The Ebolavirus VP24 Protein Blocks Phosphorylation of p38 Mitogen-Activated Protein Kinase

Halfmann, Peter; Neumann, Gabriele; Kawaoka, Yoshihiro

doi:10.1093/infdis/jir325

Cited by 41 publications

(25 citation statements)

References 14 publications

(36 reference statements)

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“…EBOV VP24 protein interacts with KPN␣1, thereby preventing translocation of STAT-I (34), and also interacts with heterogeneous nuclear ribonuclear protein complex C1/C2 (hnRNP C1/C2), partially altering its nuclear transport (35). VP24 also blocks the phosphorylation of p38 (36), which triggers the phosphorylation of transcription factors mediating the IFN response (37). The interaction of VP24 with KPN␣1 is completely prevented by a K142A mutation (38).…”

mentioning

confidence: 99%

The Lack of Maturation of Ebola Virus-Infected Dendritic Cells Results from the Cooperative Effect of at Least Two Viral Domains

Lubaki

Ilinykh

Pietzsch

et al. 2013

J Virol

127

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dEbola virus (EBOV) infections are characterized by deficient T lymphocyte responses, T lymphocyte apoptosis, and lymphopenia in the absence of direct infection of T lymphocytes. In contrast, dendritic cells (DC) are infected but fail to mature appropriately, thereby impairing the T cell response. We investigated the contributions of EBOV proteins in modulating DC maturation by generating recombinant viruses expressing enhanced green fluorescent protein and carrying mutations affecting several potentially immunomodulating domains. They included envelope glycoprotein (GP) domains, as well as innate response antagonist domains (IRADs) previously identified in the VP24 and VP35 proteins. GP expressed by an unrelated vector, but not the wild-type EBOV, was found to strongly induce DC maturation, and infections with recombinant EBOV carrying mutations disabling GP functional domains did not restore DC maturation. In contrast, each of the viruses carrying mutations disabling any IRAD in VP35 induced a dramatic upregulation of DC maturation markers. This was dependent on infection, but not interaction with GP. Disabling of IRADs also resulted in up to a several hundredfold increase in secretion of cytokines and chemokines. Furthermore, these mutations induced formation of homotypic DC clusters, which represent close correlates of their maturation and presumably facilitate transfer of antigen from migratory DC to lymph node DC. Thus, an individual IRAD is insufficient to suppress DC maturation; rather, the suppression of DC maturation and the "immune paralysis" observed during EBOV infections results from a cooperative effect of two or more individual IRADs.

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confidence: 99%

The Lack of Maturation of Ebola Virus-Infected Dendritic Cells Results from the Cooperative Effect of at Least Two Viral Domains

Lubaki

Ilinykh

Pietzsch

et al. 2013

J Virol

127

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“…Infection of the APCs can result in functional defects such as causing a decrease in the production of cytokines from APCs, downregulation of MHC I (23,40) or apoptosis/anergy of the NK and T and B lymphocytes. EBOV proteins VP24 and VP35, which are antagonists to the interferons required to control an EBOV infection (6,22), effectively inhibit the activation of hundreds of immune response genes. Upon exposure to VSVDG/EBOV GP early in a MA-EBOV infection, the production of IFN-b by macrophages and potent antiviral molecule IFN-c from NK cells may be part of the protective function that counteracts the IFN block by EBOV.…”

Section: Discussionmentioning

confidence: 99%

VSVΔG/EBOV GP-Induced Innate Protection Enhances Natural Killer Cell Activity to Increase Survival in a Lethal Mouse Adapted Ebola Virus Infection

et al. 2015

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Members of the species Zaire ebolavirus cause severe hemorrhagic fever with up to a 90% mortality rate in humans. The VSVΔG/EBOV GP vaccine has provided 100% protection in the mouse, guinea pig, and nonhuman primate (NHP) models, and has also been utilized as a post-exposure therapeutic to protect mice, guinea pigs, and NHPs from a lethal challenge of Ebola virus (EBOV). EBOV infection causes rapid mortality in human and animal models, with death occurring as early as 6 days after infection, suggesting a vital role for the innate immune system to control the infection before cells of the adaptive immune system can assume control. Natural killer (NK) cells are the predominant cell of the innate immune response, which has been shown to expand with VSVΔG/EBOV GP treatment. In the current study, an in vivo mouse model of the VSVΔG/EBOV GP post-exposure treatment was used for a mouse adapted (MA)-EBOV infection, to determine the putative VSVΔG/EBOV GP-induced protective mechanism of NK cells. NK depletion studies demonstrated that mice with NK cells survive longer in a MA-EBOV infection, which is further enhanced with VSVΔG/EBOV GP treatment. NK cell mediated cytotoxicity and IFN-γ secretion was significantly higher with VSVΔG/EBOV GP treatment. Cell mediated cytotoxicity assays and perforin knockout mice experiments suggest that there are perforin-dependent and -independent mechanisms involved. Together, these data suggest that NK cells play an important role in VSVΔG/EBOV GP-induced protection of EBOV by increasing NK cytotoxicity, and IFN-γ secretion.

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“…One study found that in HEK-293T cells, VP24 was able to block the interferon-β induced phosphorylation of p38-α. However, this finding was cell type-specific and the blocking mechanism has yet to be demonstrated or generalized to cells that are primary targets of infection (e.g., macrophages, dendritic cells) (Halfmann et al, 2011). …”

Section: Snipping the Alarm-wire: Preventing The Interferon Alarmmentioning

confidence: 99%

Camouflage and Misdirection: The Full-On Assault of Ebola Virus Disease

Misasi

Sullivan

2014

Cell

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Ebolaviruses cause a severe hemorrhagic fever syndrome that is rapidly fatal to humans and non-human primates. Ebola protein interactions with host cellular proteins disrupt Type I and Type II interferon responses, RNAi anti-viral responses, antigen presentation, T-cell mediated antibody responses, humoral antibodies and cell mediated immunity. This multifaceted approach to evasion and suppression of innate and adaptive immune responses in their target hosts leads to the severe immune dysregulation and “cytokine storm” that is characteristic of fatal ebolavirus infection. Here we highlight some of the processes by which Ebola interacts with its mammalian hosts to evade anti-viral defenses.

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The Ebolavirus VP24 Protein Blocks Phosphorylation of p38 Mitogen-Activated Protein Kinase

Cited by 41 publications

References 14 publications

The Lack of Maturation of Ebola Virus-Infected Dendritic Cells Results from the Cooperative Effect of at Least Two Viral Domains

The Lack of Maturation of Ebola Virus-Infected Dendritic Cells Results from the Cooperative Effect of at Least Two Viral Domains

VSVΔG/EBOV GP-Induced Innate Protection Enhances Natural Killer Cell Activity to Increase Survival in a Lethal Mouse Adapted Ebola Virus Infection

Camouflage and Misdirection: The Full-On Assault of Ebola Virus Disease

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