Chapter 15 : Filoviruses

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Filoviruses—Ebola viruses (EBOVs) and Marburg viruses (MBGVs)—are infamous for their ability to cause a highly lethal viral hemorrhagic fever. Nonhuman primates experimentally infected with Zaire EBOV exhibit a disease that resembles human EBOV infection, although these infections progress more rapidly and are almost invariably lethal. The ability of filoviruses to elicit pathological host responses is likely coupled with the ability of these viruses to replicate systemically to high titers. The ability of the virus to suppress adaptive immunity both by impairing dendritic cells (DCs) function and promoting lymphocyte apoptosis may also contribute to uncontrolled virus replication. Understanding how filoviruses overcome these early host responses may therefore lead to effective therapies targeting virus-encoded antagonists of innate immunity. Infection of cells with filoviruses impairs the capacity of cells to either produce interferon (IFN)-α/β or to respond to IFNs. Separately, microarray studies support the view that filoviruses suppress IFN responses. These observations demonstrate that different filoviruses influence cellular signaling pathways in similar but not identical ways. One major way in which EBOVs modulate host-cell signaling pathways is by antagonizing the IFN response, inhibiting both IFN-α/β production and IFN-α/β and IFN-γ-induced signaling. It will also be important to carefully assess whether the VP35 and VP24 proteins of other filoviruses function with similar efficiency as the Zaire EBOV VP35 and VP24. Identification of the triggers of potent cytokine responses with the aim of devising strategies to mitigate damaging host responses to infection is yet to be carried out.

Citation: Basler C. 2009. Filoviruses, p 229-246. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch15
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Image of Figure 1
Figure 1

Structure of the EBOV genome. Each box represents an individual gene. The proteins produced from each gene are indicated above the boxes. (Note that MBGV has a similar genome but does not encode an sGP protein.) The viral proteins shown have the following functions: NP, RNA synthesis, structural role; VP35, RNA synthesis, inhibits IFNα/β production; VP40, viral budding, structural role; GP, viral attachment and entry, induces cell rounding; sGP, uncertain function, nonstructural secreted protein; VP30, viral transcription factor; VP24, inhibits IFN signaling, role in assembly; L, RNA polymerase.

Citation: Basler C. 2009. Filoviruses, p 229-246. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch15
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Image of Figure 2
Figure 2

Viral induction of the host IFN system. A simplified schematic diagram of the signaling pathways leading to IFN-α/β synthesis following virus infection (left-side pathway) and the signaling pathways activated by IFN-α/β (center pathway) or by IFN-γ (right-side pathway). Virus infection can activate cellular transcription factors including the AP-1 transcription factor complex ATF-2/c-Jun, IRF3, and NF-κB. These transcription factors cooperate to activate transcription of the IFN-β gene. Expressed IFN-β is secreted and binds to the IFN-α/β receptor (IFNAR), triggering the activation of IFNAR-associated Jak family tyrosine kinases Jak1 and Tyk2. Tyrosine-phosphorylate Stat1 and Stat2, which form heterodimers, further interact with IRF9, forming the transcription factor complex ISGF3. ISGF3, when in the nucleus, activates transcription of genes with ISREs. IFN-γ binds to a distinct receptor, the IFN-γ receptor (IFNGR), leading to the activation of Jak1 and Jak2 and the formation of Stat1-Stat1 heterodimers, which move to the nucleus and activate promoters with gamma-activated sequence (GAS) elements.

Citation: Basler C. 2009. Filoviruses, p 229-246. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch15
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Figure 3

Model of EBOV VP35’s IFN-antagonist function. Depicted are the basic components of the pathways that lead from detection of viral replication products by the cellular RNA helicases RIG-I or MDA-5 to the production of IFN-β. RIG-I and MDA-5 signal in an IPS-1-dependent manner and activate the IRF3 kinases IKK-ε or TBK1. These participate in the activation of transcription factors, including IRF3, required for IFN-β promoter activity. Present data suggest that VP35 inhibits these pathways at or near the level of the IRF3 kinases.

Citation: Basler C. 2009. Filoviruses, p 229-246. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch15
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Figure 4

Model of EBOV VP24 inhibition of Stat1 nuclear accumulation. (A) Tyrosine phosphorylation of Stat1 by Jak family kinases results in dimerization of Stat1 with itself or other Stat proteins. In the case of Stat1-Stat1 homodimers, such as are activated by IFN-γ (depicted here) or Stat1-Stat2 heterodimers such as are activated by IFN-α/β, Stat1 nuclear accumulation is mediated by karyopherin α1 (K-α1). (B) VP24 binds to K-α1, preventing Stat1 from interacting with K-α1. This results in a failure of Stat1 to enter the nucleus and activate gene expression.

Citation: Basler C. 2009. Filoviruses, p 229-246. In Brasier A, García-Sastre A, Lemon S (ed), Cellular Signaling and Innate Immune Responses to RNA Virus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555815561.ch15
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