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Home > Departments > Virology and Host-Pathogens Interactions > Audrey ESCLATINE: Virulence and Latency of herpes Viruses

Audrey ESCLATINE : Group Presentation

Our team, located in the Faculty of Pharmacy of Univ Paris- Sud until its moving in the I2BC building in 2019, is interested for many years now, in viruses belonging to the Herpesviridae family and able to infect humans. During these last years, we have worked on Herpes Simplex virus type 1 (HSV-1), cytomegalovirus (HCMV) and Epstein-Barr virus (EBV). These viruses are known for their ability to largely modulate and counteract antiviral cellular mechanisms, in particular because of the important size of their genome (for viruses, of course!) and their high coding capacity. We have thus studied relationships existing between viral infection and regulation of the autophagic process in different contexts.

Research Topics

Our team, located in the Faculty of Pharmacy of Univ Paris- Sud until its moving in the I2BC building in 2019, is interested for many years now, in viruses belonging to the Herpesviridae family and able to infect humans. During these last years, we have worked on Herpes Simplex virus type 1 (HSV-1), cytomegalovirus (HCMV) and Epstein-Barr virus (EBV). These viruses are known for their ability to largely modulate and counteract antiviral cellular mechanisms, in particular because of the important size of their genome (for viruses, of course!) and their high coding capacity. We have thus studied relationships existing between viral infection and regulation of the autophagic process in different contexts.

Viral proteins specialized in autophagy modulation
We have identified in the laboratory, proteins of different Herpesviruses able to modulate autophagy during the viral multiplication and we have characterized their mechanisms of action. Us11 protein, expressed by HSV-1, is able to block autophagosome formation, both in the course of infection and when ectopically expressed. Us11 acts by preventing the kinase activity of PKR, which can detect double stranded RNA coming from viruses and the activation of which leads to inhibition of protein synthesis and stimulation of autophagy [5]. Us11 thus complements the defense arsenal of HSV-1 against autophagy, since another protein, ICP34.5, had been initially identified by Beth Levine’s laboratory in 2002. Us11 acts later than ICP34.5 in the productive growth cycle of HSV-1. We have also demonstrated that HCMV prevents autophagy thanks to at least two inhibitory proteins [3, 6, 7]. Two highly homologous proteins, called TRS1 and IRS1, block by different ways the whole autophagic process. These proteins, when expressed separately, are able to decrease autophagosome formation by interaction with the coiled coil domain of Beclin1. When expressed simultaneously, they are also able to block autophagic flux [3]. More recently, we have been able to demonstrate, in collaboration with Vincent Maréchal (CIMI, Hôpital Pitié Salpêtrière, Paris) that a EBV protein (BHRF1), this time, can stimulate autophagosome formation.

We have identified in the laboratory several viral proteins modulating autophagy and their mechanisms of action

Why should viruses modulate autophagy?
Numerous viruses, including several Herpesviruses, are able to modulate autophagy [1, 2]. A virus may block this antiviral defence mechanism established by the cell. But, it can also by a good way for a virus to hijack all or parts of the autophagic process, in order to optimize its productive growth cycle or to manipulate antiviral immunity to mitigate its impact.
We have demonstrated in collaboration with the Italian laboratory of Pr Maria-Teresa Sciortino that autophagy can be hijacked by HSV-1 to its own profit [4]. Indeed, infection of monocytic cells by HSV-1 leads to a transient activation of autophagy at the beginning of the infection to improve its entry by endocytosis in the cells. HCMV, although inhibiting the autophagic process, also hijacks parts of the autophagic machinery to improve its production in human fibroblasts [3]. Indeed, invalidation of different autophagic genes leads to a global decrease of the viral production, demonstrating the proviral effect of autophagy on HCMV. EBV also takes advantage of autophagy activation mediated by the BHRF1 protein to limit the cell-autonomous antiviral immune response, by playing in particular on mitochondria morphology and fate.
These studies were funded by ANR and by Région Ile de France.

References
1. Lussignol &. Esclatine (2017), Viruses, 9: .
2. Vergne et al. (2017) médecine/sciences, 33: 312-318
3. Mouna, et al. (2016) Autophagy, 12: 327-342
4. Siracusano et al. (2016) Scientific Reports,6: 31302
5. Lussignol et al. (2013) J Virol 87: 859-871
6. Chaumorcel et al.(2012) J Virol 86 : 2571-2584
7. Chaumorcel et al.(2008) Autophagy 4:46-53

Keywords :

Herpesvirus, cytomegalovirus (CMV), virus Herpes Simplex 1 (HSV-1), virus Epstein-Barr (EBV), antiviral immune escape, assembly compartment, autophagy, Beclin1, selective autophagy, LC3

Contact :


ESCLATINE Audrey [Professor - UPSud]
Virulence and Latency of Herpes viruses [Leader]
+331 4683 5292 Fac. Pharma - Chatenay

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