Immunopathology of highly virulent pathogens: insights from Ebola virus

Article metrics

Abstract

Ebola virus is a highly virulent pathogen capable of inducing a frequently lethal hemorrhagic fever syndrome. Accumulating evidence indicates that the virus actively subverts both innate and adaptive immune responses and triggers harmful inflammatory responses as it inflicts direct tissue damage. The host immune system is ultimately overwhelmed by a combination of inflammatory factors and virus-induced cell damage, particularly in the liver and vasculature, often leading to death from septic shock. We summarize the mechanisms of immune dysregulation and virus-mediated cell damage in Ebola virus–infected patients. Future approaches to prevention and treatment of infection will be guided by answers to unresolved questions about interspecies transmission, molecular mechanisms of pathogenesis, and protective adaptive and innate immune responses to Ebola virus.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Infection, spread and target cell destruction by Ebola virus.

References

  1. 1

    Bowen, E.T. et al. Viral haemorrhagic fever in southern Sudan and northern Zaire. Preliminary studies on the aetiological agent. Lancet 1, 571–573 (1977).

  2. 2

    Johnson, K.M., Lange, J.V., Webb, P.A. & Murphy, F.A. Isolation and partial characterisation of a new virus causing acute haemorrhagic fever in Zaire. Lancet 1, 569–571 (1977).

  3. 3

    Leroy, E.M. et al. Fruit bats as reservoirs of Ebola virus. Nature 438, 575–576 (2005).

  4. 4

    Zaki, S.R. & Goldsmith, C.S. Pathologic features of filovirus infections in humans. Curr. Top. Microbiol. Immunol. 235, 97–116 (1999).

  5. 5

    Bwaka, M.A. et al. Ebola hemorrhagic fever in Kikwit, Democratic Republic of the Congo: clinical observations in 103 patients. J. Infect. Dis. 179 (suppl. 1), S1–S7 (1999).

  6. 6

    Ksiazek, T.G. et al. Clinical virology of Ebola hemorrhagic fever (EHF): virus, virus antigen, and IgG and IgM antibody findings among EHF patients in Kikwit, Democratic Republic of the Congo, 1995. J. Infect. Dis. 179 (suppl. 1), S177–S187 (1999).

  7. 7

    Sanchez, A. et al. Filoviridae: Marburg and Ebola Viruses. In Fields Virology (eds. Knipe, D.M. & Howley, P.M.) 1279–1304 (Lippincott, Williams & Wilkins, Philadelphia, 2001).

  8. 8

    Geisbert, T.W. et al. Pathogenesis of Ebola hemorrhagic fever in cynomolgus macaques: evidence that dendritic cells are early and sustained targets of infection. Am. J. Pathol. 163, 2347–2370 (2003).

  9. 9

    Connolly, B.M. et al. Pathogenesis of experimental Ebola virus infection in guinea pigs. J. Infect. Dis. 179, S203–S217 (1999).

  10. 10

    Hensley, L.E., Young, H.A., Jahrling, P.B. & Geisbert, T.W. Proinflammatory response during Ebola virus infection of primate models: possible involvement of the tumor necrosis factor receptor superfamily. Immunol. Lett. 80, 169–179 (2002).

  11. 11

    Feldmann, H. et al. Filovirus-induced endothelial leakage triggered by infected monocytes/macrophages. J. Virol. 70, 2208–2214 (1996).

  12. 12

    Bray, M. & Geisbert, T.W. Ebola virus: the role of macrophages and dendritic cells in the pathogenesis of Ebola hemorrhagic fever. Int. J. Biochem. Cell Biol. 37, 1560–1566 (2005).

  13. 13

    Mohamadzadeh, M. et al. Activation of triggering receptor expressed on myeloid cells-1 on human neutrophils by Marburg and Ebola viruses. J. Virol. 80, 7235–7244 (2006).

  14. 14

    Geisbert, T.W. 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. 188, 1618–1629 (2003).

  15. 15

    Gupta, M., Spiropoulou, C. & Rollin, P.E. Ebola virus infection of human PBMCs causes massive death of macrophages, CD4 and CD8 T cell sub-populations in vitro. Virology 364, 45–54 (2007).

  16. 16

    Bosio, C.M. et al. Ebola and Marburg viruses replicate in monocyte-derived dendritic cells without inducing the production of cytokines and full maturation. J. Infect. Dis. 188, 1630–1638 (2003).

  17. 17

    Mahanty, S. et al. Cutting edge: impairment of dendritic cells and adaptive immunity by Ebola and Lassa viruses. J. Immunol. 170, 2797–2801 (2003).

  18. 18

    Bosio, C.M. et al. Ebola and Marburg virus-like particles activate human myeloid dendritic cells. Virology 326, 280–287 (2004).

  19. 19

    Martinez, O., Valmas, C. & Basler, C.F. Ebola virus-like particle-induced activation of NF-κB and Erk signaling in human dendritic cells requires the glycoprotein mucin domain. Virology 364, 342–354 (2007).

