Zika virus antagonizes interferon response in patients and disrupts RIG-I-MAVS interaction through its CARD-TM domains
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ABSTRACT:
PROVIDER: PRJNA510012 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8316890_1.fastq.gz | Fastqsanger.gz | |||
| SRR8316890_2.fastq.gz | Fastqsanger.gz | |||
| SRR8316891_1.fastq.gz | Fastqsanger.gz | |||
| SRR8316891_2.fastq.gz | Fastqsanger.gz | |||
| SRR8316892_1.fastq.gz | Fastqsanger.gz |
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Project description:The emerging threat to global health associated with the Zika virus (ZIKV) epidemics and its link to severe complications highlights a growing need to better understand the pathogenic mechanisms of ZIKV. Accumulating evidence for a critical role of type I interferon (IFN-I) in protecting hosts from ZIKV infection lies in the findings that ZIKV has evolved various strategies to subvert the host defense line by counteracting the early IFN induction or subsequent IFN signaling. Yet, mechanisms underlying the counter-IFN capability of ZIKV and its proteins, which might contribute to the well-recognized broad cellular tropisms and persistence of ZIKV, remain to be fully understood. In our current study, using RNA sequencing-based transcriptional profiling from the whole blood cells isolated from patients acutely infected by ZIKV, we found that transcriptional signatures of antiviral interferon-stimulated genes and innate immune sensors was absent in ZIKV-infected patients presents inactive as compared to healthy donors, suggesting that ZIKV might suppress the induction of IFN-I during the natural infection process in human. Furthermore, utilizing cellular or extracellular analysis of molecular interaction in a ZIKV NS4A-overexpression system, or in the context of actual ZIKV infection, we have identified that ZIKV NS4A directly binds MAVS and thereby interrupts RIG-I/MAVS interaction through its CARD-TM domains, leading to attenuated production of IFN-I. Taken together, these findings originated from patient studies have added new knowledge and molecular details to our understanding regarding how ZIKV mediates suppression of the IFN-I system and may provide new basis for future development of anti-ZIKV strategies.
2019-06-16 | GSE123835 | GEO
Project description:BackgroundThe emerging threat to global health associated with the Zika virus (ZIKV) epidemics and its link to severe complications highlights a growing need to better understand the pathogenic mechanisms of ZIKV. Accumulating evidence for a critical role of type I interferon (IFN-I) in protecting hosts from ZIKV infection lies in the findings that ZIKV has evolved various strategies to subvert the host defense line by counteracting the early IFN induction or subsequent IFN signaling. Yet, mechanisms underlying the counter-IFN capability of ZIKV and its proteins, which might contribute to the well-recognized broad cellular tropisms and persistence of ZIKV, remain incompletely understood.ResultsUsing RNA sequencing-based transcriptional profiling of whole blood cells isolated from patients acutely infected by ZIKV, we found that transcriptional signature programs of antiviral interferon-stimulated genes and innate immune sensors in ZIKV-infected patients remained inactive as compared to those of healthy donors, suggesting that ZIKV was able to suppress the induction of IFN-I during the natural infection process in humans. Furthermore, by analyzing the molecular interaction in a ZIKV NS4A-overexpression system, or in the context of actual ZIKV infection, we identified that ZIKV NS4A directly bound MAVS and thereby interrupted the RIG-I/MAVS interaction through the CARD-TM domains, leading to attenuated production of IFN-I.ConclusionsOur findings collectively revealed that ZIKV NS4A targeted MAVS and contributed to ZIKV immune evasion through abrogating MAVS-mediated IFN production. These findings obtained from patient studies have added new knowledge and molecular details to our understanding regarding how ZIKV mediates suppression of the IFN-I system and may provide a new basis for the future development of anti-ZIKV strategies.
| S-EPMC6555941 | biostudies-literature
Project description:Zika virus antagonizes interferon response in patients and disrupts RIG-I-MAVS interaction through its CARD-TM domains
| PRJNA509788 | ENA
Project description:Purpose: The goals of this study are to compare Next-generation sequencing (NGS)-derived transcriptome profiling (RNA-seq) in the lung of three tyeps of mice during influenza infection. Methods: Total RNA from lung was extracted using a modified TRIzol protocol and spectrophometrically quantitated. Library preparation and sequencing were conducted using 3’ inTAG next-generation sequencing . Differential gene expression for day 6 post influenza infection was determined relative to mock inoculated mice. Results: Differentially expressed genes were defined using p-value <0.01 and FDR-corrected p-value <0.1 cutoffs. We identified the transcripts in the lung of RIG-I-/-, MAVS -/- mice during influenza infection Our study represents the first detailed analysis of lung transcriptomes of Wild Type , RIG-I-/-, MAVS -/- mice during influenza infection , with biologic replicates, generated by RNA-seq technology.
