VP24-Karyopherin Alpha Binding Affinities Differ between Ebolavirus Species, Influencing Interferon Inhibition and VP24 Stability

Schwarz, Toni M.; Edwards, Megan R.; Diederichs, Audrey; Alinger, Joshua B.; Leung, Daisy W.; Amarasinghe, Gaya K.; Basler, Christopher F.

doi:10.1128/jvi.01715-16

Cited by 25 publications

(48 citation statements)

References 40 publications

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“…We have previously shown that RESTV is less capable than EBOV of counteracting IFN responses in Huh7 cells (41), suggesting a complex correlation between IFN antagonism and virus control in specific cell types. Along those lines, studies on the ebolavirus IFN antagonists VP35 and VP24 provide evidence that RESTV VP35 and VP24 might be less efficient in counteracting the IFN response (19,23,24,(69)(70)(71). It is likely that multiple factors contribute to the reduced pathogenicity of RESTV, and our data indicate that the lack of TLR4 activation might be one of them.…”

Section: Discussionmentioning

confidence: 54%

“…EBOV is known to efficiently suppress the type I interferon (IFN) response and expresses at least two IFN antagonists, the viral protein 35 (VP35) and VP24 (reviewed in references 17 and 18). RESTV VP35 and VP24 have also been shown to antagonize the type I IFN response, albeit less efficiently (19)(20)(21)(22)(23)(24). The primary in vivo target cells of ebolaviruses are thought to be cells of the mononuclear phagocyte system, including monocytes, macrophages, and myeloid dendritic cells (9,25).…”

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confidence: 99%

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Ebolaviruses Associated with Differential Pathogenicity Induce Distinct Host Responses in Human Macrophages

Olejnik

Forero

Deflubé

et al. 2017

J Virol

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Ebola virus (EBOV) and Reston virus (RESTV) are members of the Ebolavirus genus which greatly differ in their pathogenicity. While EBOV causes a severe disease in humans characterized by a dysregulated inflammatory response and elevated cytokine and chemokine production, there are no reported disease-associated human cases of RESTV infection, suggesting that RESTV is nonpathogenic for humans. The underlying mechanisms determining the pathogenicity of different ebolavirus species are not yet known. In this study, we dissected the host response to EBOV and RESTV infection in primary human monocyte-derived macrophages (MDMs). As expected, EBOV infection led to a profound proinflammatory response, including strong induction of type I and type III interferons (IFNs). In contrast, RESTV-infected macrophages remained surprisingly silent. Early activation of IFN regulatory factor 3 (IRF3) and NF-B was observed in EBOV-infected, but not in RESTV-infected, MDMs. In concordance with previous results, MDMs treated with inactivated EBOV and Ebola virus-like particles (VLPs) induced NF-B activation mediated by Toll-like receptor 4 (TLR4) in a glycoprotein (GP)-dependent manner. This was not the case in cells exposed to live RESTV, inactivated RESTV, or VLPs containing RESTV GP, indicating that RESTV GP does not trigger TLR4 signaling. Our results suggest that the lack of immune activation in RESTV-infected MDMs contributes to lower pathogenicity by preventing the cytokine storm observed in EBOV infection. We further demonstrate that inhibition of TLR4 signaling abolishes EBOV GP-mediated NF-B activation. This finding indicates that limiting the excessive TLR4-mediated proinflammatory response in EBOV infection should be considered as a potential supportive treatment option for EBOV disease.IMPORTANCE Emerging infectious diseases are a major public health concern, as exemplified by the recent devastating Ebola virus (EBOV) outbreak. Different ebolavirus species are associated with widely varying pathogenicity in humans, ranging from asymptomatic infections for Reston virus (RESTV) to severe disease with fatal outcomes for EBOV. In this comparative study of EBOV-and RESTV-infected human macrophages, we identified key differences in host cell responses. Consistent with previous data, EBOV infection is associated with a proinflammatory signature triggered by the surface glycoprotein (GP), which can be inhibited by blocking TLR4 signaling. In contrast, infection with RESTV failed to stimulate a strong host response in infected macrophages due to the inability of RESTV GP to stimulate TLR4. We propose that disparate proinflammatory host signatures contribute to the differences in pathogenicity reported for ebolavirus species and suggest that proinflammatory pathways represent an intriguing target for the development of novel therapeutics.

