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Accueil > Départements > Virologie > Audrey ESCLATINE : Virulence et Latence des Herpesvirus

Publications de l’équipe

2017

2016


  • M. A. Maroui, A. Callé, C. Cohen, N. Streichenberger, P. Texier, J. Takissian, A. Rousseau, N. Poccardi, J. Welsch, A. Corpet, L. Schaeffer, M. Labetoulle, et P. Lomonte, « Latency Entry of Herpes Simplex Virus 1 Is Determined by the Interaction of Its Genome with the Nuclear Environment », PLoS pathogens, vol. 12, nᵒ 9, p. e1005834, 2016.
    Résumé : Herpes simplex virus 1 (HSV-1) establishes latency in trigeminal ganglia (TG) sensory neurons of infected individuals. The commitment of infected neurons toward the viral lytic or latent transcriptional program is likely to depend on both viral and cellular factors, and to differ among individual neurons. In this study, we used a mouse model of HSV-1 infection to investigate the relationship between viral genomes and the nuclear environment in terms of the establishment of latency. During acute infection, viral genomes show two major patterns: replication compartments or multiple spots distributed in the nucleoplasm (namely "multiple-acute"). Viral genomes in the "multiple-acute" pattern are systematically associated with the promyelocytic leukemia (PML) protein in structures designated viral DNA-containing PML nuclear bodies (vDCP-NBs). To investigate the viral and cellular features that favor the acquisition of the latency-associated viral genome patterns, we infected mouse primary TG neurons from wild type (wt) mice or knock-out mice for type 1 interferon (IFN) receptor with wt or a mutant HSV-1, which is unable to replicate due to the synthesis of a non-functional ICP4, the major virus transactivator. We found that the inability of the virus to initiate the lytic program combined to its inability to synthesize a functional ICP0, are the two viral features leading to the formation of vDCP-NBs. The formation of the "multiple-latency" pattern is favored by the type 1 IFN signaling pathway in the context of neurons infected by a virus able to replicate through the expression of a functional ICP4 but unable to express functional VP16 and ICP0. Analyses of TGs harvested from HSV-1 latently infected humans showed that viral genomes and PML occupy similar nuclear areas in infected neurons, eventually forming vDCP-NB-like structures. Overall our study designates PML protein and PML-NBs to be major cellular components involved in the control of HSV-1 latency, probably during the entire life of an individual.
    Mots-clés : HERPES, VIRO.

  • L. Mouna, E. Hernandez, D. Bonte, R. Brost, L. Amazit, L. R. Delgui, W. Brune, A. P. Geballe, I. Beau, et A. Esclatine, « Analysis of the role of autophagy inhibition by two complementary human cytomegalovirus BECN1/Beclin 1-binding proteins », Autophagy, vol. 12, nᵒ 2, p. 327-342, 2016.
    Résumé : Autophagy is activated early after human cytomegalovirus (HCMV) infection but, later on, the virus blocks autophagy. Here we characterized 2 HCMV proteins, TRS1 and IRS1, which inhibit autophagy during infection. Expression of either TRS1 or IRS1 was able to block autophagy in different cell lines, independently of the EIF2S1 kinase, EIF2AK2/PKR. Instead, TRS1 and IRS1 interacted with the autophagy protein BECN1/Beclin 1. We mapped the BECN1-binding domain (BBD) of IRS1 and TRS1 and found it to be essential for autophagy inhibition. Mutant viruses that express only IRS1 or TRS1 partially controlled autophagy, whereas a double mutant virus expressing neither protein stimulated autophagy. A mutant virus that did not express IRS1 and expressed a truncated form of TRS1 in which the BBD was deleted, failed to control autophagy. However, this mutant virus had similar replication kinetics as wild-type virus, suggesting that autophagy inhibition is not critical for viral replication. In fact, using pharmacological modulators of autophagy and inhibition of autophagy by shRNA knockdown, we discovered that stimulating autophagy enhanced viral replication. Conversely, inhibiting autophagy decreased HCMV infection. Thus, our results demonstrate a new proviral role of autophagy for a DNA virus.
    Mots-clés : Autophagy, Beclin-1, BECN1, Cytomegalovirus, Cytomegalovirus Infections, eIF-2 Kinase, EIF2AK2/PKR, HeLa Cells, HERPES, Humans, IRS1, Male, Mutation, Protein Binding, Protein Domains, Recombination, Genetic, TRS1, Viral Proteins, VIRO.

