Block of death-receptor apoptosis protects mouse cytomegalovirus from macrophages and is a determinant of virulence in immunodeficient hosts.

The inhibition of death-receptor apoptosis is a conserved viral function. The murine cytomegalovirus (MCMV) gene M36 is a sequence and functional homologue of the human cytomegalovirus gene UL36, and it encodes an inhibitor of apoptosis that binds to caspase-8, blocks downstream signaling and thus contributes to viral fitness in macrophages and in vivo. Here we show a direct link between the inability of mutants lacking the M36 gene (ΔM36) to inhibit apoptosis, poor viral growth in macrophage cell cultures and viral in vivo fitness and virulence. ΔM36 grew poorly in RAG1 knockout mice and in RAG/IL-2-receptor common gamma chain double knockout mice (RAGγC(-/-)), but the depletion of macrophages in either mouse strain rescued the growth of ΔM36 to almost wild-type levels. This was consistent with the observation that activated macrophages were sufficient to impair ΔM36 growth in vitro. Namely, spiking fibroblast cell cultures with activated macrophages had a suppressive effect on ΔM36 growth, which could be reverted by z-VAD-fmk, a chemical apoptosis inhibitor. TNFα from activated macrophages synergized with IFNγ in target cells to inhibit ΔM36 growth. Hence, our data show that poor ΔM36 growth in macrophages does not reflect a defect in tropism, but rather a defect in the suppression of antiviral mediators secreted by macrophages. To the best of our knowledge, this shows for the first time an immune evasion mechanism that protects MCMV selectively from the antiviral activity of macrophages, and thus critically contributes to viral pathogenicity in the immunocompromised host devoid of the adaptive immune system

Herpesviruses and Autophagy: Catch Me If You Can!

Autophagy is an evolutionarily conserved cellular degradation pathway involving the digestion of intracellular components via the lysosomal pathway. The autophagic pathway constitutively maintains cellular homeostasis by recycling cytoplasmic organelles and proteins, but it is also stimulated by environmental stress conditions, such as starvation, oxidative stress, and the accumulation of misfolded proteins. It also acts as a cellular defense mechanism against microorganisms by contributing to both the innate and adaptive immunity, and by eliminating intracellular pathogens (xenophagy). There is growing evidence that host cells try to control Herpesvirus infections by activating the autophagic machinery. However, it is well-known that Herpesviruses are smart pathogens and several, such as HSV-1, HCMV and HHV-8, are known to have developed numerous defense strategies for evading the host’s immune response. Inhibition of the antiviral autophagic mechanism has also been reported. Autophagy has also been shown to enhance the major histocompatibility complex presentation of at least two viral proteins, the EBV-encoded EBNA-1 and the HSV-1 encoded gB. In this review, we present an overview of recent advances in our understanding of the complex interplay between autophagy and Herpesviruses

Régulation des mécanismes d'autophagie par les herpesviridae (l'exemple du cytomégalovirus humain)

Bien qu asymptomatique chez les sujets sains, le cytomégalovirus (CMV) est responsable d infections opportunistes graves chez les patients immunodéprimés. L autophagie est un mécanisme de dégradation du matériel cytoplasmique permettant le maintien de l homéostasie. Il s agit aussi d un mécanisme de défense contre les microorganismes en modulant l immunité. Certains virus contrecarrent cette autophagie. Dans une première partie, nous avons montré que le CMV inhibe l autophagie dès 24h d infection dans les fibroblastes. Dans un second temps, nous avons recherché les mécanismes impliqués dans cette inhibition. Le CMV est capable d activer mTOR, un régulateur négatif de l autophagie. Nous avons ensuite étudié le rôle du complexe Beclin-1/Bcl-2 au cours de l infection et observé une surexpression et une phosphorylation de Bcl-2, mais qui ne sont pas impliquées dans cette inhibition. Du côté des protéines virales, nous montrons que la protéine précoce TRS1 est capable d inhiber l autophagie.Although asymptomatic in healthy people, human cytomegalovirus (CMV) is responsible of severe opportunistic infections in immunocompromised patients. Autophagy is an evolutionarily conserved process responsible for the degradation of cytoplasmic content to maintain homeostasis and was also described to contribute to immunity against viral infections. Some viruses counteract this antiviral defense mechanism. First, we showed that CMV inhibition of autophagy by from 24 hours of infection in fibroblasts. Second, we looked for mechanisms involved in this CMV-induced inhibition of autophagy. CMV is able to activate mTOR, a negative regulator of autophagy. We also studied role of Beclin-1 complex during infection and observed an overexpression of Bcl-2 which could be responsible for autophagy inhibition. Nevertheless, phosphorylation of Bcl-2 by JNK leads to dissociation of Beclin-1/Bcl-2 complex. Regarding viral proteins, we showed that the early protein TRS1 blocks autophagy.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Autophagy activation and antiviral activity by a licorice triterpene

The triterpene glycyrrhizic acid (GRA), the main product from the Glycyrrhiza glabra medicinal plant, is known for its antiinflammatory and antimicrobial activity. In this work, GRA was studied for its ability to induce the autophagic process activator Beclin 1 in epithelial cells and to observe how this property could influence its antiviral activity. After 24h of treatment, GRA induced a Beclin 1 production that was more than twofold higher than that produced by rapamycin, used as a reference compound. When the compounds were added to HeLa cells together with the viruses, GRA demonstrated a strong antiherpes simplex virus type 1 (HSV1) activity, whereas rapamycin had no activity. However, if the compounds were added to the cells 24h before the viruses, GRA induced the production of an even higher amount of Beclin 1 and showed an improved antiviral effect; under these conditions, rapamycin was also able to exert a significant anti-HSV1 activity. In conclusion, GRA is a strong inducer of the autophagy activator Beclin 1, which establishes a resistance state to HSV1 replicatio

Correction for Chaumorcel et al., "The Human Cytomegalovirus Protein TRS1 Inhibits Autophagy via Its Interaction with Beclin 1"

International audienceErratum for The human cytomegalovirus protein TRS1 inhibits autophagy via its interaction with Beclin 1. [J Virol. 2012