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DOI: 10.1160/TH05-03-0153
The contribution of the endothelium to the development of coagulation disorders that characterize Ebola hemorrhagic fever in primates
Publikationsverlauf
Received: 04. März 2005
Accepted after major revision: 04. Mai 2005
Publikationsdatum:
05. Dezember 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/200502/lookinside/thumbnails/10-1160-th05-03-0153-1.jpg)
Summary
Recently, there have been substantdevelopments ial in the understanding of Ebola hemorrhagic fever pathogenesis, but there are still major gaps. These infections occur in underdeveloped areas of the world,and much of our knowledge of naturally occurring disease is derived from sporadic outbreaks that occurred decades in the past. Recently conducted laboratory animal studies have provided insight into Ebola pathogenesis and may help guide clinical investigations of disease using contemporary methodologies that were not available previously. A better understanding of the relevant host and viral factors that influence clinical and virologic outcome will be critical to our ability to combat this aggressive pathogen. This article reviews the most relevant information relating to the postulated pathogenesis of this disease, focusing on the role of the endothelium in contributing to the coagulation disorders that characterize Ebola hemorrhagic fever in primates. Some of the remaining and key unanswered questions relating to the role of the vascular system in the pathogenesis of this disease, that need to be addressed in further research, are highlighted.
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References
- 1 Borio L, Inglesby T, Peters CJ. et al. Hemorrhagic fever viruses as biological weapons: medical and public health management. JAMA 2002; 287: 2391-405.
- 2 Sanchez A, Khan AS, Zaki SR, Nabel GJ, Ksiazek TG, Peters CJ. Filoviridae. Fields Virology.. Knipe DM, Howley PM. Philadelphia: Lippincott Williams & Wilkins; 2001: 1279-304.
- 3 Khan AS, Tshioko K, Heymann DL. et al. The reemergence of Ebola hemorrhagic fever, Democratic Republic of the Congo, 1995. J Infect Dis 1999; 179 (Suppl. 01) S76-S86.
- 4 Isaacson M, Sureau P, Courteille G, Pattyn SR. Clinical aspects of Ebola virus disease at the Ngaliema hospital, Kinshasa, Zaire, 1976. Ebola Virus Haemorrhagic Fever.. Pattyn S.R.. Elsevier/North-Holland Biomedical Press; New York: 1978: 15-20.
- 5 Piot P, Sureau P, Breman JG. et al. Clinical aspects of Ebola virus infection in Yambuku area, Zaire, 1976. Ebola Virus Haemorrhagic Fever.. Pattyn S.R.. Elsevier/ North-Holland Biomedical Press; New York: 1978: 7-14.
- 6 Smith DH, Francis F, Simpson DIH. African haemorrhagic fever in the southern Sudan, 1976: the clinical manifestations. Ebola Virus Haemorrhagic Fever.. Pattyn S.R.. Elsevier/North-Holland Biomedical Press; New York: 1978: 21-26.
- 7 WHO. Ebola haemorrhagic fever in Sudan, 1976. Report of a WHO/International Study Team. Bull World Health Organ 1978; 56: 247-270.
- 8 WHO. Ebola haemorrhagic fever in Zaire, 1976. Report of an International Commission. Bull World Health Organ 1978; 56: 271-93.
- 9 Bwaka MA, Bonnet MJ, Calain P. et al. Ebola hemorrhagic fever in Kikwit, Democratic Republic of the Congo: clinical observations in 103 patients. J Infect Dis 1999; 179 (Suppl. 01) S1-S7.
- 10 Geisbert TW, Pushko P, Anderson K. et al. Evaluation in nonhuman primates of vaccines against Ebola virus. Emerg Infect Dis 2002; 8: 503-7.
- 11 Bray M, Hatfill S, Hensley L. et al. Haematological, biochemical and coagulation changes in mice, guineapigs and monkeys infected with a mouse-adapted variant of Ebola Zaire virus. J Comp Pathol 2001; 125: 243-53.
- 12 Chepurnov AA, Dadaeva AA, Zhukov VA. et al. Change in biochemical and hemostatic indicators in guinea pigs upon administering Ebola virus preparations. Vopr Virusol 1997; 42: 171-5.
- 13 Geisbert TW, Jahrling PB, Larsen T. et al. Filovirus Pathogenesis in Nonhuman Primates. Klenk H-D, Feldmann H. Ebola and Marburg Viruses: Molecular and Cellular Biology. Horizon Bioscience. Norfolk, UK: 2004: 203-38.
- 14 Sullivan NJ, Geisbert TW, Geisbert JB. et al. Accelerated vaccination for Ebola virus haemorrhagic fever in non-human primates. Nature 2003; 424: 681-4.
