Activation of the PI3K-AKT Pathway by Old World Alphaviruses

Huizen, Eline Van; McInerney, Gerald M.

doi:10.3390/cells9040970

Cited by 22 publications

(17 citation statements)

References 58 publications

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“…However, several Old World Alphaviruses, such as CHIKV, SFV, and RRV, seem able to activate the phosphatidylinositol-3-kinase (PI3K)-AKT-mTOR pathway, involved in cell survival and autophagy inhibition. Furthermore, inhibition of this pathway has a negative effect on viral replication [145]. This apparent discrepancy with the previous observations may indicate that, more than autophagy per se, cell survival is the key process which favors viral replication.…”

Section: Interplay Between Cell Death and Alphaviral Replication And contrasting

confidence: 68%

Infection of Mammals and Mosquitoes by Alphaviruses: Involvement of Cell Death

Cappuccio

Maisse

2020

Cells

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Alphaviruses, such as the chikungunya virus, are emerging and re-emerging viruses that pose a global public health threat. They are transmitted by blood-feeding arthropods, mainly mosquitoes, to humans and animals. Although alphaviruses cause debilitating diseases in mammalian hosts, it appears that they have no pathological effect on the mosquito vector. Alphavirus/host interactions are increasingly studied at cellular and molecular levels. While it seems clear that apoptosis plays a key role in some human pathologies, the role of cell death in determining the outcome of infections in mosquitoes remains to be fully understood. Here, we review the current knowledge on alphavirus-induced regulated cell death in hosts and vectors and the possible role they play in determining tolerance or resistance of mosquitoes.

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Section: Interplay Between Cell Death and Alphaviral Replication And contrasting

confidence: 68%

Infection of Mammals and Mosquitoes by Alphaviruses: Involvement of Cell Death

Cappuccio

Maisse

2020

Cells

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“…Cellular cap-dependent translation is regulated by the PI3K-AKT-mTOR, RAS-RAF-MEK-ERK and p38 MAP kinase pathways by modulating phosphorylation of the protein, eIF4E [31]. A schematic diagram of the pathways that regulate cap-dependent translation is shown in Fig.…”

Section: Chikv Infection Modulates Cellular Phospho-p38 Mapk and Perkmentioning

confidence: 99%

Targeting cap-dependent translation to inhibit Chikungunya virus replication: selectivity of p38 MAPK inhibitors to virus-infected cells due to autophagy-mediated down regulation of phospho-ERK

Mudaliar

Pradeep

Abraham

et al. 2021

Journal of General Virology

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The 5′ capped, message-sense RNA genome of Chikungunya virus (CHIKV) utilizes the host cell machinery for translation. Translation is regulated by eIF2 alpha at the initiation phase and by eIF4F at cap recognition. Translational suppression by eIF2 alpha phosphorylation occurs as an early event in many alphavirus infections. We observe that in CHIKV-infected HEK293 cells, this occurs as a late event, by which time the viral replication has reached an exponential phase, implying its minimal role in virus restriction. The regulation by eIF4F is mediated through the PI3K-Akt-mTOR, p38 MAPK and RAS-RAF-MEK-ERK pathways. A kinetic analysis revealed that CHIKV infection did not modulate AKT phosphorylation, but caused a significant reduction in p38 MAPK phosphorylation. It caused degradation of phospho-ERK 1/2 by increased autophagy, leaving the PI3K-Akt-mTOR and p38 MAPK pathways for pharmacological targeting. mTOR inhibition resulted in moderate reduction in viral titre, but had no effect on CHIKV E2 protein expression, indicating a minimal role of the mTOR complex in virus replication. Inhibition of p38 MAPK using SB202190 caused a significant reduction in viral titre and CHIKV E2 and nsP3 protein expression. Furthermore, inhibiting the two pathways together did not offer any synergism, indicating that inhibiting the p38 MAPK pathway alone is sufficient to cause restriction of CHIKV replication. Meanwhile, in uninfected cells the fully functional RAS-RAF-MEK-ERK pathway can circumvent the effect of p38 MAPK inhibition on cap-dependent translation. Thus, our results show that host-directed antiviral strategies targeting cellular p38 MAPK are worth exploring against Chikungunya as they could be selective against CHIKV-infected cells with minimal effects on uninfected host cells.

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“…In contrast with other alphaviruses, which internalize membrane spherules by activation of the phosphatidylinositol-3-kinase-Akt-mammalian target of rapamycin signaling, CHIKV replication compartments are mostly maintained at the plasma membrane. This feature was assigned to the poor capacity of CHIKV to activate this pathway (94). Currently, the clear benefit of spherule endocytosis is not clearly understood (23).…”

Section: Building Membrane Spherules To Ensure Viral Replicationmentioning

confidence: 99%

New Insights into Chikungunya Virus Infection and Pathogenesis

et al. 2021

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Chikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus responsible for major outbreaks of disease since 2004 in the Indian Ocean islands, South east Asia, and the Americas. CHIKV causes debilitating musculoskeletal disorders in humans that are characterized by fever, rash, polyarthralgia, and myalgia. The disease is often self-limiting and nonlethal; however, some patients experience atypical or severe clinical manifestations, as well as a chronic rheumatic syndrome. Unfortunately, no efficient antivirals against CHIKV infection are available so far, highlighting the importance of deepening our knowledge of CHIKV host cell interactions and viral replication strategies. In this review, we discuss recent breakthroughs in the molecular mechanisms that regulate CHIKV infection and lay down the foundations to understand viral pathogenesis. We describe the role of the recently identified host factors co-opted by the virus for infection and pathogenesis, and emphasize the importance of CHIKV nonstructural proteins in both replication complex assembly and host immune response evasion. Expected final online publication date for the Annual Review of Virology, Volume 8 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Activation of the PI3K-AKT Pathway by Old World Alphaviruses

Cited by 22 publications

References 58 publications

Infection of Mammals and Mosquitoes by Alphaviruses: Involvement of Cell Death

Infection of Mammals and Mosquitoes by Alphaviruses: Involvement of Cell Death

Targeting cap-dependent translation to inhibit Chikungunya virus replication: selectivity of p38 MAPK inhibitors to virus-infected cells due to autophagy-mediated down regulation of phospho-ERK

New Insights into Chikungunya Virus Infection and Pathogenesis

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