Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Immunobiology of Ebola and Lassa virus infections

Nature Reviews Immunology volume 17, pages 195–207 (2017)Cite this article

Subjects

Key Points

  • Ebola virus (EBOV) and Lassa virus (LASV) are two of the most important contemporary emerging viruses in Africa, both causing severe haemorrhagic fever in humans. However, licensed vaccines and specific therapeutics are not currently available as countermeasures to infection.

  • Both viruses initially infect myeloid cells, including dendritic cells and macrophages, and both viruses encode strategies to prevent signalling through the RIG-I-like receptor (RLR)–mitochondrial antiviral signalling protein (MAVS) pathway and therefore the production of type I interferon.

  • The temporal regulation of inflammatory responses and the relative importance of specific arms of the adaptive immune response seem to differ in humans infected with EBOV compared with LASV.

  • Severe disease following EBOV infection is associated with early activation of T cell responses followed by high levels of anti-inflammatory cytokines. By contrast, fatal LASV infection is associated with very little activation of adaptive immune responses. Infection with either virus induces high levels of inflammatory cytokines characterized as a 'cytokine storm' that probably contributes to coagulopathy, oedema and multi-organ failure.

  • Understanding the contribution of specific immune responses to protective or pathogenic responses will aid in the development of therapeutics and vaccines.

Abstract

Two of the most important contemporary emerging viruses that affect human health in Africa are Ebola virus (EBOV) and Lassa virus (LASV). The 2013–2016 West African outbreak of EBOV was responsible for more than 11,000 deaths, primarily in Guinea, Sierra Leone and Liberia. LASV is constantly emerging in these and surrounding West African countries, with an estimate of more than 500,000 cases of Lassa fever, and approximately 5,000 deaths, annually. Both EBOV and LASV are zoonotic, and human infection often results in a severe haemorrhagic fever in both cases. However, the contribution of specific immune responses to disease differs between EBOV and LASV. This Review examines innate and adaptive immune responses to these viruses with the goal of delineating responses that are associated with protective versus pathogenic outcomes.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Visualization of EBOV and LASV and their distribution in Africa.
Figure 2: Innate immune activation and antagonism by EBOV and LASV.
Figure 3: Disparate immunological events that correlate with fatality or survival from infection with LASV or EBOV.

Similar content being viewed by others

References

  1. Paessler, S. & Walker, D. H. Pathogenesis of the viral hemorrhagic fevers. Annu. Rev. Pathol. 8, 411–440 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Baize, S. et al. Emergence of Zaire Ebola virus disease in Guinea. N. Engl. J. Med. 371, 1418–1425 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Feldmann, F., Sanchez, A. & Geisbert, T. W. in Fields Virology 6th edn (eds M Knipe, D. & Howley, P. M.) 923–956 (Lippincott Williams and Wilkins, 2013).

    Google Scholar 

  4. Kuhn, J. H. et al. in Virus Taxonomy: Ninth Report of the International Committee on Taxonomy of Viruses (eds King, A. M. Q., Adams, M. J., Carstens, E. B., & Lefkowitz, E. J.) 665–671 (Elsevier/Academic Press, 2011).

    Google Scholar 

  5. Frame, J. D., Baldwin, J. M. Jr, Gocke, D. J. & Troup, J. M. Lassa fever, a new virus disease of man from West Africa. I. Clinical description and pathological findings. Am. J. Trop. Med. Hyg. 19, 670–676 (1970).

    Article  CAS  PubMed  Google Scholar 

  6. Fichet-Calvet, E. & Rogers, D. J. Risk maps of Lassa fever in West Africa. PLoS Negl. Trop. Dis. 3, e388 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Sogoba, N., Feldmann, H. & Safronetz, D. Lassa fever in West Africa: evidence for an expanded region of endemicity. Zoonoses Public Health 59 (Suppl. 2), 43–47 (2012).

    Article  PubMed  Google Scholar 

  8. Ogbu, O., Ajuluchukwu, E. & Uneke, C. J. Lassa fever in West African sub-region: an overview. J. Vector Borne Dis. 44, 1–11 (2007).