  20. 20

    Harcourt, B.H., Sanchez, A. & Offermann, M.K. Ebola virus inhibits induction of genes by double-stranded RNA in endothelial cells. Virology 252, 179–188 (1998).

  21. 21

    Jahrling, P.B. et al. Evaluation of immune globulin and recombinant interferon-α2b for treatment of experimental Ebola virus infections. J. Infect. Dis. 179 (suppl. 1), S224–S234 (1999).

  22. 22

    Kash, J.C. et al. Global suppression of the host antiviral response by Ebola- and Marburgviruses: increased antagonism of the type I interferon response is associated with enhanced virulence. J. Virol. 80, 3009–3020 (2006).

  23. 23

    Mahanty, S. et al. Protection from lethal infection is determined by innate immune responses in a mouse model of Ebola virus infection. Virology 312, 415–424 (2003).

  24. 24

    Harcourt, B.H., Sanchez, A. & Offermann, M.K. Ebola virus selectively inhibits responses to interferons, but not to interleukin-1β, in endothelial cells. J. Virol. 73, 3491–3496 (1999).

  25. 25

    Bray, M. The role of the type I interferon response in the resistance of mice to filovirus infection. J. Gen. Virol. 82, 1365–1373 (2001).

  26. 26

    Basler, C.F. et al. The Ebola virus VP35 protein inhibits activation of interferon regulatory factor 3. J. Virol. 77, 7945–7956 (2003).

  27. 27

    Reid, S.P. et al. Ebola virus VP24 binds karyopherin α1 and blocks STAT1 nuclear accumulation. J. Virol. 80, 5156–5167 (2006).

  28. 28

    Cardenas, W.B. et al. Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling. J. Virol. 80, 5168–5178 (2006).

  29. 29

    Feng, Z., Cerveny, M., Yan, Z. & He, B. The VP35 protein of Ebola virus inhibits the antiviral effect mediated by double-stranded RNA-dependent protein kinase PKR. J. Virol. 81, 182–192 (2007).

  30. 30

    Baize, S. et al. Defective humoral responses and extensive intravascular apoptosis are associated with fatal outcome in Ebola virus-infected patients. Nat. Med. 5, 423–426 (1999).

  31. 31

    Reed, D.S., Hensley, L.E., Geisbert, J.B., Jahrling, P.B. & Geisbert, T.W. Depletion of peripheral blood T lymphocytes and NK cells during the course of Ebola hemorrhagic fever in cynomolgus macaques. Viral Immunol. 17, 390–400 (2004).

  32. 32

    Geisbert, T.W. et al. Apoptosis induced in vitro and in vivo during infection by Ebola and Marburg viruses. Lab. Invest. 80, 171–186 (2000).

  33. 33

    Sanchez, A. 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. 78, 10370–10377 (2004).

  34. 34

    Geisbert, T.W. & Jahrling, P.B. Exotic emerging viral diseases: progress and challenges. Nat. Med. 10, S110–S121 (2004).

  35. 35

    Feldmann, H. et al. Effective post-exposure treatment of Ebola infection. PLoS Pathog. [online] 3, e2 (2007).

  36. 36

    Sullivan, N.J., Sanchez, A., Rollin, P.E., Yang, Z.-Y. & Nabel, G.J. Development of a preventive vaccine for Ebola virus infection in primates. Nature 408, 605–609 (2000).

  37. 37

    Sullivan, N.J. et al. Accelerated vaccination for Ebola virus haemorrhagic fever in non-human primates. Nature 424, 681–684 (2003).

  38. 38

    Bukreyev, A. et al. Successful topical respiratory tract immunization of primates against Ebola virus. J. Virol. 81, 6379–6388 (2007).

  39. 39

    Warfield, K.L. et al. Induction of humoral and CD8+ T cell responses are required for protection against lethal Ebola virus infection. J. Immunol. 175, 1184–1191 (2005).

  40. 40

    Oswald, W.B. et al. Neutralizing antibody fails to impact the course of Ebola virus infection in monkeys. PLoS Pathog. [online] 3, e9 (2007).

  41. 41

    Mahanty, S. & Bray, M. Pathogenesis of filoviral haemorrhagic fevers. Lancet Infect. Dis. 4, 487–498 (2004).

  42. 42

    Mohamadzadeh, M., Chen, L. & Schmaljohn, A.L. How Ebola and Marburg viruses battle the immune system. Nat. Rev. Immunol. 7, 556–567 (2007).

  43. 43

    Dietrich, M., Schumacher, H.H., Peters, D. & Knobloch, J. Human pathology of Ebola (Maridi) virus infection in the Sudan. In Ebola Virus Haemorrhagic Fever (ed. Pattyn, S.R.) 37–42 (Elsevier, Amsterdam, 1978).

  44. 44

    Murphy, F. An atlas of viral disease pathogenesis. In Viral Pathogenesis (eds. Nathanson, N. et al.) 433–463 (Lippincott Williams & Wilkins, Philadelphia, 1997).

