologischen Regulationen des Gefäßsystems, insbesondere des Endothels.

Einige der zu Grunde liegenden molekularen Mechanismen der Endothelreaktionen werden diskutiert, z. B. die Regulation des vaskulären endothelialen Cadherin/Catenin- Komplexes der Zellkontakte, die Tyrosin-Phosphorylierung, die Expression von Zelladhäsionsmolekülen und des Tissue- Faktors sowie die Bedeutung von löslichen Virusproteinen auf das Gefäßsystem.

Keywords

Haemorrhagic fever

Schlüsselwörter

Hämorrhagisches Fieber
 

  • References

  • 1 Alazard-Dany N, Volchkova V, Reynard O. et al. Ebola virus glycoprotein GP is not cytotoxic when expressed constitutively at a moderate level. J Gen Virol 2006; 87: 1247-1257.
    CrossrefPubMedGoogle Scholar
  • 2 Alvarez CP, Lasala F, Carrillo J. et al. C-type lectins DC-SIGN and L-SIGN mediate cellular entry by Ebola virus in cis and in trans. J Virol 2002; 76: 6841-6844.
    CrossrefPubMedGoogle Scholar
  • 3 Baize S, Leroy EM, Georges AJ. et al. Inflammatory responses in Ebola virus-infected patients. Clin Exp Immunol 2002; 128: 163-168.
    CrossrefPubMedGoogle Scholar
  • 4 Baize S, Leroy EM, Georges-Courbot MC. et al. Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients. Nat Med 1999; 5: 423-426.
    CrossrefPubMedGoogle Scholar
  • 5 Baize S, Leroy EM, Mavoungou E. et al. Apoptosis in fatal Ebola infection. Does the virus toll the bell for immune system? Apoptosis 2000; 5: 5-7.
    PubMedGoogle Scholar
  • 6 Bavari S, Bosio CM, Wiegand E. et al. Lipid raft microdomains: a gateway for compartmentalized trafficking of Ebola and Marburg viruses. J Exp Med 2002; 195: 593-602.
    CrossrefPubMedGoogle Scholar
  • 7 Bazzoni G, Dejana E. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev 2004; 84: 869-901.
    CrossrefPubMedGoogle Scholar
  • 8 Becker S, Spiess M, Klenk HD. The asialoglycoprotein receptor is a potential liver-specific receptor for Marburg virus. J Gen Virol 1995; 76: 393-399.
    CrossrefPubMedGoogle Scholar
  • 9 Bockeler M, Stroher U, Seebach J. et al. Breakdown of paraendothelial barrier function during Marburg virus infection is associated with early tyrosine phosphorylation of platelet endothelial cell adhesion molecule-1. J Infect Dis 2007; 196 Suppl 2 S337-S346.
    CrossrefPubMedGoogle Scholar
  • 10 Bogatcheva NV, Garcia JG, Verin AD. Molecular mechanisms of thrombin-induced endothelial cell permeability. Biochemistry (Mosc) 2002; 67: 75-84.
    PubMedGoogle Scholar
  • 11 Bosio CM, Aman MJ, Grogan C. et al. Ebola and Marburg viruses replicate in monocyte-derived dendritic cells without inducing the production of cytokines and full maturation. J Infect Dis 2003; 188: 1630-1638.
    CrossrefPubMedGoogle Scholar
  • 12 Chan SY, Empig CJ, Welte FJ. et al. Folate receptor- alpha is a cofactor for cellular entry by Marburg and Ebola viruses. Cell 2001; 106: 117-126.
    CrossrefPubMedGoogle Scholar
  • 13 Chandran K, Sullivan NJ, Felbor U. et al. Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science 2005; 308: 1643-1645.
    CrossrefPubMedGoogle Scholar
  • 14 Colebunders R, Tshomba A, Van Kerkhove MD. et al. Marburg hemorrhagic fever in Durba and Watsa, Democratic Republic of the Congo: clinical documentation, features of illness, and treatment. J Infect Dis 2007; 196 Suppl 2 S148-S153.
    CrossrefPubMedGoogle Scholar
  • 15 Dejana E. Endothelial cell-cell junctions: happy together. Nat Rev Mol Cell Biol 2004; 5: 261-270.
    CrossrefPubMedGoogle Scholar
  • 16 Drees F, Pokutta S, Yamada S. et al. Alpha-catenin is a molecular switch that binds E-cadherin-betacatenin and regulates actin-filament assembly. Cell 2005; 123: 903-915.
    CrossrefPubMedGoogle Scholar
  • 17 Empig CJ, Goldsmith MA. Association of the caveola vesicular system with cellular entry by filoviruses. J Virol 2002; 76: 5266-5270.
    CrossrefPubMedGoogle Scholar
