Inhibition of host extracellular signal-regulated kinase (ERK) activation decreases new world alphavirus multiplication in infected cells

Voss, Kelsey; Amaya, Moushimi; Mueller, Claudius; Roberts, Brian; Kehn-Hall, Kylene; Bailey, Charles; Petricoin, Emanuel F.; Narayanan, Aarthi

doi:10.1016/j.virol.2014.09.005

Cited by 24 publications

(33 citation statements)

References 55 publications

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“…We have previously demonstrated that VEEV infection leads to robust activation of the MEK/ERK signaling cascade, which is important for the virus to establish a productive infection. 7 In the case of HCV infected cells, similar clustering of mitochondria was demonstrated. 59 In HIV infected cells, mitochondria displayed morphological alterations including disappearance of cristae.…”

Section: Discussionmentioning

confidence: 69%

“…We utilized the TC-83 virus to study the consequences of infection on astrocytoma cells (U87MG cells), as we have demonstrated in the past that TC-83 infection induces several innate immune signaling events and leads to death of infected cells. 6,7 Cumulatively, our studies indicate that VEEV infection disrupts mitochondrial structure and function. We demonstrate that mitochondrial fission may partially contribute to apoptosis that occurs in infected cells.…”

Section: Introductionmentioning

confidence: 74%

“…U87MG cells are readily infected by VEEV and display robust viral replication kinetics. [6][7][8][28][29][30] U87MG cells were infected with the TC-83 strain of VEEV at increasing multiplicities of infection (MOIs). Changes in mitochondrial membrane potential were quantified by labeling active mitochondria with TMRE reagent (TetraMethyl Rhodamine, Ethyl ester).…”

Section: Veev Infection Results In Loss Of Mitochondrial Membrane Potmentioning

confidence: 99%

“…[6][7][8] Many host proteins have been shown to interact with VEEV proteins that critically influence viral multiplication. 9,10 Thus, multiple lines of evidence allude to the importance of host components in viral multiplication and host pathology.…”

Section: Introductionmentioning

confidence: 99%

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Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection

et al. 2017

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Mitochondria are sentinel organelles that are impacted by various forms of cellular stress, including viral infections. While signaling events associated with mitochondria, including those activated by pathogen associated molecular patterns (PAMPs), are widely studied, alterations in mitochondrial distribution and changes in mitochondrial dynamics are also beginning to be associated with cellular insult. Cells of neuronal origin have been demonstrated to display remarkable alterations in several instances, including neurodegenerative disorders. Venezuelan Equine Encephalitis Virus (VEEV) is a New World alphavirus that infects neuronal cells and contributes to an encephalitic phenotype. We demonstrate that upon infection by the vaccine strain of VEEV (TC-83), astrocytoma cells experience a robust drop in mitochondrial activity, which corresponds with an increased accumulation of reactive oxygen species (ROS) in an infection-dependent manner. Infection status also corresponds with a prominent perinuclear accumulation of mitochondria. Cellular enzymatic machinery, including PINK1 and Parkin, appears to be enriched in mitochondrial fractions as compared with uninfected cells, which is indicative of mitochondrial damage. Dynamin related protein 1 (Drp1), a protein that is associated with mitochondrial fission, demonstrated a modest enrichment in mitochondrial fractions of infected cells. Treatment with an inhibitor of mitochondrial fission, Mdivi-1, led to a decrease in caspase cleavage, suggesting that mitochondrial fission was likely to contribute to apoptosis of infected cells. Finally, our data demonstrate that mitophagy ensues in infected cells. In combination, our data suggest that VEEV infection results in significant changes in the mitochondrial landscape that may influence pathological outcomes in the infected cell.