  45. 45

    Anonymous. Ebola haemorrhagic fever in Zaire, 1976. Bull. World Health Organ. 56, 271–293 (1978).

  46. 46

    Jahrling, P.B. et al. Passive immunization of Ebola virus-infected cynomolgus monkeys with immunoglobulin from hyperimmune horses. Arch. Virol. Suppl. 11, 135–140 (1996).

  47. 47

    Towner, J.S. et al. Rapid diagnosis of Ebola hemorrhagic fever by reverse transcription-PCR in an outbreak setting and assessment of patient viral load as a predictor of outcome. J. Virol. 78, 4330–4341 (2004).

  48. 48

    Fisher-Hoch, S.P. et al. Pathogenic potential of filoviruses: role of geographic origin of primate host and virus strain. J. Infect. Dis. 166, 753–763 (1992).

  49. 49

    Johnson, E., Jaax, N., White, J. & Jahrling, P. Lethal experimental infections of rhesus monkeys by aerosolized Ebola virus. Int. J. Exp. Pathol. 76, 227–236 (1995).

  50. 50

    Ryabchikova, E.I., Kolesnikova, L.V. & Luchko, S.V. An analysis of features of pathogenesis in two animal models of Ebola virus infection. J. Infect. Dis. 179 (suppl. 1), S199–S202 (1999).

  51. 51

    Stolpen, A.H., Guinan, E.C., Fiers, W. & Pober, J.S. Recombinant tumor necrosis factor and immune interferon act singly and in combination to reorganize human vascular endothelial cell monolayers. Am. J. Pathol. 123, 16–24 (1986).

  52. 52

    Simmons, G., Wool-Lewis, R.J., Baribaud, F., Netter, R.C. & Bates, P. Ebola virus glycoproteins induce global surface protein down-modulation and loss of cell adherence. J. Virol. 76, 2518–2528 (2002).

  53. 53

    Sullivan, N.J. et al. Ebola virus glycoprotein toxicity is mediated by a dynamin-dependent protein-trafficking pathway. J. Virol. 79, 547–553 (2005).

  54. 54

    Ito, H. et al. Ebola virus glycoprotein: proteolytic processing, acylation, cell tropism, and detection of neutralizing antibodies. J. Virol. 75, 1576–1580 (2001).

  55. 55

    Dolnik, O. et al. Ectodomain shedding of the glycoprotein GP of Ebola virus. EMBO J. 23, 2175–2184 (2004).

  56. 56

    Sanchez, A. et al. Biochemical analysis of the secreted and virion glycoproteins of Ebola virus. J. Virol. 72, 6442–6447 (1998).

  57. 57

    Yang, Z. et al. Distinct cellular interactions of secreted and transmembrane Ebola virus glycoproteins. Science 279, 1034–1037 (1998).

  58. 58

    Chandran, K., Sullivan, N.J., Felbor, U., Whelan, S.P. & Cunningham, J.M. Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science 308, 1643–1645 (2005).

  59. 59

    Schornberg, K. et al. Role of endosomal cathepsins in entry mediated by the Ebola virus glycoprotein. J. Virol. 80, 4174–4178 (2006).

  60. 60

    Barrientos, L.G. & Rollin, P.E. Release of cellular proteases into the acidic extracellular milieu exacerbates Ebola virus-induced cell damage. Virology 358, 1–9 (2007).

  61. 61

    Yang, Z.-Y. et al. Identification of the Ebola virus glycoprotein as the main viral determinant of vascular cell cytotoxicity and injury. Nat. Med. 6, 886–889 (2000).

  62. 62

    Alazard-Dany, N. et al. Ebola virus glycoprotein GP is not cytotoxic when expressed constitutively at a moderate level. J. Gen. Virol. 87, 1247–1257 (2006).

  63. 63

    Volchkov, V.E. et al. Recovery of infectious Ebola virus from complementary DNA: RNA editing of the GP gene and viral cytotoxicity. Science 291, 1965–1969 (2001).

  64. 64

    Ksiazek, T.G., West, C.P., Rollin, P.E., Jahrling, P.B. & Peters, C.J. ELISA for the detection of antibodies to Ebola viruses. J. Infect. Dis. 179, S192–S198 (1999).

  65. 65

    Baize, S. et al. Inflammatory responses in Ebola virus-infected patients. Clin. Exp. Immunol. 128, 163–168 (2002).

  66. 66

    Ahmed, R., Oldstone, M.B.A. & Palese, P. Protective immunity and susceptibility to infectious diseases: lessons from the 1918 influenza pandemic. Nat. Immunol. 8, 1188–1193 (2007).

  67. 67

    Kobasa, D. et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature 445, 319–323 (2007).

Download references

Acknowledgements

We thank M. Cichanowski, A. Tislerics and T. Suhana for help with manuscript preparation and submission.

Author information

Correspondence to Gary J Nabel.

Rights and permissions

Reprints and Permissions

About this article

Further reading