    CAS  PubMed  Google Scholar 

  9. Paweska, J. T. et al. Nosocomial outbreak of novel arenavirus infection, southern Africa. Emerg. Infect. Dis. 15, 1598–1602 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Fisher-Hoch, S. P. et al. Review of cases of nosocomial Lassa fever in Nigeria: the high price of poor medical practice. BMJ 311, 857–859 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Geisbert, T. W., Strong, J. E. & Feldmann, H. Considerations in the use of nonhuman primate models of Ebola virus and Marburg virus infection. J. Infect. Dis. 212 (Suppl. 2), S91–S97 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Smith, D. R., Holbrook, M. R. & Gowen, B. B. Animal models of viral hemorrhagic fever. Antiviral Res. 112, 59–79 (2014).

    Article  CAS  PubMed  Google Scholar 

  13. Cheng, Y. et al. Principles of regulatory information conservation between mouse and human. Nature 515, 371–375 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chertow, D. S. et al. Ebola virus disease in West Africa — clinical manifestations and management. N. Engl. J. Med. 371, 2054–2057 (2014). This study provides a comprehensive view of the outcome and management of patients with EVD from the 2013–2016 outbreak in Liberia.

    Article  PubMed  Google Scholar 

  15. Schieffelin, J. S. et al. Clinical illness and outcomes in patients with Ebola in Sierra Leone. N. Engl. J. Med. 371, 2092–2100 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mattia, J. G. et al. Early clinical sequelae of Ebola virus disease in Sierra Leone: a cross-sectional study. Lancet Infect. Dis. 16, 331–338 (2016).

    Article  PubMed  Google Scholar 

  17. Tiffany, A. et al. Ebola virus disease complications as experienced by survivors in Sierra Leone. Clin. Infect. Dis. 62, 1360–1366 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Caluwaerts, S. et al. Dilemmas in managing pregnant women with Ebola: 2 case reports. Clin. Infect. Dis. 62, 903–905 (2016).

    Article  PubMed  Google Scholar 

  19. Mupapa, K. et al. Ebola hemorrhagic fever and pregnancy. J. Infect. Dis. 179 (Suppl. 1), S11–S12 (1999).

    Article  PubMed  Google Scholar 

  20. Bausch, D. G. et al. Lassa fever in Guinea: I. Epidemiology of human disease and clinical observations. Vector Borne Zoonotic Dis. 1, 269–281 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Frame, J. D. Clinical features of Lassa fever in Liberia. Rev. Infect. Dis. 11 (Suppl. 4), S783–S789 (1989).

    Article  PubMed  Google Scholar 

  22. McCormick, J. B. & Fisher-Hoch, S. P. Lassa fever. Curr. Top. Microbiol. Immunol. 262, 75–109 (2002).

    CAS  PubMed  Google Scholar 

  23. Gunther, S. & Lenz, O. Lassa virus. Crit. Rev. Clin. Lab. Sci. 41, 339–390 (2004).

    Article  PubMed  CAS  Google Scholar 

  24. Qiu, X. et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature 514, 47–53 (2014). This study showed that monoclonal antibody therapy can prevent the death of macaques infected with EBOV as late as 5 days after inoculation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sissoko, D. et al. Experimental treatment with favipiravir for Ebola virus disease (the JIKI Trial): a historically controlled, single-arm proof-of-concept trial in Guinea. PLoS Med. 13, e1001967 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Henao-Restrepo, A. M. et al. Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial. Lancet 386, 857–866 (2015). This study provides evidence of the positive effect of a ring vaccination approach using a VSV-based EBOV vaccine.

    Article  CAS  PubMed  Google Scholar 

  27. 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). This paper describes the cellular tropism of EBOV in vitro.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    Article  PubMed  Google Scholar 

  29. Walker, D. H., Wulff, H., Lange, J. V. & Murphy, F. A. Comparative pathology of Lassa virus infection in monkeys, guinea-pigs, and Mastomys natalensis. Bull. World Health Organ. 52, 523–534 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Banadyga, L., Dolan, M. A. & Ebihara, H. Rodent-adapted filoviruses and the molecular basis of pathogenesis. J. Mol. Biol. 428, 3449–3466 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bray, M., Davis, K., Geisbert, T., Schmaljohn, C. & Huggins, J. A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever. J. Infect. Dis. 178, 651–661 (1998). This paper describes the adaptation of EBOV to cause disease in mice, thereby enabling studies of EBOV in a small animal model.

