Filovirus Strategies to Escape Antiviral Responses

Olejnik, Judith; Hume, Adam J.; Leung, Daisy W.; Amarasinghe, Gaya K.; Basler, Christopher F.; Mühlberger, Elke

doi:10.1007/82_2017_13

Cited by 25 publications

(30 citation statements)

References 248 publications

(376 reference statements)

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“…The present study demonstrates the capacity of MLAV VP35 and VP40 to counteract IFN responses in human and bat cells. Inhibition of RIG-I induced IFN responses is thus far a common feature of filoviruses (52). The suppression of IFN-induced signaling and gene expression by VP40, rather than via VP24, parallels MARV and draws a functional distinction between MLAV and EBOV.…”

Section: Discussionmentioning

confidence: 99%

Impact of Měnglà virus proteins on human and bat innate immune pathways

Williams

Gibbons

Keiffer

et al. 2019

Preprint

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AbstractMěnglà virus (MLAV), identified in Rousettus bats, is a phylogenetically distinct member of the family Filoviridae. Because filoviruses Ebola virus (EBOV) and Marburg virus (MARV) modulate host innate immune pathways, MLAV VP35, VP40 and VP24 proteins were compared with their EBOV and MARV homologs for innate immune pathway modulation. In human and Rousettus cells, MLAV VP35 behaved like EBOV and MARV VP35s, inhibiting virus-induced activation of the interferon (IFN)-β promoter. MLAV VP35 inhibited IRF3 phosphorylation and interacted with PACT, a host protein engaged by EBOV VP35 to inhibit RIG-I signaling. MLAV VP35 also inhibited PKR activation. MLAV VP40 was demonstrated to inhibit type I IFN induced gene expression in human and bat cells. It blocked STAT1 tyrosine phosphorylation induced either by type I IFN or over-expressed Jak1, paralleling MARV VP40. MLAV VP40 also inhibited virus-induced IFNβ promoter activation, a property shared by MARV VP40 and EBOV VP24. The inhibition of IFN induction was preserved in the presence of a Jak kinase inhibitor, demonstrating that inhibition of Jak-STAT signaling is not sufficient to explain inhibition of IFNβ promoter activation. MLAV VP24 did not inhibit IFN-induced gene expression or bind karyopherin α5, properties of EBOV VP24. MLAV VP24 also differed from MARV VP24 in that it failed to interact with Keap1 or activate an antioxidant response element reporter gene, due to the absence of a Keap1-binding motif. These studies demonstrate similarities between MLAV and MARV in how they suppress IFN responses and differences in how MLAV VP24 interacts with host pathways.ImportanceEBOV and MARV, members of the family Filoviridae, are highly pathogenic zoonotic viruses that cause severe disease in humans. Both viruses use several mechanisms to modulate the host innate immune response, and these likely contribute to severity of disease. Here, we demonstrate that MLAV, a filovirus newly discovered in a bat, suppresses antiviral type I interferon responses in both human and bat cells. Inhibitory activities are possessed by MLAV VP35 and VP40, which parallels how MARV blocks IFN responses. However, whereas MARV activates cellular antioxidant responses through an interaction between its VP24 protein and host protein Keap1, MLAV VP24 lacks a Keap1 binding motif and fails to activate this cytoprotective response. These data indicate that MLAV possesses immune suppressing functions that could facilitate human infection. They also demonstrate key differences in MLAV versus either EBOV or MARV engagement of host signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Impact of Měnglà virus proteins on human and bat innate immune pathways

Williams

Gibbons

Keiffer

et al. 2019

Preprint

Self Cite

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“…Multiple studies have demonstrated that EBOV employs an array of mechanisms to effectively evade the host immune responses ( Figure 2 ), where viral GP, VP24, VP35 and VP40 play a significant role (reviewed in [ 104 ]). The efficacy of host immune evasion by EBOV is indicated by the rapid replication rate displayed by the virus inside the host cells [ 27 ].…”