  • 18 Falzarano D, Krokhin O, Van Domselaar G. et al. Ebola sGP – the first viral glycoprotein shown to be C-mannosylated. Virology 2007; 368: 83-90.
    CrossrefPubMedGoogle Scholar
  • 19 Feldmann H, Bugany H, Mahner F. et al. Filovirusinduced endothelial leakage triggered by infected monocytes/macrophages. J Virol 1996; 70: 2208-2214.
    PubMedGoogle Scholar
  • 20 Feldmann H, Geisbert TW, Jahrling PB. et al. Filoviridae. In: Fauquet CM, Mayo MA, Maniloff J. et al (eds). Virus taxonomy 2005; VIII Report of the ICTV. London: Elsevier/Academic Press; 645-653.
    Google Scholar
  • 21 Feldmann H, Steven J, Klenk HD. et al. Ebola virus: From discovery to vaccine. Nat Rev Imunol 2003; 3: 77-85.
    PubMedGoogle Scholar
  • 22 Feldmann H, Volchkov VE, Volchkova VA. et al. The glycoproteins of Marburg and Ebola virus and their potential roles in pathogenesis. Arch Virol Suppl 1999; 15: 159-169.
    PubMedGoogle Scholar
  • 23 Geisbert TW, Hensley LE. Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions. Expert Rev Mol Med 2004; 6: 1-24.
    PubMedGoogle Scholar
  • 24 Geisbert TW, Hensley LE, Gibb TR. et al. Apoptosis induced in vitro and in vivo during infection by Ebola and Marburg viruses. Lab Invest 2000; 80: 171-186.
    CrossrefPubMedGoogle Scholar
  • 25 Geisbert TW, Hensley LE, Jahrling PB. et al. Treatment of Ebola virus infection with a recombinant inhibitor of factor VIIa/tissue factor: a study in rhesus monkeys. Lancet 2003; 362: 1953-1958.
    CrossrefPubMedGoogle Scholar
  • 26 Geisbert TW, Hensley LE, Larsen T. et al. Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. Am J Pathol 2003; 163: 2347-2370.
    CrossrefPubMedGoogle Scholar
  • 27 Geisbert TW, Jahrling PB. Exotic emerging viral diseases: progress and challenges. Nat Med 2004; 10 (Suppl. 12) S110-S121.
    CrossrefPubMedGoogle Scholar
  • 28 Geisbert TW, Young HA, Jahrling PB. et al. Mechanisms underlying coagulation abnormalities in ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event. J Infect Dis 2003; 188: 1618-1629.
    CrossrefPubMedGoogle Scholar
  • 29 Hensley LE, Stevens EL, Yan SB. et al. Recombinant human activated protein C for the postexposure treatment of Ebola hemorrhagic fever. J Infect Dis 2007; 196 (Suppl. 02) S390-S399.
    CrossrefPubMedGoogle Scholar
  • 30 Hensley LE, Young HA, Jahrling PB. et al. Proinflammatory response during Ebola virus infection of primate models: possible involvement of the tumor necrosis factor receptor superfamily. Immunol Lett 2002; 80: 169-179.
    CrossrefPubMedGoogle Scholar
  • 31 Hoenen T, Groseth A, Falzarano D. et al. Ebola virus: unravelling pathogenesis to combat a deadly disease. Trends in molecular medicine 2006; 12: 206-215.
    CrossrefPubMedGoogle Scholar
  • 32 Jezek Z, Szczeniowski MY, Muyembe-Tamfum JJ. et al. Ebola between outbreaks: intensified Ebola hemorrhagic fever surveillance in the Democratic Republic of the Congo, 1981–1985. J Infect Dis 1999; 179 (Suppl. 01) S60-S64.
    CrossrefPubMedGoogle Scholar
  • 33 Kanke T, Takizawa T, Kabeya M. et al. Physiology and pathophysiology of proteinase-activated receptors (PARs): PAR-2 as a potential therapeutic target. J Pharmacol Sci 2005; 97: 38-42.
    CrossrefPubMedGoogle Scholar
  • 34 Kiley MP, Bowen ET, Eddy GA. et al. Filoviridae: a taxonomic home for Marburg and Ebola viruses?. Intervirology 1982; 18: 24-32.
    CrossrefPubMedGoogle Scholar
  • 35 Kiley MP, Regnery RL, Johnson KM. Ebola virus: identification of virion structural proteins. J Gen Virol 1980; 49: 333-341.
    CrossrefPubMedGoogle Scholar
  • 36 Leroy EM, Baize S, Volchkov VE. et al. Human asymptomatic Ebola infection and strong inflammatory response. Lancet 2000; 355: 2210-2215.
    CrossrefPubMedGoogle Scholar
  • 37 Leroy EM, Kumulungui B, Pourrut X. et al. Fruit bats as reservoirs of Ebola virus. Nature 2005; 438: 575-576.
