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  • Review Article
  • Published:

Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus

Nature Reviews Microbiology volume 13, pages 663–676 (2015)Cite this article

Subjects

Key Points

  • The 2014–2015 Ebola virus outbreak in West Africa is the largest filovirus outbreak to date.

  • Filovirus infections in humans are acquired by direct contact with infected bodily fluid through breaks in the skin or mucosal membranes, and the virus typically targets macrophages, monocytes and dendritic cells, among other cell types.

  • Severe infection with filoviruses can lead to viral haemorrhagic fever and other coagulation abnormalities.

  • Filoviruses evade and alter the innate immune response through various mechanisms.

  • Viral protein 35 (VP35) antagonizes the innate immune system by blocking signalling through RIG-I-like receptors (RLRs) and further impairing the interferon (IFN) response.

  • VP35 can bind to double-stranded RNA (dsRNA), further suppressing the RLR-mediated IFN response, and can interact with PACT, an activator of the IFN-induced antiviral kinase protein kinase (PKR).

  • Ebola virus VP24 can bind to karyopherin-α (KPNA) proteins, preventing their interaction with tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1), which then prevents the activation of IFN-stimulated response elements.

  • Marburg virus VP40 blocks the activation and function of Janus kinase 1 (JAK1), inhibiting the type I IFN-induced phosphorylation of STAT1 and STAT2.

  • Filoviruses adapt to their host in order to sustain viral replication and to subvert translational regulation mechanisms.

  • Marburg virus VP24 can modulate the function of kelch-like ECH-associated protein 1 (KEAP1), enabling activation of antioxidant response elements (AREs) and promoting survival of virus-infected host cells.

  • Further understanding of filoviruses is necessary to develop better therapeutics and more efficiently combat infection.

Abstract

Ebola viruses and Marburg viruses, members of the filovirus family, are zoonotic pathogens that cause severe disease in people, as highlighted by the latest Ebola virus epidemic in West Africa. Filovirus disease is characterized by uncontrolled virus replication and the activation of host responses that contribute to pathogenesis. Underlying these phenomena is the potent suppression of host innate antiviral responses, particularly the type I interferon response, by viral proteins, which allows high levels of viral replication. In this Review, we describe the mechanisms used by filoviruses to block host innate immunity and discuss the links between immune evasion and filovirus pathogenesis.

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Figure 1: Filovirus genome structure and life cycle.
Figure 2: Subversion of IFN induction.
Figure 3: Subversion of IFN-induced signalling and of IFN-induced protein tetherin.
Figure 4: Subversion of host translation mechanisms to support virus replication.

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Acknowledgements

The authors thank C. Schwall for critical reading of this manuscript. The authors were supported by US National Institutes of Health (NIH) grants U19 AI109945 to C.F.B. (Basler- PI), I.M. and G.K.A.; R01 AI059536 and U19 AI109664 to C.F.B.; and U19 AI070489 (Holtzman- PI) and R01 AI081914 to G.K.A. The authors are also supported by the US Department of Defense and the Defense Threat Reduction Agency grants HDTRA1-12-1-0051 and HDTRA1-14-1-0013 to C.F.B. and G.K.A. The content of this Review does not necessarily reflect the position or the policy of the federal government, and no official endorsement should be inferred.

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Authors and Affiliations

  1. School of Medicine, University of California Riverside, Riverside, 92521, California, USA

    Ilhem Messaoudi

  2. The Division of Biology & Biomedical Sciences, Washington University in St. Louis, St. Louis, 63110, Missouri, USA

    Gaya K. Amarasinghe

  3. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, USA

    Christopher F. Basler

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  1. Ilhem Messaoudi
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  3. Christopher F. Basler
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Correspondence to Christopher F. Basler.

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Glossary

Negative-strand RNA viruses

Viruses possessing single-stranded RNA genomes that are negative sense (that is, complementary to the viral mRNAs).

Haemorrhagic fevers

Severe illnesses typically associated with bleeding that are caused by various viral infections, including filovirus infections.

Index case

The first identified case of a particular disease or epidemic, or the case from which the disease initially progressed.

Type I interferon

A group that comprises interferon-β and multiple types of interferon-α.

Macropinocytosis

An actin-dependent form of endocytosis that results in the formation of large fluid-filled vacuoles.

Cathepsins

Endosomal cysteine proteases that cleave the filovirus glycoprotein during viral entry.

Phosphatidylserine

A phospholipid found on the surface of apoptotic bodies and on viral membranes that can promote intracellular uptake through interaction with specific cell surface receptors.

Lymphopenia

Low levels of lymphocytes in the blood.

Isotype class switching

A recombination process that alters the isotype of an antibody (for example, from immunoglobulin M to immunoglobulin G).

Necrosis

A non-apoptotic form of cell death.

Fibrin

A non-globular protein involved in blood clotting.

Extrinsic pathway of coagulation

The blood coagulation pathway that is initiated at the site of injury in response to tissue factor.

Thrombocytopenia

Low levels of platelets in the blood.

Pro-thrombin time

A blood test that measures clotting time.

Sumoylation

A post-translational modification that influences protein stability and other cellular processes.

Monopartite

Involving one part. In the case of nuclear localization signals, the recognized sequence is composed of a single stretch of amino acids.

Bipartite

Involving two parts. In the case of nuclear localization signals, the recognized sequence is composed of two separate amino acid sequences connected by a linker region.

293 cells

Human embryonic kidney-derived cell line.

Lipid rafts

Microdomains within a lipid membrane. It is postulated that lipid rafts support the concentration of viral proteins for more efficient viral assembly and budding.

Kelch

A repeated motif within proteins that predicts a conserved βpropeller structure.

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Messaoudi, I., Amarasinghe, G. & Basler, C. Filovirus pathogenesis and immune evasion: insights from Ebola virus and Marburg virus. Nat Rev Microbiol 13, 663–676 (2015). https://doi.org/10.1038/nrmicro3524

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