Section: Evasion Of Host Immune Response By Ebovmentioning

confidence: 99%

“…This results in interference with the type I and II IFN response by restricting the JAK-STAT to the cytoplasm [ 105 , 107 , 108 ] ( Figure 2 ). However, EBOV, SUDV and TAFV inhibit IFN-signaling with greater efficacy as compared to BDBV and RESTV, a feature attributed to high KPNA binding ability of the former viruses [ 104 , 109 ]. A host cell-type dependent restriction of IFN signaling through mitogen-activated protein kinases (MAPK) pathway by VP24 has also been reported [ 105 , 110 ].…”

Section: Evasion Of Host Immune Response By Ebovmentioning

confidence: 99%

Immunological Perspective for Ebola Virus Infection and Various Treatment Measures Taken to Fight the Disease

2020

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Ebolaviruses, discovered in 1976, belongs to the Filoviridae family, which also includes Marburg and Lloviu viruses. They are negative-stranded RNA viruses with six known species identified to date. Ebola virus (EBOV) is a member of Zaire ebolavirus species and can cause the Ebola virus disease (EVD), an emerging zoonotic disease that results in homeostatic imbalance and multi-organ failure. There are three EBOV outbreaks documented in the last six years resulting in significant morbidity (> 32,000 cases) and mortality (> 13,500 deaths). The potential factors contributing to the high infectivity of this virus include multiple entry mechanisms, susceptibility of the host cells, employment of multiple immune evasion mechanisms and rapid person-to-person transmission. EBOV infection leads to cytokine storm, disseminated intravascular coagulation, host T cell apoptosis as well as cell mediated and humoral immune response. In this review, a concise recap of cell types targeted by EBOV and EVD symptoms followed by detailed run-through of host innate and adaptive immune responses, virus-driven regulation and their combined effects contributing to the disease pathogenesis has been presented. At last, the vaccine and drug development initiatives as well as challenges related to the management of infection have been discussed.

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“…A higher basal (rather than inducible) expression of RNASEL was observed in Egyptian rousette cells (29), which could further support the hypothesis of a species-specific difference among bats. There are a number of ISGs that were shown to have antiviral activity against filoviruses, including tetherin, Zinc finger antiviral protein (ZAP), interferon-induced transmembrane (IFITM) proteins, and ISG15 [reviewed in (30)]. While ZAP was not induced under any condition, ISG15 expression was induced by both IFN-ωs and UIFN, and tetherin and IFITM3 were only induced by IFN-ω treatment.…”

Section: Ifn-ω Proteins Induced Novel and Known Isgsmentioning

confidence: 99%

Egyptian Rousette IFN-ω Subtypes Elicit Distinct Antiviral Effects and Transcriptional Responses in Conspecific Cells

et al. 2020

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Bats host a number of viruses that cause severe disease in humans without experiencing overt symptoms of disease themselves. While the mechanisms underlying this ability to avoid sickness are not known, deep sequencing studies of bat genomes have uncovered genetic adaptations that may have functional importance in the antiviral response of these animals. Egyptian rousette bats (Rousettus aegyptiacus) are the natural reservoir hosts of Marburg virus (MARV). In contrast to humans, these bats do not become sick when infected with MARV. A striking difference to the human genome is that Egyptian rousettes have an expanded repertoire of IFNW genes. To probe the biological implications of this expansion, we synthesized IFN-ω4 and IFN-ω9 proteins and tested their antiviral activity in Egyptian rousette cells. Both IFN-ω4 and IFN-ω9 showed antiviral activity against RNA viruses, including MARV, with IFN-ω9 being more efficient than IFN-ω4. Using RNA-Seq, we examined the transcriptional response induced by each protein. Although the sets of genes induced by the two IFNs were largely overlapping, IFN-ω9 induced a more rapid and intense response than did IFN-ω4. About 13% of genes induced by IFN-ω treatment are not found in the Interferome or other ISG databases, indicating that they may be uniquely IFN-responsive in this bat.

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Filovirus Strategies to Escape Antiviral Responses

Cited by 25 publications

References 248 publications

Impact of Měnglà virus proteins on human and bat innate immune pathways

Impact of Měnglà virus proteins on human and bat innate immune pathways

Immunological Perspective for Ebola Virus Infection and Various Treatment Measures Taken to Fight the Disease

Egyptian Rousette IFN-ω Subtypes Elicit Distinct Antiviral Effects and Transcriptional Responses in Conspecific Cells

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