    Article  CAS  PubMed  Google Scholar 

  32. Ebihara, H. et al. Molecular determinants of Ebola virus virulence in mice. PLoS Pathog. 2, e73 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Ebihara, H. et al. A Syrian golden hamster model recapitulating Ebola hemorrhagic fever. J. Infect. Dis. 207, 306–318 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Gibb, T. R. et al. Pathogenesis of experimental Ebola Zaire virus infection in BALB/c mice. J. Comp. Pathol. 125, 233–242 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Baize, S. et al. Lassa virus infection of human dendritic cells and macrophages is productive but fails to activate cells. J. Immunol. 172, 2861–2869 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Baize, S. et al. Role of interferons in the control of Lassa virus replication in human dendritic cells and macrophages. Microbes Infect. 8, 1194–1202 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Bowen, M. D., Peters, C. J. & Nichol, S. T. Phylogenetic analysis of the Arenaviridae: patterns of virus evolution and evidence for cospeciation between arenaviruses and their rodent hosts. Mol. Phylogenet. Evol. 8, 301–316 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Fisher-Hoch, S. P., Hutwagner, L., Brown, B. & McCormick, J. B. Effective vaccine for lassa fever. J. Virol. 74, 6777–6783 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hawiger, D. et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 194, 769–779 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Stroher, U. et al. Infection and activation of monocytes by Marburg and Ebola viruses. J. Virol. 75, 11025–11033 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Schneider, W. M., Chevillotte, M. D. & Rice, C. M. Interferon-stimulated genes: a complex web of host defenses. Annu. Rev. Immunol. 32, 513–545 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Brannan, J. M. et al. Interferon alpha/beta receptor-deficient mice as a model for Ebola virus disease. J. Infect. Dis. 212 (Suppl. 2), S282–S294 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. 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).

