3-Deazaneplanocin A induces massively increased interferon-α production in Ebola virus-infected mice

Bray, Mike; Raymond, Jo Lynne; Geisbert, Tom; Baker, Richard L.

doi:10.1016/s0166-3542(02)00018-9

Cited by 99 publications

(72 citation statements)

References 25 publications

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“…The IFN system clearly plays a key role in the susceptibility of mice to lethal EBOV infection (6,8,37). While adult immunocompetent mice are resistant, type I IFN receptor or STAT1 knockout mice are susceptible to lethal EBOV infection (6).…”

Section: Discussionmentioning

confidence: 99%

Ebola Virus VP24 Proteins Inhibit the Interaction of NPI-1 Subfamily Karyopherin α Proteins with Activated STAT1

Reid

Valmas

Martinez

et al. 2007

J Virol

224

249

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The Zaire ebolavirus protein VP24 was previously demonstrated to inhibit alpha/beta interferon (IFN-␣/␤)-and IFN-␥-induced nuclear accumulation of tyrosine-phosphorylated STAT1 (PY-STAT1) and to inhibit IFN-␣/␤-and IFN-␥-induced gene expression. These properties correlated with the ability of VP24 to interact with the nuclear localization signal receptor for PY-STAT1, karyopherin ␣1. Here, VP24 is demonstrated to interact not only with overexpressed but also with endogenous karyopherin ␣1. Mutational analysis demonstrated that VP24 binds within the PY-STAT1 binding region located in the C terminus of karyopherin ␣1. In addition, VP24 was found to inhibit PY-STAT1 binding to both overexpressed and endogenous karyopherin ␣1. We assessed the binding of both PY-STAT1 and the VP24 proteins from Zaire, mouse-adapted Zaire, and Reston Ebola viruses for interaction with all six members of the human karyopherin ␣ family. We found, in contrast to previous studies, that PY-STAT1 can interact not only with karyopherin ␣1 but also with karyopherins ␣5 and ␣6, which together comprise the NPI-1 subfamily of karyopherin ␣s. Similarly, all three VP24s bound and inhibited PY-STAT1 interaction with karyopherins ␣1, ␣5, and ␣6. Consistent with their ability to inhibit the karyopherin-PY-STAT1 interaction, Zaire, mouse-adapted Zaire, and Reston Ebola virus VP24s displayed similar capacities to inhibit IFN-␤-induced gene expression in human and mouse cells. These findings suggest that VP24 inhibits interaction of PY-STAT1 with karyopherins ␣1, ␣5, or ␣6 by binding within the PY-STAT1 binding region of the karyopherins and that this function is conserved among the VP24 proteins of different Ebola virus species.

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Section: Discussionmentioning

confidence: 99%

Ebola Virus VP24 Proteins Inhibit the Interaction of NPI-1 Subfamily Karyopherin α Proteins with Activated STAT1

Reid

Valmas

Martinez

et al. 2007

J Virol

224

249

View full text Add to dashboard Cite

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“…In this study, we have taken advantage of a spectrum of transgenic and knockout mice to probe the mechanisms of cell death that occur in both hepatocytes and lymphocytes during EBOV infection and our results have strong correlates with empirical studies in humans and nonhuman primates. Although the mouse model for EBOV infection does not completely recapitulate the hemorrhagic clinical presentation in humans and nonhuman primates, particularly in a lack of fibrin deposition (7,14), it has served a valuable role in testing vaccines and therapeutics, as well as providing a controlled in vivo environment for basic research regarding the pathogenesis of EBOV infection (4,8,(44)(45)(46)(47)(48)(49)(50)(51)(52).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms and Consequences of Ebolavirus-Induced Lymphocyte Apoptosis

Bradfute

Swanson

Smith

et al. 2009

The Journal of Immunology

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Ebolavirus (EBOV) is a member of the filovirus family and causes severe hemorrhagic fever, resulting in death in up to 90% of infected humans. EBOV infection induces massive bystander lymphocyte apoptosis; however, neither the cellular apoptotic pathway(s) nor the systemic implications of lymphocyte apoptosis in EBOV infection are known. In this study, we show data suggesting that EBOV-induced lymphocyte apoptosis in vivo occurs via both the death receptor (extrinsic) and mitochondrial (intrinsic) pathways, as both Fas-associated death domain dominant negative transgenic mice and mice overexpressing bcl-2 were resistant to EBOV-induced lymphocyte apoptosis. Surprisingly, inhibiting lymphocyte apoptosis during EBOV infection did not result in improved animal survival. Furthermore, we show for the first time that hepatocyte apoptosis likely occurs in EBOV infection, and that mice lacking the proapoptotic genes Bim and Bid had reduced hepatocyte apoptosis and liver enzyme levels postinfection. Collectively, these data suggest that EBOV induces multiple proapoptotic stimuli and that blocking lymphocyte apoptosis is not sufficient to improve survival in EBOV infection. These data suggest that hepatocyte apoptosis may play a role in the pathogenesis of EBOV infection, whereas lymphocyte apoptosis appears to be nonessential for EBOV disease progression.

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“…inoculation of the virus, the mouse model is not considered ideal for studies of the human disease. Mice have, however, been used as a tool for studying innate immunity, screening vaccine candidates, and elucidating protective epitopes for humoral and cellular immunity to ZEBOV [49][50][51][52][53][54][55][56][57][58].…”

Section: Animal Models Of the Human Diseasementioning

confidence: 99%