    CrossrefPubMedGoogle Scholar
  • 38 Luscinskas FW, Ma S, Nusrat A. et al. The role of endothelial cell lateral junctions during leukocyte trafficking. Immunol Rev 2002; 186: 57-67.
    CrossrefPubMedGoogle Scholar
  • 39 Mahanty S, Bausch DG, Thomas RL. et al. Low levels of interleukin-8 and interferon-inducible protein-10 in serum are associated with fatal infections in acute Lassa fever. J Infect Dis 2001; 183: 1713-1721.
    CrossrefPubMedGoogle Scholar
  • 40 Marzi A, Moller P, Hanna SL. et al. Analysis of the interaction of Ebola virus glycoprotein with DCSIGN (dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin) and its homologue DC-SIGNR. J Infect Dis 2007; 196 (Suppl. 02) S237-S346.
    CrossrefPubMedGoogle Scholar
  • 41 Minshall RD, Malik AB. Transport across the endothelium: regulation of endothelial permeability. Handb Exp Pharmacol 2006; 176: 107-144.
    PubMedGoogle Scholar
  • 42 Pawlinski R, Mackman N. Tissue factor, coagulation proteases, and protease-activated receptors in endotoxemia and sepsis. Crit Care Med 2004; 32 (Suppl. 05) S293-S297.
    CrossrefPubMedGoogle Scholar
  • 43 Pourrut X, Kumulungui B, Wittmann T. et al. The natural history of Ebola virus in Africa. Microbes and infection / Institut Pasteur 2005; 7: 1005-1014.
    CrossrefPubMedGoogle Scholar
  • 44 Reed DS, Hensley LE, Geisbert JB. et al. Depletion of peripheral blood T lymphocytes and NK cells during the course of ebola hemorrhagic Fever in cynomolgus macaques. Viral Immunol 2004; 17: 390-400.
    CrossrefPubMedGoogle Scholar
  • 45 Rollin PE, Bausch DG, Sanchez A. Blood chemistry measurements and D-Dimer levels associated with fatal and nonfatal outcomes in humans infected with Sudan Ebola virus. J Infect Dis 2007; 196 (Suppl. 02) S364-S371.
    CrossrefPubMedGoogle Scholar
  • 46 Ruf W. Emerging roles of tissue factor in viral hemorrhagic fever. Trends Immunol 2004; 25: 461-464.
    CrossrefPubMedGoogle Scholar
  • 47 Ruf W. Is APC activation of endothelial cell PAR1 important in severe sepsis?: Yes. J Thromb Haemost 2005; 3: 1912-1914.
    CrossrefPubMedGoogle Scholar
  • 48 Ruf W. PAR1 signaling: more good than harm?. Nat Med 2003; 9: 258-260.
    CrossrefPubMedGoogle Scholar
  • 49 Sanchez A. Analysis of filovirus entry into vero e6 cells, using inhibitors of endocytosis, endosomal acidification, structural integrity, and cathepsin (B and L) activity. J Infect Dis 2007; 196 (Suppl. 02) S251-S258.
    CrossrefPubMedGoogle Scholar
  • 50 Sanchez A, Geisbert TW, Feldmann H. Marburg and Ebola viruses. In: Knipe DM, Howley PM. et al. Fields Virology 5th ed. Vol 1 Philadelphia: Wolters Kluwert/Lippincott and Wilkins; 2007: 1409-1448.
    Google Scholar
  • 51 Sanchez A, Lukwiya M, Bausch D. et al. Analysis of human peripheral blood samples from fatal and nonfatal cases of Ebola (Sudan) hemorrhagic fever: cellular responses, virus load, and nitric oxide levels. J Virol 2004; 78: 10370-10377.
    CrossrefPubMedGoogle Scholar
  • 52 Schnitter H-J, Ströher U, Afanasieva T. et al. The role of endothelial cells in filovirus hemorrhagic fever. In: Klenk H-D, Feldmann H. (eds). Ebola and Marburg Viruses – Molecular and Cellular Biology. Norfolk, UK: Horizon Bioscience; 2004: 279-303.
    Google Scholar
  • 53 Schnittler HJ. Structural and functional aspects of intercellular junctions in vascular endothelium. Basic Res Cardiol 1998; 93 (Suppl. 03) 30-39.
    CrossrefPubMedGoogle Scholar
  • 54 Schnittler HJ, Feldmann H. Marburg and Ebola hemorrhagic fevers: does the primary course of infection depend on the accessibility of organspecific macrophages?. Clin Infect Dis 1998; 27: 404-406.
    CrossrefPubMedGoogle Scholar
  • 55 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
  • 56 Schnittler HJ, Feldmann H. Viral hemorrhagic fever. A vascular disease? Thromb Haemost 2003; 89: 967-972.