- 15 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-S202.
- 16 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: 1618-29.
- 17 Geisbert TW, Young HA, Jahrling PB. et al. Pathogenesis of Ebola hemorrhagic fever in primate models: evidence that hemorrhage is not a direct effect of virusinduced cytolysis of endothelial cells. Am J Pathol 2003; 163: 2371-82.
- 18 Yang Z, Delgado R, Xu L. et al. Distinct cellular interactions of secreted and transmembrane Ebola virus glycoproteins. Science 1998; 279: 1034-7.
- 19 Sullivan N, Yang ZY, Nabel GJ. Ebola virus pathogenesis: implications for vaccines and therapies. J Virol 2003; 77: 9733-7.
- 20 Dvorak HF, Brown LF, Detmar M. et al. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 1995; 146: 1029-39.
- 21 Kevil CG, Payne DK, Mire E. et al. Vascular permeability factor/vascular endothelial cell growth factor- mediated permeability occurs through disorganization of endothelial junctional proteins. J Biol Chem 1998; 273: 15099-103.
- 22 Walker DH. Pathology and pathogenesis of the vasculotropic rickettsioses. Biology of Rickettsial Diseases.. Walker DH. Boca Raton: CRC Press; 1988: 115-38.
- 23 Wong KT, Shieh WJ, Kumar S. et al. Nipah virus infection: pathology and pathogenesis of an emerging paramyxoviral zoonosis. Am J Pathol 2002; 161: 2153-67.
- 24 Murphy FA. Pathology of Ebola virus infection. Ebola Virus Haemorrhagic Fever.. Pattyn S.R.. Elsevier/ North-Holland Biomedical Press; New York: 1978: 43-60.
- 25 Yang Z, Delgado R, Xu L. et al. Distinct cellular interactions of secreted and transmembrane Ebola virus glycoproteins. Science 1998; 279: 1034-7.
- 26 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: 2155-9.
- 27 Simmons G, Wool-Lewis RJ, Baribaud F. et al. Ebola virus glycoproteins induce global surface protein down-modulation and loss of cell adherence. J Virol 2002; 76: 2518-28.
- 28 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: 1965-9.
- 29 Dietrich M, Schumacher HH, Peters D. et al. Human pathology of Ebola (Maridi) virus infection in the Sudan. Ebola Virus Haemorrhagic Fever.. Pattyn S.R.. Elsevier/North-Holland Biomedical Press; New York: 1978: 37-42.
- 30 Zaki SR, Goldsmith CS. Pathologic features of filovirus infections in humans. Curr Top Microbiol Immunol 1999; 235: 97-116.
- 31 Baskerville A, Fisher-Hoch SP, Neild GH. et al. Ultrastructural pathology of experimental Ebola haemorrhagic fever virus infection. J Pathol 1985; 147: 199-209.
- 32 Geisbert TW, Jahrling PB, Hanes MA. et al. 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.
- 33 Jaax NK, Davis KJ, Geisbert TW. et al. Lethal experimental infection of rhesus monkeys with Ebola- Zaire (Mayinga) virus by the oral and conjunctival route of exposure. Arch Pathol Lab Med 1996; 120: 140-55.
- 34 Davis KJ, Anderson AO, Geisbert TW. et al. Pathology of experimental Ebola virus infection in African green monkeys. Arch Pathol Lab Med 1997; 121: 805-19.
- 35 Ryabchikova EI, Kolesnikova LV, Netesov SV. Animal pathology of filoviral infections. Curr Top Microbiol Immunol 1999; 235: 145-73.
- 36 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: 2347-70.
- 37 Harcourt BH, Sanchez A, Offermann MK. Ebola virus inhibits induction of genes by doublestranded RNA in endothelial cells. Virology 1998; 252: 179-88.
- 38 Schnittler HJ, Feldmann H. Viral hemorrhagic fever – a vascular disease?. Thromb Haemost 2003; 89: 967-72.
- 39 Schnittler HJ, Stroher U, Afanasieva T. et al. The role of endothelial cells in filovirus hemorrhagic fever. Klenk H-D, Feldmann H. Ebola and Marburg Viruses: Molecular and Cellular Biology. Horizon Bioscience. Norfolk, UK: 2004: 279-303.
- 40 Schnittler H-J, 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.
- 41 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: 6841-4.
- 42 Lin G, Simmons G, Pohlmann S. et al. Differential N-linked glycosylation of human immunodeficiency virus and Ebola virus envelope glycoproteins modulates interactions with DC-SIGN and DC-SIGNR. J Virol 2003; 77: 1337-46.
