Recognition of copy-back defective interfering rabies virus genomes by RIG-I triggers efficient immune response against vaccine strains
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ABSTRACT:
ORGANISM(S): Lyssavirus rabies Homo sapiens Rabies virus SAD B19
PROVIDER: GSE196051 | GEO | 2024/03/22
REPOSITORIES: GEO
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Project description:Recognition of copy-back defective interfering rabies virus genomes by RIG-I triggers efficient immune response against vaccine strains
| PRJNA803174 | ENA
Project description:Attenuated measles virus (MV) is one of the most effective and safe vaccines available, making it an attractive candidate vector for preventing other infectious diseases. Yet the great capacity of this vaccine still needs to be understood at the molecular level. MV vaccine strains have different type I interferon (IFN)-inducing abilities that partially depend on the presence of 5' copy-back defective interfering genomes (DI-RNAs). DI-RNAs are pathogen-associated molecular patterns recognized by RIG-I-like receptors (RLRs) (RIG-I, MDA5, and LGP2) that activate innate immune signaling and shape the adaptive immune response. In this study, we characterized the DI-RNAs produced by various modified recombinant MVs (rMVs), including vaccine candidates, as well as wild-type MV. All tested rMVs produced 5' copy-back DI-RNAs that were different in length and nucleotide sequence but still respected the so-called "rule of six." We correlated the presence of DI-RNAs with a larger stimulation of the IFN-β pathway and compared their immunostimulatory potentials. Importantly, we revealed that encapsidation of DI-RNA molecules within the MV nucleocapsid abolished their immunoactive properties. Furthermore, we identified specific interactions of DI-RNAs with both RIG-I and LGP2 but not MDA5. Our results suggest that DI-RNAs produced by rMV vaccine candidates may indeed strengthen their efficiency by triggering RLR signaling.IMPORTANCE Having been administered to hundreds of millions of children, the live attenuated measles virus (MV) vaccine is the safest and most widely used human vaccine, providing high protection with long-term memory. Additionally, recombinant MVs carrying heterologous antigens are promising vectors for new vaccines. The great capacity of this vaccine still needs to be elucidated at the molecular level. Here we document that recombinant MVs produce defective interfering genomes that have high immunostimulatory properties via their binding to RIG-I and LGP2 proteins, both of which are cytosolic nonself RNA sensors of innate immunity. Defective interfering genome production during viral replication should be considered of great importance due to the immunostimulatory properties of these genomes as intrinsic adjuvants produced by the vector that increase recognition by the innate immune system.
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Project description:Coronavirus RNA-dependent RNA polymerases produce subgenomic RNAs (sgRNAs) that encode viral structural and accessory proteins. The kinetics and efficiency of sgRNAs production during viral replication in different cell types or sgRNA transcription by individual viral strains or variants are yet to be studied to shed light on fundamental mechanisms necessary for viral replication. User-friendly bioinformatic tools to detect and quantify sgRNA production are urgently needed to study a growing number of next-generation sequencing (NGS) data of SARS-CoV-2. Starting from DI-tector, a bioinformatic tool for the detection of viral defective interfering genomes, here we introduced sgDI-tector to identify and quantify sgRNA in SARS-CoV-2 NGS data. This new tool allowed detection of sgRNA without initial knowledge of the transcription-regulatory sequences. As a proof of principle, we analyzed new data sets and successfully detected the nested set of sgRNAs produced with the ranking M>ORF3a>N>ORF6>ORF7a>ORF8>S>E>ORF7b. Our study also compared, for the first time for SARS-CoV-2, the level of sgRNA production with other types of viral RNA products such as defective interfering viral genomes.
2021-12-28 | GSE180632 | GEO
Project description:Replication competent vesicular stomatitis virus (VSV) is the basis of a vaccine against Ebola and VSV strains are developed as oncolytic viruses. Both functions depend on the ability of VSV to induce adequate amounts of interferon-α/β. It is therefore important to understand how VSV triggers interferon responses. VSV activates innate immunity via retinoic acid-inducible gene I (RIG-I), a sensor for viral RNA. Our results show that VSV needs to replicate for a robust interferon response. Analysis of RIG-I-associated RNA identified a copy-back defective-interfering (DI) genome and full-length viral genomes as main trigger of RIG-I. VSV stocks depleted of DI genomes lost most of their interferon-stimulating activity. The remaining full-length genome and leader-N-read-through sequences, however, still triggered RIG-I. Awareness for DI genomes as trigger of innate immune responses will help to standardize DI genome content and to purposefully deplete or use DI genomes as natural adjuvants in VSV-based therapeutics.
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Project description:Influenza defective interfering (DI) viruses have long been considered promising antiviral candidates because of their ability to interfere with replication-competent viruses and to induce antiviral immunity. However, the mechanisms underlying DI-mediated antiviral immunity have not been extensively explored. Here, we demonstrated interferon (IFN) independent protection conferred by influenza DI virus against homologous virus infection in mice deficient in type I and III IFN signaling. By integrating transcriptional and post-transcriptional regulatory data we identified unique host signatures in response to DI co-infection. DI-treated mice exhibited reduced viral transcription, less intense inflammatory and innate immune responses, and primed multiciliated cell differentiation in their lungs at an early stage of infection, even in the absence of type I or III IFNs. This increased multiciliogenesis could also be detected at the protein level by immunofluorescence staining of lung tissue from DI-treated mice. Overall, our study provides mechanistic insight into the protection mediated by DIs, implying a unifying theme involving inflammation and multiciliogenesis in maintaining respiratory homeostasis, and reveals their IFN-independent antiviral activity.