    Article  CAS  PubMed  Google Scholar 

  45. Oestereich, L. et al. Chimeric mice with competent hematopoietic immunity reproduce key features of severe Lassa fever. PLoS Pathog. 12, e1005656 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Yun, N. E. et al. Functional interferon system is required for clearance of lassa virus. J. Virol. 86, 3389–3392 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Baize, S. et al. Early and strong immune responses are associated with control of viral replication and recovery in lassa virus-infected cynomolgus monkeys. J. Virol. 83, 5890–5903 (2009). This manuscript highlights the features of the cellular immune response that are protective during Lassa fever, and indicates that antibody responses are less important than cell-mediated immune responses for protection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jouvenet, N. et al. Broad-spectrum inhibition of retroviral and filoviral particle release by tetherin. J. Virol. 83, 1837–1844 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Sakuma, T., Noda, T., Urata, S., Kawaoka, Y. & Yasuda, J. Inhibition of Lassa and Marburg virus production by tetherin. J. Virol. 83, 2382–2385 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Messaoudi, I., Amarasinghe, G. K. & Basler, C. F. Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus. Nat. Rev. Microbiol. 13, 663–676 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chan, Y. K. & Gack, M. U. RIG-I-like receptor regulation in virus infection and immunity. Curr. Opin. Virol. 12, 7–14 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. MacMicking, J. D. Interferon-inducible effector mechanisms in cell-autonomous immunity. Nat. Rev. Immunol. 12, 367–382 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Versteeg, G. A. & Garcia-Sastre, A. Viral tricks to grid-lock the type I interferon system. Curr. Opin. Microbiol. 13, 508–516 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Basler, C. F. et al. The Ebola virus VP35 protein functions as a type I IFN antagonist. Proc. Natl Acad. Sci. USA 97, 12289–12294 (2000). This is the first paper to identify EBOV VP35 as an interferon antagonist.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hartman, A. L., Towner, J. S. & Nichol, S. T. A. C-Terminal basic amino acid motif of Zaire ebolavirus VP35 is essential for type I interferon antagonism and displays high identity with the RNA-binding domain of another interferon antagonist, the NS1 protein of influenza A virus. Virology 328, 177–184 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Leung, D. W. et al. Structural basis for dsRNA recognition and interferon antagonism by Ebola VP35. Nat. Struct. Mol. Biol. 17, 165–172 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Luthra, P. et al. Mutual antagonism between the Ebola virus VP35 protein and the RIG-I activator PACT determines infection outcome. Cell Host Microbe 14, 74–84 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Prins, K. C., Cardenas, W. B. & Basler, C. F. Ebola virus protein VP35 impairs the function of interferon regulatory factor-activating kinases IKKɛ and TBK-1. J. Virol. 83, 3069–3077 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Chang, T. H. et al. Ebola Zaire virus blocks type I interferon production by exploiting the host SUMO modification machinery. PLoS Pathog. 5, e1000493 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Kubota, T. et al. Virus infection triggers SUMOylation of IRF3 and IRF7, leading to the negative regulation of type I interferon gene expression. J. Biol. Chem. 283, 25660–25670 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yen, B. C. & Basler, C. F. Effects of filovirus interferon antagonists on responses of human monocyte-derived dendritic cells to RNA virus infection. J. Virol. 90, 5108–5118 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Reid, S. P. et al. Ebola virus VP24 binds karyopherin alpha1 and blocks STAT1 nuclear accumulation. J. Virol. 80, 5156–5167 (2006). This is the first paper to identify EBOV VP24 as an interferon antagonist.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Reid, S. P., Valmas, C., Martinez, O., Sanchez, F. M. & Basler, C. F. Ebola virus VP24 proteins inhibit the interaction of NPI-1 subfamily karyopherin alpha proteins with activated STAT1. J. Virol. 81, 13469–13477 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Xu, W. et al. Ebola virus VP24 targets a unique NLS binding site on karyopherin alpha 5 to selectively compete with nuclear import of phosphorylated STAT1. Cell Host Microbe 16, 187–200 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hartman, A. L. et al. Inhibition of IRF-3 activation by VP35 is critical for the high level of virulence of Ebola virus. J. Virol. 82, 2699–2704 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Prins, K. C. et al. Mutations abrogating VP35 interaction with double-stranded RNA render Ebola virus avirulent in guinea pigs. J. Virol. 84, 3004–3015 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Carrera Silva, E. A. et al. T cell-derived protein S engages TAM receptor signaling in dendritic cells to control the magnitude of the immune response. Immunity 39, 160–170 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lemke, G. Biology of the TAM receptors. Cold Spring Harb. Perspect. Biol. 5, a009076 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Freeman, G. J., Casasnovas, J. M., Umetsu, D. T. & DeKruyff, R. H. TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol. Rev. 235, 172–189 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Richard, A. S. et al. Virion-associated phosphatidylethanolamine promotes TIM1-mediated infection by Ebola, dengue, and West Nile viruses. Proc. Natl Acad. Sci. USA 112, 14682–14687 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Dahlmann, F. et al. Analysis of Ebola virus entry into macrophages. J. Infect. Dis. 212 (Suppl. 2), S247–S257 (2015).

    Article  CAS  PubMed  Google Scholar 

  73. Bhattacharyya, S. et al. Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors. Cell Host Microbe 14, 136–147 (2013). This paper describes the mechanism by which viruses use phosphatidylserine in the viral envelope to disable intrinsic cellular responses to infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Okumura, A., Pitha, P. M., Yoshimura, A. & Harty, R. N. Interaction between Ebola virus glycoprotein and host toll-like receptor 4 leads to induction of proinflammatory cytokines and SOCS1. J. Virol. 84, 27–33 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Okumura, A. et al. Suppressor of cytokine signaling 3 is an inducible host factor that regulates virus egress during Ebola virus infection. J. Virol. 89, 10399–10406 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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).

