Lloviu virus VP24 and VP35 proteins function as innate immune antagonists in human and bat cells

Feagins, Alicia R.; Basler, Christopher F.

doi:10.1016/j.virol.2015.07.010

Cited by 39 publications

(45 citation statements)

References 40 publications

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“…A central feature of extant filoviral VP35s is potent suppression of RIG-I signaling and IFN production (Edwardset al, 2016; Fea- ginsand Basler, 2015; Leung etal., 2010; Ramanan etal., 2012). The most intensively studied, eVP35, inhibits IFN responses through several mechanisms (Basler et al, 2000; Leung et al, 2010; Luthra et al, 2013; Prins et al, 2009, 2010b; Yen and Basler, 2016).…”

Section: Discussionmentioning

confidence: 99%

Conservation of Structure and Immune Antagonist Functions of Filoviral VP35 Homologs Present in Microbat Genomes

et al. 2018

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Non-retroviral integrated RNA viral sequences (NIRVs) potentially encoding ∼280 amino acid homologs to filovirus VP35 proteins are present across the Myotis genus of bats. These are estimated to have been maintained for ∼18 million years, indicating their co-option. To address the reasons for co-option, 16 Myotis VP35s were characterized in comparison to VP35s from the extant filoviruses Ebola virus and Marburg virus, in which VP35s play critical roles in immune evasion and RNA synthesis. The Myotis VP35s demonstrated a conserved suppression of innate immune signaling, albeit with reduced potency, in either human or Myotis cells. Their attenuation reflects a lack of dsRNA binding that in the filoviral VP35s correlates with potent suppression of interferon responses. Despite divergent function, evolution has preserved in Myotis the structure of the filoviral VP35s, indicating that this structure is critical for co-opted function, possibly as a regulator of innate immune signaling.

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Section: Discussionmentioning

confidence: 99%

Conservation of Structure and Immune Antagonist Functions of Filoviral VP35 Homologs Present in Microbat Genomes

et al. 2018

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“…VP30 and NP play an important role in the RNA‐binding activity . The multifunctional protein, VP35, suppresses host‐innate immunity and has been found to be involved in transcription/replication processes together with nucleocapsid assembly . The interactions between these proteins (ie, NP‐NP and NP‐VP35) are essential to regulate the formation of the EBOV replication complex for efficient transcription/replication.…”

Section: Introductionmentioning

confidence: 99%

Perspectives towards antiviral drug discovery against Ebola virus

Mirza

Vanmeert

Ali

et al. 2019

Journal of Medical Virology

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Ebola virus disease (EVD), caused by Ebola viruses, resulted in more than 11 500 deaths according to a recent 2018 WHO report. With mortality rates up to 90%, it is nowadays one of the most deadly infectious diseases. However, no Food and Drug Administration‐approved Ebola drugs or vaccines are available yet with the mainstay of therapy being supportive care. The high fatality rate and absence of effective treatment or vaccination make Ebola virus a category‐A biothreat pathogen. Fortunately, a series of investigational countermeasures have been developed to control and prevent this global threat. This review summarizes the recent therapeutic advances and ongoing research progress from research and development to clinical trials in the development of small‐molecule antiviral drugs, small‐interference RNA molecules, phosphorodiamidate morpholino oligomers, full‐length monoclonal antibodies, and vaccines. Moreover, difficulties are highlighted in the search for effective countermeasures against EVD with additional focus on the interplay between available in silico prediction methods and their evidenced potential in antiviral drug discovery.

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“…In addition to playing a key structural role in condensing viral nucleocapsids, VP24 also acts as potent antagonist of the interferon (IFN) pathway—but only in ebolaviruses and cuevaviruses. Both EBOV and LLOV VP24 interact with the NPI-1 subfamily of karyopherin-α proteins and restrict their ability to translocate phosphorylated STAT1 homodimers or STAT1-STAT2 heterodimers into the nucleus [42–46]. In this way, VP24 prevents the induction of anti-viral IFN-stimulated genes (ISG) in response to type I IFN signaling.…”

Section: Introductionmentioning

confidence: 99%

Rodent-Adapted Filoviruses and the Molecular Basis of Pathogenesis

Banadyga

Dolan

Ebihara

2016

Journal of Molecular Biology

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Ebola, Marburg, and Ravn virus, all filoviruses, are the causative agents of severe hemorrhagic fever. Much of what we understand about the pathogenesis of filovirus disease is derived from work with animal models, including non-human primates (NHPs), which are considered the “gold standard” filovirus model since they faithfully recapitulate the clinical hallmarks of filovirus disease. However, rodent models, including the mouse, guinea pig, and hamster, also exist for Ebola, Marburg, and Ravn viruses, and although they may not reproduce all the clinical signs of filovirus disease, thanks to their relative ease-of-use and low cost they are often the first choice for initial descriptions of virus pathogenesis and evaluation of anti-viral prophylactics and therapeutics. Since filoviruses do not cause significant disease in adult, immunocompetent rodents, these models rely on “rodent-adapted” viruses that have been passaged several times through their host until virulence and lethality are achieved. In the process of adaptation, the viruses acquire numerous nucleotide/amino acid mutations that contribute to virulence in their rodent host. Interestingly, virus protein 24 (VP24) and nucleoprotein (NP) appear to be major virulence factors for ebolaviruses in rodents, whereas VP40 appears to be the major virulence factor for marburgviruses. By characterizing these mutations and understanding the molecular mechanisms that lead to the acquisition of virulence, we can gain better insight into the pathogenic processes that underlie filovirus disease in humans. These processes, and the viral and/or cellular proteins that contribute to them, will make attractive targets for the development of novel therapeutics and countermeasures.

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Lloviu virus VP24 and VP35 proteins function as innate immune antagonists in human and bat cells

Cited by 39 publications

References 40 publications

Conservation of Structure and Immune Antagonist Functions of Filoviral VP35 Homologs Present in Microbat Genomes

Conservation of Structure and Immune Antagonist Functions of Filoviral VP35 Homologs Present in Microbat Genomes

Perspectives towards antiviral drug discovery against Ebola virus

Rodent-Adapted Filoviruses and the Molecular Basis of Pathogenesis

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