Autor(es): Joubert Pierre-Emmanuel, Stapleford Kenneth, Guivel-Benhassine Florence, Vignuzzi Marco, Schwartz Olivier, Albert Matthew L

Resumo: Chikungunya virus (CHIKV), the causative agent of a major epidemic spanning five continents, is a positive str-ed mRNA virus that replicates using the cell's cap-dependent translation machinery. Despite viral infection inhibiting mTOR, a metabolic sensor controls cap-dependent translation, viral proteins are efficiently translated. Rapalog treatment, silencing of mtor or raptor genes, but not rictor, further enhanced CHIKV infection in culture cells. Using biochemical assays - real time imaging, we demonstrate that this effect is independent of autophagy or type I interferon production. Providing in vivo evidence for the relevance of our findings, mice treated with mTORC1 inhibitors exhibited increased lethality - showed a higher sensitivity to CHIKV. A systematic evaluation of the viral life cycle indicated that inhibition of mTORC1 has a specific positive effect on viral proteins, enhancing viral replication by increasing the translation of both structural - nonstructural proteins. Molecular analysis defined a role for phosphatidylinositol-3 kinase (PI3K) - MAP kinase-activated protein kinase (MnKs) activation, leading to the hyper-phosphorylation of eIF4E. Finally, we demonstrated that in the context of CHIKV inhibition of mTORC1, viral replication is prioritized over host translation via a similar mechanism. Our study reveals an unexpected bypass pathway by which CHIKV protein translation overcomes viral induced mTORC1 inhibition.

Imprenta: PLoS Pathogens, v. 11, n. 8, p. e1005091, 2015

Identificador do objeto digital: 10.1371/journal.ppat.1005091

Descritores: Chikungunya virus - Cell ; Chikungunya virus - Proteins ; Chikungunya Virus - Virus ; Chikungunya virus - Epidemic

Data de publicação: 2015