An adjuvant strategy enabled by modulation of the physical properties of fungal ligands expands viral glycoprotein immunogenicity
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE193419 | GEO | 2022/01/13
REPOSITORIES: GEO
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Project description:Pattern recognition receptors (PRRs) protect against microbial 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 remains overlooked. Here, we characterize the landscape of endogenous ligands that engage RIG-I-like receptors (RLRs) upon infection by different RNA viruses. In each infection, several RNAs transcribed by RNA polymerase III (Pol3) specifically engaged RLRs, particularly the family of Y RNAs. Sensing of Y RNAs was dependent on their mimicking of viral secondary structure and their 5’-triphosphate extremity. Further, we found that HIV-1 triggered a VPR-dependent downregulation of RNA triphosphatase DUSP11 in vitro and in vivo, inducing a transcriptome-wide change of cellular RNA 5’-triphosphorylation that licenses Y RNA immunogenicity. Overall, our work uncovers the contribution of endogenous RNAs to antiviral immunity and demonstrates the importance of this pathway in HIV-1 infection.
2022-05-19 | GSE203128 | GEO
Project description: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 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), and in particular the Y-RNA family of small non-coding repeats, bind and activate RIG-I. 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 RNAs ligands to antiviral immunity and demonstrates the role of this pathway in HIV-1 infection.
2022-08-01 | GSE134859 | GEO
Project description: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 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), and in particular the Y-RNA family of small non-coding repeats, bind and activate RIG-I. 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 RNAs ligands to antiviral immunity and demonstrates the role of this pathway in HIV-1
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Project description: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 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), and in particular the Y-RNA family of small non-coding repeats, bind and activate RIG-I. 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 RNAs ligands to antiviral immunity and demonstrates the role of this pathway in HIV-1 infection.
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Project description: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 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), and in particular the Y-RNA family of small non-coding repeats, bind and activate RIG-I. 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 RNAs ligands to antiviral immunity and demonstrates the role of this pathway in HIV-1 infection.
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Project description: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 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), and in particular the Y-RNA family of small non-coding repeats, bind and activate RIG-I. 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 RNAs ligands to antiviral immunity and demonstrates the role of this pathway in HIV-1 infection.
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Project description:Successful host defense against pathogens requires innate immune recognition of the correct pathogen associated molecular patterns (PAMPs) by pathogen recognition receptors (PRRs) to trigger the appropriate gene program tailored to the pathogen. While many PRR pathways have been shown to contribute to the innate immune response to specific pathogens, the relative importance of each pathway for the complete transcriptional program elicited has not been examined in detail. Herein, we used RNA-sequencing with wildtype and mutant macrophages to delineate the innate immune pathways responsible for the early transcriptional response to Staphylococcus aureus, a ubiquitous microorganism that can activate a wide variety of PRRs. Unexpectedly, only two PRR pathways – the Toll-like receptor (TLR) and Stimulator of Interferon Gene (STING) pathways - were identified as dominant regulators of approximately 95% of the genes that were potently induced within the first four hours of macrophage infection with live S. aureus. TLR signaling predominantly activated an inflammatory program, STING signaling activated an antiviral/type I interferon response, and both pathways contributed to a program linking innate and adaptive immunity. Only a small number of genes were induced in the absence of TLR or STING signaling, and these genes possessed a strong hypoxia signature. STING pathway activation required live S. aureus and was largely dependent on the DNA sensor cyclic guanosine-adenosine synthase (cGAS) recognition of S. aureus DNA. Interestingly, using a cutaneous infection model, we found that the TLR and STING pathways played opposite roles in host defense to S. aureus, with TLR signaling being required for protective interleukin (IL)-1 and neutrophil recruitment and STING signaling having an opposite effect. These results provide novel insights into the complex interplay of innate immune signaling pathways triggered byS. aureus and uncover opposing roles of TLR and STING in cutaneous host defense to S. aureus.
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Project description:EZH2 is a histone methyltransferase that deposits H3K27me2/3 in heterochromatin and it is misregulated in tumorigenesis. Inhibition of heterochromatin can induce viral mimicry in cancer cells, where upregulated repetitive elements are detected by cytosolic pattern recognition receptors (PRRs) to activate inflammatory signaling. Here we demonstrate that EZH2 inhibitors stimulate inflammation and immune self-recognition of resting splenic B cells. We generated a PRR loss-of-function mouse model called RIC with mutations in Rigi, Ifih1 (MDA5), and Cgas. In both WT and RIC mutant B cells, EZH2 inhibition caused loss of H3K27me3 at repetitive elements and upregulated their expression. However, expression of inflammatory chemokines in B cells was interrupted by the RIC mutations. Furthermore, recruitment of cytotoxic T cells and neutrophils in response to EZH2 inhibition was blocked in RIC mutants preserving viability of B cells. This study demonstrates a pharmacologically induced mechanism of inflammation that causes self-recognition and B cell death.
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