    Article  CAS  PubMed  Google Scholar 

  77. Schumann, M., Gantke, T. & Muhlberger, E. Ebola virus VP35 antagonizes PKR activity through its C-terminal interferon inhibitory domain. J. Virol. 83, 8993–8997 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Gustin, J. K., Bai, Y., Moses, A. V. & Douglas, J. L. Ebola virus glycoprotein promotes enhanced viral egress by preventing Ebola VP40 from associating with the host restriction factor BST2/tetherin. J. Infect. Dis. 212 (Suppl. 2), S181–S190 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kaletsky, R. L., Francica, J. R., Agrawal-Gamse, C. & Bates, P. Tetherin-mediated restriction of filovirus budding is antagonized by the Ebola glycoprotein. Proc. Natl Acad. Sci. USA 106, 2886–2891 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Vande Burgt, N. H., Kaletsky, R. L. & Bates, P. Requirements within the Ebola viral glycoprotein for tetherin antagonism. Viruses 7, 5587–5602 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Xing, J., Ly, H. & Liang, Y. The Z proteins of pathogenic but not nonpathogenic arenaviruses inhibit RIG-I-like receptor-dependent interferon production. J. Virol. 89, 2944–2955 (2015).

    Article  PubMed  CAS  Google Scholar 

  82. Hastie, K. M., King, L. B., Zandonatti, M. A. & Saphire, E. O. Structural basis for the dsRNA specificity of the Lassa virus NP exonuclease. PLoS ONE 7, e44211 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Jiang, X. et al. Structures of arenaviral nucleoproteins with triphosphate dsRNA reveal a unique mechanism of immune suppression. J. Biol. Chem. 288, 16949–16959 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Pythoud, C. et al. Arenavirus nucleoprotein targets interferon regulatory factor-activating kinase IKKɛ. J. Virol. 86, 7728–7738 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Rodrigo, W. W. et al. Arenavirus nucleoproteins prevent activation of nuclear factor kappa B. J. Virol. 86, 8185–8197 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Shimojima, M., Stroher, U., Ebihara, H., Feldmann, H. & Kawaoka, Y. Identification of cell surface molecules involved in dystroglycan-independent Lassa virus cell entry. J. Virol. 86, 2067–2078 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 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). This paper describes the large-scale by standerapoptosis of lymphocytes that is seen during EBOV infection.

    Article  CAS  PubMed  Google Scholar 

  88. 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).

    Article  CAS  PubMed  Google Scholar 

  89. Wauquier, N., Becquart, P., Padilla, C., Baize, S. & Leroy, E. M. Human fatal zaire ebola virus infection is associated with an aberrant innate immunity and with massive lymphocyte apoptosis. PLoS Negl. Trop. Dis. 4, e837 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Paulsen, M. & Janssen, O. Pro- and anti-apoptotic CD95 signaling in T cells. Cell. Commun. Signal. 9, 7 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. McElroy, A. K. et al. Human Ebola virus infection results in substantial immune activation. Proc. Natl Acad. Sci. USA 112, 4719–4724 (2015). This study of patients with EVD treated at Emory Hospital shows that the immune response is strongly stimulated in these survivors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 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).

    Article  CAS  PubMed  Google Scholar 

  93. Baize, S. et al. Inflammatory responses in Ebola virus-infected patients. Clin. Exp. Immunol. 128, 163–168 (2002). This paper uses human sera from EBOV-infected patients to measure immune markers, and shows that strong anti-inflammatory responses correlate with poor outcome.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Schroder, K., Hertzog, P. J., Ravasi, T. & Hume, D. A. Interferon-gamma: an overview of signals, mechanisms and functions. J. Leukoc. Biol. 75, 163–189 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Villinger, F. et al. Markedly elevated levels of interferon (IFN)-gamma, IFN-alpha, interleukin (IL)-2, IL-10, and tumor necrosis factor-α associated with fatal Ebola virus infection. J. Infect. Dis. 179 (Suppl. 1), S188–S191 (1999).

