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1.
Virology ; 496: 175-185, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27318793

RESUMO

Rift Valley fever (RVF) is a zoonotic disease that can cause severe illness in humans and livestock, triggering spontaneous abortion in almost 100% of pregnant ruminants. In this study, we demonstrate that signal transducer and activator of transcription 3 (STAT3) is phosphorylated on its conserved tyrosine residue (Y705) following RVFV infection. This phosphorylation was dependent on a major virulence factor, the viral nonstructural protein NSs. Loss of STAT3 had little effect on viral replication, but rather resulted in cells being more susceptible to RVFV-induced cell death. Phosphorylated STAT3 translocated to the nucleus, coinciding with inhibition of fos, jun, and nr4a2 gene expression, and the presence of STAT3 and NSs at the nr4a2 promoter. NSs was found predominantly in the cytoplasm of STAT3 null cells, indicating that STAT3 influences NSs nuclear localization. Collectively, these data demonstrate that STAT3 functions in a pro-survival capacity through modulation of NSs localization.


Assuntos
Febre do Vale de Rift/metabolismo , Febre do Vale de Rift/virologia , Vírus da Febre do Vale do Rift/fisiologia , Fator de Transcrição STAT3/metabolismo , Animais , Apoptose/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Núcleo Celular/metabolismo , Células Cultivadas , Chlorocebus aethiops , Humanos , Fosforilação , Regiões Promotoras Genéticas , Ligação Proteica , Transporte Proteico , Febre do Vale de Rift/genética , Vírus da Febre do Vale do Rift/efeitos dos fármacos , Tirosina/metabolismo , Células Vero , Proteínas não Estruturais Virais/metabolismo , Replicação Viral
2.
Antiviral Res ; 127: 79-89, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26801627

RESUMO

Rift Valley fever virus (RVFV), genus Phlebovirus family Bunyaviridae, is an arthropod-borne virus endemic throughout sub-Saharan Africa. Recent outbreaks have resulted in cyclic epidemics with an increasing geographic footprint, devastating both livestock and human populations. Despite being recognized as an emerging threat, relatively little is known about the virulence mechanisms and host interactions of RVFV. To date there are no FDA approved therapeutics or vaccines for RVF and there is an urgent need for their development. The Ser/Thr protein phosphatase 1 (PP1) has previously been shown to play a significant role in the replication of several viruses. Here we demonstrate for the first time that PP1 plays a prominent role in RVFV replication early on during the viral life cycle. Both siRNA knockdown of PP1α and a novel PP1-targeting small molecule compound 1E7-03, resulted in decreased viral titers across several cell lines. Deregulation of PP1 was found to inhibit viral RNA production, potentially through the disruption of viral RNA transcript/protein interactions, and indicates a potential link between PP1α and the viral L polymerase and nucleoprotein. These results indicate that PP1 activity is important for RVFV replication early on during the viral life cycle and may prove an attractive therapeutic target.


Assuntos
Antivirais/farmacologia , Replicação do DNA/fisiologia , Indóis/farmacologia , Proteína Fosfatase 1/metabolismo , Vírus da Febre do Vale do Rift/enzimologia , Vírus da Febre do Vale do Rift/fisiologia , Ureia/análogos & derivados , Replicação Viral/fisiologia , Animais , Antivirais/química , Antivirais/uso terapêutico , Linhagem Celular , Replicação do DNA/efeitos dos fármacos , Genoma Viral/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Humanos , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Proteína Fosfatase 1/antagonistas & inibidores , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , RNA Viral/biossíntese , RNA Viral/efeitos dos fármacos , Febre do Vale de Rift/tratamento farmacológico , Febre do Vale de Rift/virologia , Vírus da Febre do Vale do Rift/efeitos dos fármacos , Vírus da Febre do Vale do Rift/genética , Ureia/farmacologia , Células Vero , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/metabolismo , Virulência , Replicação Viral/efeitos dos fármacos
3.
Front Microbiol ; 6: 676, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26217313

RESUMO

There are currently no FDA-approved therapeutics available to treat Rift Valley fever virus (RVFV) infection. In an effort to repurpose drugs for RVFV treatment, a library of FDA-approved drugs was screened to determine their ability to inhibit RVFV. Several drugs from varying compound classes, including inhibitors of growth factor receptors, microtubule assembly/disassembly, and DNA synthesis, were found to reduce RVFV replication. The hepatocellular and renal cell carcinoma drug, sorafenib, was the most effective inhibitor, being non-toxic and demonstrating inhibition of RVFV in a cell-type and virus strain independent manner. Mechanism of action studies indicated that sorafenib targets at least two stages in the virus infectious cycle, RNA synthesis and viral egress. Computational modeling studies also support this conclusion. siRNA knockdown of Raf proteins indicated that non-classical targets of sorafenib are likely important for the replication of RVFV.