2023-05-15 | GSE188122 | GEO
Project description:Defective interfering particles (DIPs), derived naturally from viral particles, are not able to replicate on their own. Several studies indicate that DIPs exert antiviral effects via multiple mechanisms. DIPs are able to activate immune responses and suppress virus replication cycles, such as competing for viral replication products, impeding the packaging, release and invasion of viruses. Other studies show that DIPs can be used as a vaccine against viral infection. Moreover, DIPs/DI genomes display antitumor effects by inducing tumor cell apoptosis and promoting dendritic cell maturation. With genetic modified techniques, it is possible to improve its safety against both viruses and tumors. In this review, a comprehensive discussion on the effects exerted by DIPs is provided. We further highlight the clinical significance of DIPs and propose that DIPs can open up a new platform for antiviral and antitumor therapies.
| S-EPMC6696905 | biostudies-literature
Project description:Defective interfering (DI) genomes, or defective viral genomes (DVGs), are truncated viral genomes generated during replication of most viruses, including live viral vaccines. Among these, "panhandle" or copy-back (cb) and "hairpin" or snap-back (sb) DI genomes are generated during RNA virus replication. 5' cb/sb DI genomes are highly relevant for viral pathogenesis since they harbor immunostimulatory properties that increase virus recognition by the innate immune system of the host. We have developed DI-tector, a user-friendly and freely available program that identifies and characterizes cb/sb genomes from next-generation sequencing (NGS) data. DI-tector confirmed the presence of 5' cb genomes in cells infected with measles virus (MV). DI-tector also identified a novel 5' cb genome, as well as a variety of 3' cb/sb genomes whose existence had not previously been detected by conventional approaches in MV-infected cells. The presence of these novel cb/sb genomes was confirmed by RT-qPCR and RT-PCR, validating the ability of DI-tector to reveal the landscape of DI genome population in infected cell samples. Performance assessment using different experimental and simulated data sets revealed the robust specificity and sensitivity of DI-tector. We propose DI-tector as a universal tool for the unbiased detection of DI viral genomes, including 5' cb/sb DI genomes, in NGS data.
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Project description:Arthropod-borne viruses pose a major threat to global public health. Thus, innovative strategies for their control and prevention are urgently needed. Here, we exploit the natural capacity of viruses to generate defective viral genomes (DVGs) to their detriment. While DVGs have been described for most viruses, identifying which, if any, can be used as therapeutic agents remains a challenge. We present a combined experimental evolution and computational approach to triage DVG sequence space and pinpoint the fittest deletions, using Zika virus as an arbovirus model. This approach identifies fit DVGs that optimally interfere with wild-type virus infection. We show that the most fit DVGs conserve the open reading frame to maintain the translation of the remaining non-structural proteins, a characteristic that is fundamental across the flavivirus genus. Finally, we demonstrate that the high fitness DVG is antiviral in vivo both in the mammalian host and the mosquito vector, reducing transmission in the latter by up to 90%. Our approach establishes the method to interrogate the DVG fitness landscape, and enables the systematic identification of DVGs that show promise as human therapeutics and vector control strategies to mitigate arbovirus transmission and disease.
| S-EPMC8052367 | biostudies-literature
Project description:During virus replication in cultured cells, copy-back defective viral genomes (cbDVG) can arise. CbDVG are powerful inducers of innate immune responses in vitro, but their occurrence and impact on natural infections of human hosts remain poorly defined. We asked whether cbDVG were generated in the brain of a patient who succumbed to subacute sclerosing panencephalitis (SSPE) about 20 years after acute measles virus (MeV) infection. Previous analyses of 13 brain specimens of this patient indicated that a collective infectious unit (CIU) drove lethal MeV spread. In this study, we identified 276 replication-competent cbDVG species, each present in over 100 copies in the brain. Six species were detected in multiple forebrain locations, implying that they travelled long-distance with the CIU. The cbDVG to full-length genomes ratio was often close to 1 (0.6-1.74). Most cbDVG were 324-2000 bases in length, corresponding to 2-12% of the full-length genome; all are predicted to have complementary terminal sequences. If improperly encapsidated, these sequences have the potential to form double-stranded structures that can induce innate immune responses. To assess this, we examined the transcriptome of all brain specimens. Several interferon- and inflammatory response genes were upregulated, but upregulation levels did not correlate with cbDVG levels in the specimens. Thus, the CIU that drove MeV pathogenesis in this brain includes, in addition to two complementary full-length genome populations, many locally restricted and few widespread cbDVG species. The widespread cbDVG species may have been positively selected but how they impacted pathogenesis remains to be determined.
2024-10-01 | GSE272560 | GEO
Project description:We developed VODKA (Viral Opensource DVG Key Algorithm) to identify cbDVGs from RNA-Seq data from infected samples and used these DVG sequences to identify signals that regulate cbDVG generation. We applied VODKA to datasets from RSV-positive patients. VODKA identified common cbDVGs across multiple samples in both patients, and predicted specific genomic loci that mediate cbDVG formation.
2019-03-19 | GSE114948 | GEO