Biology subjects

Chauveau, L.

Publications and source records attributed to Chauveau, L..

3 recordsLinked to original sources

bioRxiv2020

Varicella-Zoster Virus ORF9 Is an Antagonist of the DNA Sensor cGAS

Varicella-Zoster virus (VZV) causes chickenpox and shingles. Although infection is associated with severe morbidity in some individuals, molecular mechanisms that determine innate immune responses remain poorly defined. We found that the cGAS/STING DNA sensing pathway was required for type I interferon (IFN) induction during VZV infection and that recognition of VZV by cGAS restricted its replication. Viral gene overexpression screening identified the essential VZV tegument protein ORF9 as a cGAS antagonist. Ectopically and virally expressed ORF9 bound to endogenous cGAS. Confocal microscopy revealed co-localisation of cGAS and ORF9, which reduced the type I IFN response to transfected DNA. ORF9 and cGAS also interacted directly in a cell-free system and phase-separated together with DNA. Furthermore, ORF9 inhibited cGAMP production by cGAS. Taken together, we uncovered the importance of the cGAS/STING DNA sensing pathway for VZV recognition and identified a VZV immune antagonist that directly interferes with DNA sensing via cGAS.

immunology↗

bioRxiv2020

cGAMP loading enhances the immunogenicity of VLP vaccines

Cyclic GMP-AMP (cGAMP) is an immunostimulatory second messenger produced by cGAS that activates STING. Soluble cGAMP acts as an adjuvant when administered with antigens. cGAMP is also incorporated into enveloped virus particles during budding. We hypothesised that inclusion of the adjuvant cGAMP within viral vaccine vectors would promote adaptive immunity against vector antigens. We immunised mice with virus-like particles (VLPs) containing the HIV-1 Gag protein and VSV-G. Inclusion of cGAMP within these VLPs augmented splenic VLP-specific CD4 and CD8 T cell responses. It also increased VLP- and VSV-G-specific serum antibody titres and enhanced in vitro virus neutralisation. The superior antibody response was accompanied by increased numbers of T follicular helper cells in draining lymph nodes. Vaccination with cGAMP-loaded VLPs containing haemagglutinin induced high titres of influenza A virus neutralising antibodies and conferred protection following subsequent influenza A virus challenge. Together, these results show that incorporating cGAMP into VLPs enhances their immunogenicity, making cGAMP-VLPs an attractive platform for novel vaccination strategies. Short summarycGAMP is an innate immune signalling molecule that can be transmitted between cells by inclusion in enveloped virions. This study demonstrates enhanced immunogenicity of HIV-derived virus-like particles containing cGAMP. Viral vectors loaded with cGAMP may thus be potent vaccines.

immunology↗

bioRxiv2019

Y-RNAs Lead an Endogenous Program of RIG-I Agonism Mobilized upon RNA Virus Infection and Targeted by HIV

Pattern recognition receptors (PRRs) protect against host invasion by detecting specific molecular patterns found in pathogens and initiating an immune response. While microbial-derived PRR ligands have been extensively characterized, the contribution and relevance of endogenous ligands to PRR activation during viral infection remain overlooked. In this work, we characterize the landscape of endogenous ligands that engage RIG-I-like receptors (RLRs) upon infection by a positive-sense RNA virus, a negative-sense RNA virus or a retrovirus. We found that several endogenous RNAs transcribed by RNA polymerase 3 (Pol3) specifically engage RLRs, and in particular the family of small non-coding repeats Y-RNAs, which presents the highest affinity as RIG-I ligands. We show that this recognition is dependent on Y-RNA mimicking viral secondary structure and its 5-triphosphate extremity. Further, we found that HIV-1 infection triggers a VPR-dependent downregulation of RNA triphosphatase DUSP11 in vitro and in vivo, leading to an increase of Y-RNA 5-triphosphorylation that enables their immunogenicity. Importantly, we show that altering DUSP11 expression is sufficient to induce a type-I interferon and T cell activation transcriptional program associated with HIV-1 infection. Overall, our work uncovers the critical contribution of endogenous repeat RNAs ligands to antiviral immunity and demonstrates the role of this pathway in HIV-1 infection.

immunology↗