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Section: Discussionmentioning

confidence: 54%

mentioning

confidence: 99%

Ebolaviruses Associated with Differential Pathogenicity Induce Distinct Host Responses in Human Macrophages

Olejnik

Forero

Deflubé

et al. 2017

J Virol

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“…Thus, it appears that NES activity is important for species of the genus Ebolavirus and Cuevavirus, but not Marburgvirus. Interestingly, MABV VP24 is unique among the VP24 proteins of filoviruses in that it is reported not to bind Ks (26,44,45). Thus, MABV VP24 would appear not to have the same requirement for interaction with nuclear trafficking machinery as the VP24 proteins of the other filoviruses.…”

Section: Vp24mentioning

confidence: 99%

“…VP24 binds competitively to this site, inhibiting nuclear import of STAT1, as well as other cellular cargoes that use the same site, but not cargoes that bind elsewhere (17,18,20,25). The interaction between VP24 and K has been the subject of intense research, revealing a well-defined VP24-K interface involving contact via three clusters of residues in VP24, with importance to IFN antagonism (19,20) and VP24 stability (26).…”

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confidence: 99%

The Ebola virus interferon antagonist VP24 undergoes active nucleocytoplasmic trafficking

Harrison

Moseley

2020

Preprint

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Viral interferon (IFN) antagonist proteins mediate evasion of IFN-mediated innate immunity and are often multifunctional, having distinct roles in viral replication processes. Functions of the Ebola virus (EBOV) IFN antagonist VP24 include nucleocapsid assembly during cytoplasmic replication and inhibition of IFN-activated signalling by STAT1. For the latter, VP24 prevents STAT1 nuclear import via competitive binding to nuclear import receptors (karyopherins). Many viral proteins, including proteins from viruses with cytoplasmic replication cycles, interact with the trafficking machinery to undergo nucleocytoplasmic transport, with key roles in pathogenesis. Despite established karyopherin interaction, the nuclear trafficking profile of VP24 has not been investigated. We find that VP24 becomes strongly nuclear following overexpression of karyopherin or inhibition of nuclear export pathways. Molecular mapping indicates that cytoplasmic localisation of VP24 depends on a CRM1-dependent nuclear export sequence at the VP24 C-terminus. Nuclear export is not required for STAT1 antagonism, consistent with competitive karyopherin binding being the principal antagonistic mechanism while export mediates return of nuclear VP24 to the cytoplasm for replication functions. Thus, nuclear export of VP24 might provide novel targets for antiviral approaches.

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“…VP24 from all ebolaviruses, but not MARV VP24, inhibit IFN signaling, although BDBV and RESTV VP24 are less efficient at inhibition. This may in part be due to decreased KPNA binding (Guito et al 2016;Schwarz 2016). LLOV VP24 inhibits the IFN pathway in a manner similar to EBOV VP24 by inhibiting IFN-induced STAT1 nuclear translocation and ISG induction presumably due to its ability to bind KPNA (Feagins and Basler 2015).…”

Section: Inhibition Of Nuclear Transport Of Stats-mentioning

confidence: 99%

Filovirus Strategies to Escape Antiviral Responses

Olejnik

Hume

Leung

et al. 2017

Current Topics in Microbiology and Immunology

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This chapter describes the various strategies filoviruses use to escape host immune responses with a focus on innate immune and cell death pathways. Since filovirus replication can be efficiently blocked by interferon (IFN), filoviruses have evolved mechanisms to counteract both type I IFN induction and IFN response signaling pathways. Intriguingly, marburg- and ebolaviruses use different strategies to inhibit IFN signaling. This chapter also summarizes what is known about the role of IFN-stimulated genes (ISGs) in filovirus infection. These fall into three categories: those that restrict filovirus replication, those whose activation is inhibited by filoviruses, and those that have no measurable effect on viral replication. In addition to innate immunity, mammalian cells have evolved strategies to counter viral infections, including the induction of cell death and stress response pathways, and we summarize our current knowledge of how filoviruses interact with these pathways. Finally, this chapter delves into the interaction of EBOV with myeloid dendritic cells and macrophages and the associated inflammatory response, which differs dramatically between these cell types when they are infected with EBOV. In summary, we highlight the multifaceted nature of the host-viral interactions during filoviral infections.

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VP24-Karyopherin Alpha Binding Affinities Differ between Ebolavirus Species, Influencing Interferon Inhibition and VP24 Stability

Cited by 25 publications

References 40 publications

Ebolaviruses Associated with Differential Pathogenicity Induce Distinct Host Responses in Human Macrophages

Ebolaviruses Associated with Differential Pathogenicity Induce Distinct Host Responses in Human Macrophages

The Ebola virus interferon antagonist VP24 undergoes active nucleocytoplasmic trafficking

Filovirus Strategies to Escape Antiviral Responses

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