Filoviral Immune Evasion Mechanisms

Parameshwaran Ramanan,Gaya K Amarasinghe,Craig S Brown,Reed S Shabman,Daisy W Leung,Christopher F Basler

doi:10.3390/v3091634

Parameshwaran Ramanan, Gaya K Amarasinghe + Show 4 more

Open Access

https://doi.org/10.3390/v3091634

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Abstract

The Filoviridae family of viruses, which includes the genera Ebolavirus (EBOV) and Marburgvirus (MARV), causes severe and often times lethal hemorrhagic fever in humans. Filoviral infections are associated with ineffective innate antiviral responses as a result of virally encoded immune antagonists, which render the host incapable of mounting effective innate or adaptive immune responses. The Type I interferon (IFN) response is critical for establishing an antiviral state in the host cell and subsequent activation of the adaptive immune responses. Several filoviral encoded components target Type I IFN responses, and this innate immune suppression is important for viral replication and pathogenesis. For example, EBOV VP35 inhibits the phosphorylation of IRF-3/7 by the TBK-1/IKKε kinases in addition to sequestering viral RNA from detection by RIG-I like receptors. MARV VP40 inhibits STAT1/2 phosphorylation by inhibiting the JAK family kinases. EBOV VP24 inhibits nuclear translocation of activated STAT1 by karyopherin-α. The examples also represent distinct mechanisms utilized by filoviral proteins in order to counter immune responses, which results in limited IFN-α/β production and downstream signaling.

Highlights

The Filoviridae family of viruses, which includes the genera Ebolavirus (EBOV) and Marburgvirus (MARV), causes severe and often times lethal hemorrhagic fever in humans
We primarily focus on the following filoviral proteins: EBOV viral protein (VP) 35, EBOV VP24, and MARV VP40
The host innate immune response is triggered upon recognition of pathogen associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs), which are located both on the surface and in the cytoplasm of cells

Summary

Filoviruses

Filoviruses are single-stranded, negative sense RNA viruses, which cause severe viral hemorrhagic fever in humans and non-human primates. All of the macaques suffered from viral hemorrhagic fever resulting in death, while the two animal handlers who came in to contact with the animals had seroconverted They did not display any disease symptoms. The lethality of filoviral infections have been attributed to the ability of the virus to efficiently suppress the host innate antiviral responses early during infection, followed by impairment and/or dysregulation of the adaptive immune response and inflammatory pathways late during infection [7]. This is proposed to be due in large part to viral replication within dendritic cells, monocytes, macrophages, and hepatocytes [8]. Having such information at hand will provide a starting point for developing countermeasures against filoviral infections

Host Innate Immune Mechanisms

Filoviral Encoded Immune Antagonists

EBOV VP35 Inhibits IFN Production

EBOV VP24 Inhibits Transcription of Antiviral Genes

MARV VP40 Inhibits the IFN-induced Phosphorylation of Jak and STAT Proteins

Conclusions