Innate immune evasion by filoviruses

Abstract

Ebola viruses and Marburg viruses, members of the filovirus family, cause severe hemorrhagic fever. The ability of these viruses to potently counteract host innate immune responses is thought to be an important component of viral pathogenesis. Several mechanisms of filoviral innate immune evasion have been defined and are reviewed here. These mechanisms include suppression of type I interferon (IFN) production; inhibition of IFN-signaling and mechanisms that either prevent cell stress responses or allow the virus to replicate in the face of such responses. A greater understanding of these innate immune evasion mechanisms may suggest novel therapeutic approaches for these deadly pathogens.

Keywords: Ebola virus; Hemorrhagic fever; Innate immunity; Interferon; Marburg virus.

Figure 1. Genome organization of filoviruses

The names of genes, designated according to proteins encoded by each, are indicated. NP, nucleoprotein; VP35, viral protein 35; VP40, viral protein 40; GP/sGP, glycoprotein, soluble glycoprotein; VP30, viral protein 30; VP24, viral protein 24; L, Large protein (the viral polymerase). Note that Marburg virus encodes GP but not sGP. The spacing between genes is variable and is not drawn to scale.

Figure 2. Filovirus VP35 proteins block RIG-I signaling at more than one step

Filoviruses enter the host cell via micropinocytosis and escape the endosome (depicted as a circle containing a virus). The viral genome escapes into the cytoplasm where replication reactions occur. Products of viral RNA synthesis, which may include RNAs with dsRNA features (depicted) and RNA with 5′-triphosphates are recognized by RIG-I or MDA5. This, aided by host protein PACT, activates RIG-I or MDA5 signaling and stimulates a signaling pathway that leads to activation of kinases IKKε and TBK1. These phosphorylate interferon regulator factors 3 or 7 (IRF3/7) which then dimerize, move to the nucleus and contribute to IFN-α/β gene expression. VP35 can bind to dsRNA, can block PACT activation of RIG-I and can prevent IKKε and TBK1 phosphorylation of IRF-3 and IRF-7.

Figure 3. Filoviruses block IFN signaling

Addition of IFNα or IFNβ to cells triggers a Jak-STAT signaling pathway which leads to tyrosine phosphorylation of STAT1 and STAT2. These dimerize and enter the nucleus through interactions with karyopherin alpha (KPNA) proteins. In the nucleus, a STAT1-STAT2-IRF9 complex activates IFN-stimulated response element (ISRE)-containing promoters. This leads to the upregulation of IFN stimulated genes such as MHC Class 1 and PKR. Ebola virus VP24 (eVP24) blocks interaction of phospho-STAT1 with KPNA proteins, preventing STAT1-STAT2 nuclear import. Marburg virus VP40 (mVP40) inhibits Jak1 function.