    PubMedGoogle Scholar
  • 57 Schnittler HJ, Wilke A, Gress T. et al. Role of actin and myosin in the control of paracellular permeability in pig, rat and human vascular endothelium. J Physiol (Lond) 1990; 431: 379-401.
    CrossrefPubMedGoogle Scholar
  • 58 Schornberg K, Matsuyama S, Kabsch K. et al. Role of endosomal cathepsins in entry mediated by the Ebola virus glycoprotein. J Virol 2006; 80: 4174-4178.
    CrossrefPubMedGoogle Scholar
  • 59 Seebach J, Donnert G, Kronstein R. et al. Regulation of endothelial barrier function during flowinduced conversion to an arterial phenotype. Cardiovasc Res 2007; 75: 596-607.
    CrossrefPubMedGoogle Scholar
  • 60 Seebach J, Mädler HJ, Wojciak-Stothard B. et al. Tyrosine phosphorylation and the small GTPase rac cross-talk in regulation of endothelial barrier function. Thromb Haemost 2005; 94: 620-629.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 61 Shimojima M, Takada A, Ebihara H. et al. Tyro3 family-mediated cell entry of Ebola and Marburg viruses. J Virol 2006; 80: 10109-10116.
    CrossrefPubMedGoogle Scholar
  • 62 Simionescu M, Simionescu N, Palade GE. Segmental differentiations of cell junctions in the vascular endothelium. The microvasculature. J Cell Biol 1975; 67: 863-885.
    CrossrefPubMedGoogle Scholar
  • 63 Stroeher U, West E, Bugany H. et al. Infection and activation of monocytes by marburg and ebola viruses. J Virol 2001; 75: 11025-11033.
    CrossrefPubMedGoogle Scholar
  • 64 Sullivan NJ, Peterson M, Yang ZY. et al. Ebola virus glycoprotein toxicity is mediated by a dynamin- dependent protein-trafficking pathway. J Virol 2005; 79: 547-553.
    CrossrefPubMedGoogle Scholar
  • 65 Swanepoel R, Leman PA, Burt FJ. et al. Experimental inoculation of plants and animals with Ebola virus. Emerg Infect Dis 1996; 2: 321-325.
    CrossrefPubMedGoogle Scholar
  • 66 Takada A, Watanabe S, Ito H. et al. Downregulation of beta1 integrins by Ebola virus glycoprotein: implication for virus entry. Virology 2000; 278: 20-26.
    CrossrefPubMedGoogle Scholar
  • 67 Towner JS, Pourrut X, Albarino CG. et al. Marburg virus infection detected in a common African bat. PLoS ONE 2007; 2: e764.
    CrossrefPubMedGoogle Scholar
  • 68 Versteeg HH, Ruf W. Emerging insights in tissue factor-dependent signaling events. Semin Thromb Haemost 2006; 32: 24-32.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 69 Vestweber D. Lymphocyte trafficking through blood and lymphatic vessels: more than just selectins, chemokines and integrins. Eur J Immunol 2003; 33: 1361-1364.
    CrossrefPubMedGoogle Scholar
  • 70 Vestweber D. Regulation of endothelial cell contacts during leukocyte extravasation. Curr Opin Cell Biol 2002; 14: 587-593.
    CrossrefPubMedGoogle Scholar
  • 71 Villinger F, Rollin PE, Brar SS. et al. Markedly elevated levels of interferon (IFN)-gamma, IFNalpha, interleukin (IL)-2, IL-10, and tumor necrosis factor-alpha associated with fatal Ebola virus infection. J Infect Dis 1999; 179 (Suppl. 01) S188-S191.
    CrossrefPubMedGoogle Scholar
  • 72 Volchkov VE, Volchkova VA, Muhlberger E. et al. Recovery of infectious Ebola virus from complementary DNA: RNA editing of the GP gene and viral cytotoxicity. Science 2001; 291: 1965-1969.
    CrossrefPubMedGoogle Scholar
  • 73 Wahl-Jensen VM, Afanasieva TA, Seebach J. et al. Effects of Ebola virus glycoproteins on endothelial cell activation and barrier function. J Virol 2005; 79: 10442-10450.
    CrossrefPubMedGoogle Scholar
  • 74 Wojciak-Stothard B, Ridley AJ. Rho GTPases and the regulation of endothelial permeability. Vascul Pharmacol 2002; 39: 187-199.
    CrossrefPubMedGoogle Scholar
  • 75 Yamada S, Pokutta S, Drees F. et al. Deconstructing the cadherin-catenin-actin complex. Cell 2005; 123: 889-901.
    CrossrefPubMedGoogle Scholar