- 43 Simmons G, Reeves JD, Grogan CC. et al. DCSIGN and DC-SIGNR bind ebola glycoproteins and enhance infection of macrophages and endothelial cells. Virology 2003; 305: 115-23.
- 44 Bashirova AA, Geijtenbeek TB, van Duijnhoven GC. et al. A dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)- related protein is highly expressed on human liver sinusoidal endothelial cells and promotes HIV-1 infection. J Exp Med 2001; 193: 671-8.
- 45 Pohlmann S, Soilleux EJ, Baribaud F. et al. DCSIGNR, a DC-SIGN homologue expressed in endothelial cells, binds to human and simian immunodeficiency viruses and activates infection in trans. Proc Natl Acad Sci USA 2001; 98: 2670-5.
- 46 Bashirova AA, Wu L, Cheng J. et al. Novel member of the CD209 (DC-SIGN) gene family in primates. J Virol 2003; 77: 217-27.
- 47 Chi JT, Chang HY, Haraldsen G. et al. Endothelial cell diversity revealed by global expression profiling. Proc Natl Acad Sci USA 2003; 100: 10623-8.
- 48 Stroher U, West E, Bugany H. et al. Infection and activation of monocytes by Marburg and Ebola viruses. J Virol 2001; 75: 11025-33.
- 49 Bray M, Mahanty S. Ebola hemorrhagic fever and septic shock. J Infect Dis 2003; 188: 1613-7.
- 50 Dewi BE, Takasaki T, Kurane I. In vitro assessment of human endothelial cell permeability: effects of inflammatory cytokines and dengue virus infection. J Virol Methods 2004; 121: 171-80.
- 51 Niikura M, Maeda A, Ikegami T. et al. Modification of endothelial cell functions by Hantaan virus infection: prolonged hyper-permeability induced by TNFalpha of hantaan virus-infected endothelial cell monolayers. Arch Virol 2004; 149: 1279-92.
- 52 Goldblum SE, Hennig B, Jay M. et al. Tumor necrosis factor alpha-induced pulmonary vascular endothelial injury. Infect Immun 1989; 57: 1218-26.
- 53 Bevilacqua MP, Pober JS, Majeau GR. et al. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin. Proc Natl Acad Sci USA 1986; 83: 4533-7.
- 54 Stolpen AH, Guinan EC, Fiers W. et al. Recombinant tumor necrosis factor and immune interferon act singly and in combination to reorganize human vascular endothelial cell monolayers. Am J Pathol 1986; 123: 16-24.
- 55 Brett J, Gerlach H, Nawroth P. et al. Tumor necrosis factor/cachectin increases permeability of endothelial cell monolayers by a mechanism involving regulatory G proteins. J Exp Med 1989; 169: 1977-91.
- 56 Bhagat K, Vallance P. Inflammatory cytokines impair endothelium-dependent dilatation in human veins in vivo. Circulation 1997; 96: 3042-7.
- 57 Hurlimann D, Forster A, Noll G. et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation 2002; 106: 2184-7.
- 58 Booth AD, Jayne DR, Kharbanda RK. et al. Infliximab improves endothelial dysfunction in systemic vasculitis: a model of vascular inflammation. Circulation 2004; 109: 1718-23.
- 59 Feldmann H, Bugany H, Mahner F. et al. Filovirusinduced endothelial leakage triggered by infected monocytes/macrophages. J Virol 1996; 70: 2208-14.
- 60 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: 169-79.
- 61 Baize S, Leroy EM, Georges AJ. et al. Inflammatory responses in Ebola virus-infected patients. Clin Exp Immunol 2002; 128: 163-8.
- 62 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: 10370-7.
- 63 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 factoralpha associated with fatal Ebola virus infection. J Infect Dis 1999; 179 (Suppl. 01) S188-S191.
- 64 Talavera D, Castillo AM, Dominguez MC. et al. IL8 release, tight junction and cytoskeleton dynamic reorganization conducive to permeability increase are induced by dengue virus infection of microvascular endothelial monolayers. J Gen Virol 2004; 85: 1801-13.
- 65 Gunnett CA, Heistad DD, Berg DJ. et al. IL-10 deficiency increases superoxide and endothelial dysfunction during inflammation. Am J Physiol Heart Circ Physiol 2000; 279: H1555-H1562.
- 66 Somers MJ, Harrison DG. Reactive oxygen species and the control of vasomotor tone. Curr Hypertens Rep 1999; 1: 102-8.
- 67 Kirkeboen KA, Strand OA. The role of nitric oxide in sepsis – an overview. Acta Anaesthesiol Scand 1999; 43: 275-88.