  • G. Siracusano, A. Venuti, D. Lombardo, A. Mastino, A. Esclatine, et M. T. Sciortino, « Early activation of MyD88-mediated autophagy sustains HSV-1 replication in human monocytic THP-1 cells », Scientific Reports, vol. 6, p. 31302, 2016.
    Résumé : Autophagy is a cellular degradation pathway that exerts numerous functions in vital biological processes. Among these, it contributes to both innate and adaptive immunity. On the other hand, pathogens have evolved strategies to manipulate autophagy for their own advantage. By monitoring autophagic markers, we showed that HSV-1 transiently induced autophagosome formation during early times of the infection of monocytic THP-1 cells and human monocytes. Autophagy is induced in THP-1 cells by a mechanism independent of viral gene expression or viral DNA accumulation. We found that the MyD88 signaling pathway is required for HSV-1-mediated autophagy, and it is linked to the toll-like receptor 2 (TLR2). Interestingly, autophagy inhibition by pharmacological modulators or siRNA knockdown impaired viral replication in both THP-1 cells and human monocytes, suggest that the virus exploits the autophagic machinery to its own benefit in these cells. Taken together, these findings indicate that the early autophagic response induced by HSV-1 exerts a proviral role, improving viral production in a semi-permissive model such as THP-1 cells and human monocytes.
    Mots-clés : HERPES, VIRO.
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Publications Principales avant 2015

1. Catez F, Picard C, Held K, Gross S, Rousseau A, Theil D, Sawtell N, Labetoulle M, Lomonte P (2012) : HSV-1 Genome Subnuclear Positioning and Associations with Host-Cell PML-NBs and Centromeres Regulate LAT Locus Transcription during Latency in Neurons. PLoS Pathog. 8:e1002852. Epub 2012 Aug.
2. Mahiet C, Ergani A, Huot N¥, Alende N, Azough A, Salvaire F, Bensimon A, Conseiller E, Wain-Hobson S, Barradeau S, Labetoulle M* (co-corresponding author) (2012) : Structural variability of the herpes simplex virus type 1 genome in vitro and in vivo. J.Virol. 86 : 8592-601
3. Klionsky DJ, …, Esclatine A, …, Zuckerbraun B (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8 : 445-544
4. Chaumorcel M¥, Lussignol M¥, Mouna L¥, Cavignac Y, Fahie K, Cotte-Laffitte J, Geballe A, Brune W, Beau I, Codogno P, Esclatine A (2012) The human cytomegalovirus protein TRS1 inhibits autophagy via its interaction with Beclin 1. J Virol 86 : 2571-2584
5. Pasdeloup D, McElwee M, Beilstein F, Labetoulle M, Rixon FJ (2013). Herpesvirus tegument protein pUL37 interacts with dystonin/BPAG1 to promote capsid transport on microtubules during egress. J Virol. 87(5) : 2857-2867
6. Pasdeloup D, Labetoulle M, Rixon FJ (2013). Differing effects of herpes simplex virus 1 and pseudorabies virus infections on centrosomal function. J Virol. 87(12):7102-12
7. Lussignol M¥, Queval C, Bernet-Camard MF, Cotte-Laffitte J, Beau I, Codogno P, Esclatine A (2013) The Herpes Simplex Virus 1 Us11 Protein Inhibits Autophagy through Its Interaction with the Protein Kinase PKR. J Virol 87 : 859-871
8. McElwee M, Beilstein F, Labetoulle M, Rixon FJ, Pasdeloup D : Dystonin/BPAG1 promotes plus-end directed transport of Herpes Simplex Virus 1 capsids on microtubules during entry. J Virol. 2013 Oct ;87(20):11008-18
9. Catez F, Rousseau A, Labetoulle M, Lomonte P.Detection of the genome and transcripts of a persistent DNA virus in neuronal tissues by fluorescent in situ hybridization combined with immunostaining. J Vis Exp. 2014 Jan 23 ;(83):e51091. doi : 10.3791/51091.

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