The innate immune response against Human Cytomegalovirus (HCMV) plays a pivotal role during primary infection. Indeed, HCMV infection of primary fibroblasts rapidly triggers a strong induction of interferons-type I (IFN-type I) accompanied by proinflammatory cytokine release. Here, we show that primary human foreskin fibroblasts (HFFs) produce IFN-type I when infected with the wild type HCMV strain TB40/E (v65Rev). However, significantly higher IFN­type I levels were observed when HFFs were infected with HCMV unable to express UL83­encoded pp65 (v65Stop), suggesting that the tegument pp65 protein may downregulate IFN­type I production. To clarify the mechanisms pp65 relies on to inhibit IFN­type I production, we analyzed the activation of the cGMP­AMP synthase (cGAS)/STING/IRF3 axis in HFFs infected with v65Rev or with a mutant unable to express pp65 (v65Stop). The results obtained reveal that pp65 selectively binds to cGAS and prevents its interaction with STING, thus inactivating the signaling pathway through the cGAS/STING/IRF3 axis. Notably, during the first 6 hours of HCMV infection, STING undergoes proteasome degradation regardless of the presence of pp65. Additionally, down-regulation of cGAS activity by pp65 blocked IRF3 dimerization and DNA binding activity, leading to the inhibition of IFN-type I production. Collectively, our data provide mechanistic insight into the interplay between HCMV pp65 and cGAS leading to subsequent immune evasion by this prominent DNA virus.

The human Cytomegalovirus tegument protein pp65 (pUL83) dampens interferon-type I production by inactivating the DNA sensor cGAS

DELL'OSTE, Valentina;BIOLATTI, MATTEO;PAUTASSO, SARA;GUGLIESI, Francesca;LANDOLFO, Santo Giuseppe
2017

Abstract

The innate immune response against Human Cytomegalovirus (HCMV) plays a pivotal role during primary infection. Indeed, HCMV infection of primary fibroblasts rapidly triggers a strong induction of interferons-type I (IFN-type I) accompanied by proinflammatory cytokine release. Here, we show that primary human foreskin fibroblasts (HFFs) produce IFN-type I when infected with the wild type HCMV strain TB40/E (v65Rev). However, significantly higher IFN­type I levels were observed when HFFs were infected with HCMV unable to express UL83­encoded pp65 (v65Stop), suggesting that the tegument pp65 protein may downregulate IFN­type I production. To clarify the mechanisms pp65 relies on to inhibit IFN­type I production, we analyzed the activation of the cGMP­AMP synthase (cGAS)/STING/IRF3 axis in HFFs infected with v65Rev or with a mutant unable to express pp65 (v65Stop). The results obtained reveal that pp65 selectively binds to cGAS and prevents its interaction with STING, thus inactivating the signaling pathway through the cGAS/STING/IRF3 axis. Notably, during the first 6 hours of HCMV infection, STING undergoes proteasome degradation regardless of the presence of pp65. Additionally, down-regulation of cGAS activity by pp65 blocked IRF3 dimerization and DNA binding activity, leading to the inhibition of IFN-type I production. Collectively, our data provide mechanistic insight into the interplay between HCMV pp65 and cGAS leading to subsequent immune evasion by this prominent DNA virus.
6th International Congenital CMV Conference / 16th International CMV/betaherpesvirus Workshop
NH Leeuwenhorst, Noordwijkerhout, the Netherlands
30/04-4/05/2017
6th International Congenital CMV Conference / 16th International CMV/betaherpesvirus Workshop
5
5
http://www.cmv2017.nl/
Dell’Oste, Valentina; Biolatti, Matteo; Pautasso, Sara; Gugliesi, Francesca; Andrea, Marco De; Einem, Jens Von; Gariglio, Marisa; Landolfo, Santo
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1634034
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