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 74%

Section: Veev Infection Results In Loss Of Mitochondrial Membrane Potmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection

et al. 2017

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“…This is to our knowledge the first experimental evidence of all major MAPK signaling pathways being concomitantly activated in the course of CHIKV infection in human cells. The induction of the Ras-Raf-MEK-ERK pathway has been shown for different RNA viruses like hepatitis C virus (53) and dengue virus (54) and also alphaviruses, namely, Sindbis virus (SINV) (20) and Venezuelan equine encephalitis virus (VEEV) (55). This pathway appears to be activated by these different viruses, potentially to confer a prosurvival status to the infected cells in order to maintain a productive infection cycle and generate sufficient progeny virions.…”

Section: Discussionmentioning

confidence: 99%

The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling

Varghese

Thaa

Amrun

et al. 2016

J Virol

121

103

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Chikungunya virus (CHIKV) has infected millions of people in the tropical and subtropical regions since its reemergence in the last decade. We recently identified the nontoxic plant alkaloid berberine as an antiviral substance against CHIKV in a highthroughput screen. Here, we show that berberine is effective in multiple cell types against a variety of CHIKV strains, also at a high multiplicity of infection, consolidating the potential of berberine as an antiviral drug. We excluded any effect of this compound on virus entry or on the activity of the viral replicase. A human phosphokinase array revealed that CHIKV infection specifically activated the major mitogen-activated protein kinase (MAPK) signaling pathways extracellular signal-related kinase (ERK), p38 and c-Jun NH 2 -terminal kinase (JNK). Upon treatment with berberine, this virus-induced MAPK activation was markedly reduced. Subsequent analyses with specific inhibitors of these kinases indicated that the ERK and JNK signaling cascades are important for the generation of progeny virions. In contrast to specific MAPK inhibitors, berberine lowered virus-induced activation of all major MAPK pathways and resulted in a stronger reduction in viral titers. Further, we assessed the in vivo efficacy of berberine in a mouse model and measured a significant reduction of CHIKV-induced inflammatory disease. In summary, we demonstrate the efficacy of berberine as a drug against CHIKV and highlight the importance of the MAPK signaling pathways in the alphavirus infectious cycle. IMPORTANCEChikungunya virus (CHIKV) is a mosquito-borne virus that causes severe and persistent muscle and joint pain and has recently spread to the Americas. No licensed drug exists to counter this virus. In this study, we report that the alkaloid berberine is antiviral against different CHIKV strains and in multiple human cell lines. We demonstrate that berberine collectively reduced the virus-induced activation of cellular mitogen-activated protein kinase signaling. The relevance of these signaling cascades in the viral life cycle was emphasized by specific inhibitors of these kinase pathways, which decreased the production of progeny virions. Berberine significantly reduced CHIKV-induced inflammatory disease in a mouse model, demonstrating efficacy of the drug in vivo. Overall, this work makes a strong case for pursuing berberine as a potential anti-CHIKV therapeutic compound and for exploring the MAPK signaling pathways as antiviral targets against alphavirus infections. C hikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disease spread by Aedes mosquitoes and characterized by a sudden onset of febrile illness, nausea, headache, and most importantly, severe and persistent musculoskeletal pain (1). It reemerged in tropical Asia and Africa 1 decade ago and since 2013 has infected more than 1.5 million people in the Americas (2). So far, no licensed vaccine or antiviral treatment exists to counter this disease. Over the years, many research groups have focused on...

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Antiviral activity of berberine

2020

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Plants are a rich source of new antiviral, pharmacologically active agents. The naturally occurring plant alkaloid berberine (BBR) is one of the phytochemicals with a broad range of biological activity, including anticancer, anti-inflammatory and antiviral activity. BBR targets different steps in the viral life cycle and is thus a good candidate for use in novel antiviral drugs and therapies. It has been shown that BBR reduces virus replication and targets specific interactions between the virus and its host. BBR intercalates into DNA and inhibits DNA synthesis and reverse transcriptase activity. It inhibits replication of herpes simplex virus (HSV), human cytomegalovirus (HCMV), human papillomavirus (HPV), and human immunodeficiency virus (HIV). This isoquinoline alkaloid has the ability to regulate the MEK-ERK, AMPK/mTOR, and NF-κB signaling pathways, which are necessary for viral replication. Furthermore, it has been reported that BBR supports the host immune response, thus leading to viral clearance. In this short review, we focus on the most recent studies on the antiviral properties of berberine and its derivatives, which might be promising agents to be considered in future studies in the fight against the current pandemic SARS-CoV-2, the virus that causes COVID-19.

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Inhibition of host extracellular signal-regulated kinase (ERK) activation decreases new world alphavirus multiplication in infected cells

Cited by 24 publications

References 55 publications

Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection

Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection

The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling

Antiviral activity of berberine

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