4.
PLoS One ; 9(5): e93483, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24809507

RESUMO

Rift Valley fever is a potentially fatal disease of humans and domestic animals caused by Rift Valley fever virus (RVFV). Infection with RVFV in ruminants can cause near 100% abortion rates and recent outbreaks in naïve human populations have suggested case fatality rates of greater than thirty percent. To elucidate the roles that host proteins play during RVFV infection, proteomic analysis of RVFV virions was conducted using complementary analytical approaches, followed by functional validation studies of select identified host factors. Coupling the more traditional Gel LC/MS/MS approach (SDS PAGE followed by liquid chromatography tandem mass spectrometry) with an alternative technique that preserves protein complexes allowed the protein complement of these viral particles to be thoroughly examined. In addition to viral proteins present within the virions and virion-associated host proteins, multiple macromolecular complexes were identified. Bioinformatic analysis showed that host chaperones were among over-represented protein families associated with virions, and functional experiments using siRNA gene silencing and small molecule inhibitors identified several of these heat shock proteins, including heat shock protein 90 (HSP90), as important viral host factors. Further analysis indicated that HSP inhibition effects occur during the replication/transcription phase of the virus life cycle, leading to significant lowering of viral titers without compromising the functional capacity of released virions. Overall, these studies provide much needed further insight into interactions between RVFV and host cells, increasing our understanding of the infection process and suggesting novel strategies for anti-viral development. In particular, considering that several HSP90 inhibitors have been advancing through clinical trials for cancer treatment, these results also highlight the exciting potential of repurposing HSP90 inhibitors to treat RVF.


Assuntos
Proteínas de Choque Térmico HSP90/metabolismo , Proteínas de Choque Térmico/metabolismo , Vírus da Febre do Vale do Rift/metabolismo , Proteínas Virais/metabolismo , Vírion/metabolismo , Inativação Gênica , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico/genética , Proteômica , RNA Interferente Pequeno , Febre do Vale de Rift/virologia , Vírus da Febre do Vale do Rift/genética , Espectrometria de Massas em Tandem , Proteínas Virais/genética , Vírion/genética
5.
Virology ; 449: 270-86, 2014 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-24418562

RESUMO

Rift Valley fever virus (RVFV) infection is often associated with pronounced liver damage. Previously, our studies revealed altered host phospho-signaling responses (NFκB, MAPK and DNA damage responses) in RVFV infected epithelial cells that correlated with a cellular stress response. Here, we report that RVFV infection of liver cells leads to an increase in reactive oxygen species (ROS). Our data suggests the presence of the viral protein NSs in the mitochondria of infected cells, hence contributing to early increase in ROS. Increased ROS levels correlated with activation of NFκB (p65) and p53 responses, which in conjunction with infection, was also reflected as macromolecular rearrangements observed using size fractionation of protein lysates. Additionally, we documented an increase in cytokine expression and pro-apoptotic gene expression with infection, which was reversed with antioxidant treatment. Collectively, we identified ROS and oxidative stress as critical contributors to apoptosis of liver cells during RVFV infection.


Assuntos
Apoptose , Fígado/citologia , Espécies Reativas de Oxigênio/metabolismo , Febre do Vale de Rift/metabolismo , Vírus da Febre do Vale do Rift/fisiologia , Fator de Transcrição RelA/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Humanos , Fígado/metabolismo , Fígado/virologia , Estresse Oxidativo , Febre do Vale de Rift/fisiopatologia , Febre do Vale de Rift/virologia , Fator de Transcrição RelA/genética , Proteína Supressora de Tumor p53/genética , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo , Replicação Viral
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