    Article  CAS  PubMed  Google Scholar 

  96. Hutchinson, K. L. & Rollin, P. E. Cytokine and chemokine expression in humans infected with Sudan Ebola virus. J. Infect. Dis. 196 (Suppl. 2), S357–S363 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Couper, K. N., Blount, D. G. & Riley, E. M. IL-10: the master regulator of immunity to infection. J. Immunol. 180, 5771–5777 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Fiorentino, D. F., Bond, M. W. & Mosmann, T. R. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J. Exp. Med. 170, 2081–2095 (1989).

    Article  CAS  PubMed  Google Scholar 

  99. Ouyang, J. et al. NRAV, a long noncoding RNA, modulates antiviral responses through suppression of interferon-stimulated gene transcription. Cell Host Microbe 16, 616–626 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Panchal, R. G. et al. Induced IL-10 splice altering approach to antiviral drug discovery. Nucleic Acid. Ther. 24, 179–185 (2014).

    Article  CAS  PubMed  Google Scholar 

  101. Leroy, E. M., Baize, S., Debre, P., Lansoud-Soukate, J. & Mavoungou, E. Early immune responses accompanying human asymptomatic Ebola infections. Clin. Exp. Immunol. 124, 453–460 (2001). This study demonstrates that an early pro- and anti-inflammatory immune response to EBOV is protective in humans.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Arend, W. P. The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev. 13, 323–340 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Ruibal, P. et al. Unique human immune signature of Ebola virus disease in Guinea. Nature 533, 100–104 (2016). This study is the largest comprehensive examination of the human T cell response to EBOV and shows that inhibitory molecules on both CD4+ and CD8+ T cells are significantly upregulated in fatal cases of EVD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Gunther, S. et al. Antibodies to Lassa virus Z protein and nucleoprotein co-occur in human sera from Lassa fever endemic regions. Med. Microbiol. Immunol. 189, 225–229 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Geisbert, T. W. et al. Development of a new vaccine for the prevention of Lassa fever. PLoS Med. 2, e183 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Zhou, X., Ramachandran, S., Mann, M. & Popkin, D. L. Role of lymphocytic choriomeningitis virus (LCMV) in understanding viral immunology: past, present and future. Viruses 4, 2650–2669 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Meulen, J. et al. Old and New World arenaviruses share a highly conserved epitope in the fusion domain of the glycoprotein 2, which is recognized by Lassa virus-specific human CD4+ T-cell clones. Virology 321, 134–143 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. ter Meulen, J. et al. Characterization of human CD4+ T-cell clones recognizing conserved and variable epitopes of the Lassa virus nucleoprotein. J. Virol. 74, 2186–2192 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Pannetier, D. et al. Human dendritic cells infected with the nonpathogenic Mopeia virus induce stronger T-cell responses than those infected with Lassa virus. J. Virol. 85, 8293–8306 (2011). This paper demonstrated that highly related viruses can differentially augment dendritic cell activation and maturation, and that infection by the pathogenic, but not non-pathogenic, arenaviruses results in inhibition of dendritic cell responses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Kiley, M. P., Lange, J. V. & Johnson, K. M. Protection of rhesus monkeys from Lassa virus by immunisation with closely related Arenavirus. Lancet 2, 738 (1979).

    Article  CAS  PubMed  Google Scholar 

  111. 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).

    CAS  PubMed  Google Scholar 

  112. Jahrling, P. B. et al. Evaluation of immune globulin and recombinant interferon-alpha2b for treatment of experimental Ebola virus infections. J. Infect. Dis. 179 (Suppl. 1), S224–S234 (1999).

    Article  CAS  PubMed  Google Scholar 

  113. Marzi, A. et al. Protective efficacy of neutralizing monoclonal antibodies in a nonhuman primate model of Ebola hemorrhagic fever. PLoS ONE 7, e36192 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Mupapa, K. et al. Treatment of Ebola hemorrhagic fever with blood transfusions from convalescent patients. J. Infect. Dis. 179 (Suppl. 1), S18–S23 (1999).