- 68 Li H, Forstermann U. Nitric oxide in the pathogenesis of vascular disease. J Pathol 2000; 190: 244-54.
- 69 Yan SB, Grinnell BW. Antithrombotic and anti-inflammatory agents of the protein C anticoagulant pathway. Ann Rep Med Chem 1994; 11: 103-12.
- 70 Murakami K, Okajima K, Uchiba M. et al. Activated protein C prevents LPS-induced pulmonary vascular injury by inhibiting cytokine production. Am J Physiol 1997; 272: L197-L202.
- 71 Esmon CT. Protein C anticoagulant pathway and its role in controlling microvascular thrombosis and inflammation. Crit Care Med 2001; 29: S48-S52.
- 72 Okajima K. Prevention of endothelial cell injury by activated protein C: the molecular mechanism(s) and therapeutic implications. Curr Vasc Pharmacol 2004; 2: 125-33.
- 73 Diamant M, Tushuizen ME, Sturk A. et al. Cellular microparticles: new players in the field of vascular disease?. Eur J Clin Invest 2004; 34: 392-401.
- 74 Martinez MC, Tesse A, Zobairi F. et al. Shed membrane microparticles from circulating and vascular cells in regulating vascular function. Am J Physiol Heart Circ Physiol 2005; 288: H1004-H1009.
- 75 Martin S, Tesse A, Hugel B. et al. Shed membrane particles from T lymphocytes impair endothelial function tion and regulate endothelial protein expression. Circulation 2004; 109: 1653-9.
- 76 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: 423-6.
- 77 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: 171-86.
- 78 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.
- 79 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: 1953-8.
- 80 Lo SK, Cheung A, Zheng Q. et al. Induction of tissue factor on monocytes by adhesion to endothelial cells. J Immunol 1995; 154: 4768-77.
- 81 Conkling PR, Greenberg CS, Weinberg JB. Tumor necrosis factor induces tissue factor-like activity in human leukemia cell line U937 and peripheral blood monocytes. Blood 1988; 72: 128-33.
- 82 Conway EM, Bach R, Rosenberg RD. et al. Tumor necrosis factor enhances expression of tissue factor mRNA in endothelial cells. Thromb Res 1989; 53: 231-41.
- 83 Neumann FJ, Ott I, Marx N. et al. Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity. Arterioscler Thromb Vasc Biol 1997; 17: 3399-405.
- 84 Grignani G, Maiolo A. Cytokines and hemostasis. Haematologica 2000; 85: 967-72.
- 85 Robson SC, Shephard EG, Kirsch RE. Fibrin degradation product D-dimer induces the synthesis and release of biologically active IL-1 beta, IL-6 and plasminogen activator inhibitors from monocytes in vitro. Br J Haematol 1994; 86: 322-6.
- 86 Lee ME, Rhee KJ, Nham SU. Fragment E derived from both fibrin and fibrinogen stimulates interleukin- 6 production in rat peritoneal macrophages. Mol Cells 1999; 9: 7-13.
- 87 Colotta F, Sciacca FL, Sironi M. et al. Expression of monocyte chemotactic protein-1 by monocytes and endothelial cells exposed to thrombin. Am J Pathol 1994; 144: 975-85.
- 88 Grandaliano G, Valente AJ, Abboud HE. A novel biologic activity of thrombin: stimulation of monocyte chemotactic protein production. J Exp Med 1994; 179: 1737-41.
- 89 Johnson K, Choi Y, DeGroot E. et al. Potential mechanisms for a proinflammatory vascular cytokine response to coagulation activation. J Immunol 1998; 160: 5130-5.
- 90 Ueno A, Murakami K, Yamanouchi K. et al. Thrombin stimulates production of interleukin-8 in human umbilical vein endothelial cells. Immunology 1996; 88: 76-81.
- 91 Naldini A, Carney DH, Pucci A. et al. Thrombin regulates the expression of proangiogenic cytokines via proteolytic activation of protease-activated receptor-1. Gen Pharmacol 2000; 35: 255-9.
- 92 Volchkov VE, Volchkova VA, Dolnik O. et al. Structural and Functional Polymorphism of the Glycoproteins of Filoviruses. Klenk H-D, Feldmann H. Ebola and Marburg Viruses: Molecular and Cellular Biology. Horizon Bioscience. Norfolk, UK: 2004: 59-89.
- 93 Wahl-Jensen V, Kurz SK, Hazelton PR. et al. Role of ebola virus secreted glycoproteins and virus-like particles in activation of human macrophages. J Virol 2005; 79: 2413-9.