    Article  PubMed  Google Scholar 

  115. van Griensven, J. et al. Evaluation of convalescent plasma for Ebola virus disease in Guinea. N. Engl. J. Med. 374, 33–42 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Parren, P. W., Geisbert, T. W., Maruyama, T., Jahrling, P. B. & Burton, D. R. Pre- and postexposure prophylaxis of Ebola virus infection in an animal model by passive transfer of a neutralizing human antibody. J. Virol. 76, 6408–6412 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Olinger, G. G. Jr et al. Delayed treatment of Ebola virus infection with plant-derived monoclonal antibodies provides protection in rhesus macaques. Proc. Natl Acad. Sci. USA 109, 18030–18035 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Pettitt, J. et al. Therapeutic intervention of Ebola virus infection in rhesus macaques with the MB-003 monoclonal antibody cocktail. Sci. Transl Med. 5, 199ra113 (2013).

    Article  PubMed  Google Scholar 

  120. Lyon, G. M. et al. Clinical care of two patients with Ebola virus disease in the United States. N. Engl. J. Med. 371, 2402–2409 (2014).

    Article  CAS  PubMed  Google Scholar 

  121. Corti, D. et al. Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody. Science 351, 1339–1342 (2016).

    Article  CAS  PubMed  Google Scholar 

  122. Leroy, E. M. et al. Human asymptomatic Ebola infection and strong inflammatory response. Lancet 355, 2210–2215 (2000).

    Article  CAS  PubMed  Google Scholar 

  123. Marzi, A. et al. Antibodies are necessary for rVSV/ZEBOV-GP-mediated protection against lethal Ebola virus challenge in nonhuman primates. Proc. Natl Acad. Sci. USA 110, 1893–1898 (2013). This manuscript demonstrates that antibodies elicited by a vaccine are necessary and sufficient for protection from EVD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Johnson, K. M. et al. Clinical virology of Lassa fever in hospitalized patients. J. Infect. Dis. 155, 456–464 (1987).

    Article  CAS  PubMed  Google Scholar 

  125. Robinson, J. E. et al. Most neutralizing human monoclonal antibodies target novel epitopes requiring both Lassa virus glycoprotein subunits. Nat. Commun. 7, 11544 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Schountz, T. et al. Regulatory T cell-like responses in deer mice persistently infected with Sin Nombre virus. Proc. Natl Acad. Sci. USA 104, 15496–15501 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Basler, C. F. Innate immune evasion by filoviruses. Virology 479–480, 122–130 (2015).

    Article  CAS  PubMed  Google Scholar 

  128. Hoenen, T. & Feldmann, H. Reverse genetics systems as tools for the development of novel therapies against filoviruses. Expert Rev. Anti Infect. Ther. 12, 1253–1263 (2014).

    Article  CAS  PubMed  Google Scholar 

  129. Martins, K. A., Jahrling, P. B., Bavari, S. & Kuhn, J. H. Ebola virus disease candidate vaccines under evaluation in clinical trials. Expert Rev. Vaccines 15, 1101–1112 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Marzi, A., Feldmann, F., Geisbert, T. W., Feldmann, H. & Safronetz, D. Vesicular stomatitis virus-based vaccines against Lassa and Ebola viruses. Emerg. Infect. Dis. 21, 305–307 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Mire, C. E., Geisbert, T. W., Feldmann, H. & Marzi, A. Ebola virus vaccines — reality or fiction? Expert Rev. Vaccines 15, 1421–1430 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Stanley, D. A. et al. Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge. Nat. Med. 20, 1126–1129 (2014).

    Article  CAS  PubMed  Google Scholar 

  133. De Santis, O. et al. Safety and immunogenicity of a chimpanzee adenovirus-vectored Ebola vaccine in healthy adults: a randomised, double-blind, placebo-controlled, dose-finding, phase 1/2a study. Lancet Infect. Dis. 16, 311–320 (2016).

    Article  CAS  PubMed  Google Scholar 

  134. Ledgerwood, J. E., Sullivan, N. J. & Graham, B. S. Chimpanzee adenovirus vector Ebola vaccine — preliminary report. N. Engl. J. Med. 373, 776 (2015).

    PubMed  Google Scholar 

  135. Jones, S. M. et al. Live attenuated recombinant vaccine protects nonhuman primates against Ebola and Marburg viruses. Nat. Med. 11, 786–790 (2005).

    Article  CAS  PubMed  Google Scholar 

  136. Marzi, A. et al. Ebola vaccine. VSV-EBOV rapidly protects macaques against infection with the 2014/15 Ebola virus outbreak strain. Science 349, 739–742 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Safronetz, D. et al. A recombinant vesicular stomatitis virus-based Lassa fever vaccine protects guinea pigs and macaques against challenge with geographically and genetically distinct Lassa viruses. PLoS Negl. Trop. Dis. 9, e0003736 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Lukashevich, I. S. et al. A live attenuated vaccine for Lassa fever made by reassortment of Lassa and Mopeia viruses. J. Virol. 79, 13934–13942 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Lukashevich, I. S. Advanced vaccine candidates for Lassa fever. Viruses 4, 2514–2557 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Zapata, J. C. et al. An attenuated Lassa vaccine in SIV-infected rhesus macaques does not persist or cause arenavirus disease but does elicit Lassa virus-specific immunity. Virol. J. 10, 52 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Division of Intramural Research, National Institutes of Allergy and Infectious Diseases, US National Institutes of Health.

Author information

Authors and Affiliations

  1. Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 S. Fourth Street, Hamilton, 59840, Montana, USA

    Joseph B. Prescott, Andrea Marzi, Shelly J. Robertson, Heinz Feldmann & Sonja M. Best

  2. Zoonotic Diseases and Special Pathogens, Public Health Agency of Canada, 1015 Arlington Street, Winnipeg, R3E 3R2, Manitoba, Canada

    David Safronetz

  3. Department of Medical Microbiology, University of Manitoba, 745 Bannatyne Avenue, Winnipeg, R3E 0J9, Manitoba, Canada

    David Safronetz & Heinz Feldmann

Authors
  1. Joseph B. Prescott
    View author publications

    Search author on:PubMed Google Scholar

  2. Andrea Marzi
    View author publications

    Search author on:PubMed Google Scholar

  3. David Safronetz
    View author publications

    Search author on:PubMed Google Scholar

  4. Shelly J. Robertson
    View author publications

    Search author on:PubMed Google Scholar

  5. Heinz Feldmann
    View author publications

    Search author on:PubMed Google Scholar

  6. Sonja M. Best
    View author publications

    Search author on:PubMed Google Scholar

Corresponding authors

Correspondence to Heinz Feldmann or Sonja M. Best.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Overview of vaccine platforms developed for EBOV or LASV (PDF 150 kb)

PowerPoint slides

Glossary

Haemorrhagic fever

A fever and bleeding disorder that can progress to shock and death in many cases.

Zoonosis

Any disease or infection that is naturally transmissible from vertebrate animals to humans.

Cytokine storm

A positive feedback loop involving the hypersecretion of cytokines with detrimental effects.

Ring vaccination

A vaccination strategy whereby the most likely contacts of an infected person are vaccinated in an attempt to control an outbreak of a highly transmissible disease.

TYRO3/AXL/MER (TAM) family

Receptor tyrosine kinases that regulate several biological activities, including coagulation, cytokine release and autoimmune disease.

Apoptotic mimicry

The exposure of phosphatidylserine on the viral surface to induce uptake by host target cells or immune antagonism.

Protein kinase R

(PKR). A kinase that is activated by RNA to shut down global mRNA synthesis in response to viral infection.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). A cell-mediated immune response whereby cells bound by specific antibodies are lysed, primarily by natural killer cells or neutrophils.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Prescott, J., Marzi, A., Safronetz, D. et al. Immunobiology of Ebola and Lassa virus infections. Nat Rev Immunol 17, 195–207 (2017). https://doi.org/10.1038/nri.2016.138

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/nri.2016.138

This article is cited by

Search

Advanced search

Quick links

Nature Briefing Microbiology

Sign up for the Nature Briefing: Microbiology newsletter — what matters in microbiology research, free to your inbox weekly.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing: Microbiology