2018-11-28 | GSE114232 | GEO
Project description:MAVS-mediated cytosolic RNA sensing plays a central role in tumor immunogenicity. However, the effects of host MAVS signaling on antitumor immunity remains uncertain. Here, we demonstrate that host MAVS pathway drives accelerated tumor growth and impairs antitumor immunity, while MAVS knockout in dendritic cells (DCs) promotes tumor-reactive CD8+ T cell responses. Specifically, the CD8+ T cell priming capacity is enhanced by lack of functional MAVS in a type I interferon-independent, but IL-12-dependent, manner. Mechanistically, loss of RIG-I/MAVS cascade activates non-canonical NF-κB pathway and in turn induces IL-12 production by DCs, resulting in CD8+ T cell: DC crosstalk licensed by IFN-γ and IL-12. Moreover, ablation of host MAVS sensitizes tumors to immunotherapy and attenuates radiation resistance, thereby facilitating the maintenance of effector CD8+ T cells. These findings identify that host MAVS pathway acts as an immune checkpoint of DC-driven antitumor immunity, indicating the development of DC-based immunotherapies through MAVS signaling antagonism.
2023-08-15 | GSE236763 | GEO
Project description:Immune signaling needs to be well-regulated to promote clearance of pathogens, while preventing aberrant inflammation. Interferons (IFNs) and antiviral genes are activated by the detection of viral RNA by RIG-I-like receptors (RLRs). Signal transduction downstream of RLRs proceeds through a multiprotein complex organized around the central adaptor protein MAVS. While protein-protein interactions and post-translational modifications are critical for the formation of the MAVS signalosome, whether RNA play a role in organizing these platforms is largely unknown. RNA can modulate protein complex function by allosteric regulation or by serving as a molecular guide or scaffold. We have found that MAVS directly interacts with the 3’ untranslated regions of cellular mRNAs through its central intrinsically disordered domain. Eliminating RNA by RNase treatment disrupts the MAVS signalosome and inhibits phosphorylation of the transcription factor IRF3. These findings support the hypothesis that RNA molecules scaffold the MAVS signaling platform to induce IFNs. Indeed, RNase treatment alters interactions between MAVS and newly identified regulators of RLR signaling. Together, this work uncovers a function for cellular RNA in promoting signaling through MAVS and highlights a generalizable principle of RNA regulatory control of cytoplasmic immune signaling complexes.
2025-03-19 | GSE244000 | GEO
Project description:Innate immunity serves as the primary defense against viral and microbial infections in humans. Among its components, retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are well-characterized intracellular pattern-recognition proteins that trigger innate immune responses upon viral infection. However, the precise influence of cellular metabolites, especially fatty acids, on the regulation of RLR-mediated antiviral innate immunity remains largely elusive. Here, through screening a metabolite library, palmitic acid (PA) has been identified as a crucial metabolite responsible for modulating antiviral infections. Mechanistically, PA induces the palmitoylation of MAVS, leading to MAVS aggregation and subsequent activation, thereby enhancing the innate immune response against viral infections. Functionally, the enzyme palmitoyl-transferase ZDHHC24 plays a key role in catalyzing the palmitoylation of MAVS at both C46 and C79 residues, thereby facilitating the transduction of RLR-mediated TBK1-IRF3-IFN signaling pathway, particularly under conditions of PA stimulation or high-fat diet feeding. Conversely, the absence of ZDHHC24 significantly attenuates virus-induced innate immune responses in both cells and mice. Moreover, APT2 counteracts with ZDHHC24 to de-palmitoylate MAVS, thus inhibiting the antiviral response. Consequently, inhibition of APT2 using compounds like ML349 effectively reverses MAVS palmitoylation and activation in response to antiviral infections. These findings underscore the critical role of PA and ZDHHC24 in regulating antiviral innate immunity through MAVS palmitoylation, and suggest potential therapeutic strategies for combating viral infections, such as enhancing PA intake or specifically targeting APT2.
2024-09-10 | PXD054077 | Pride
Project description:Epstein-Barr virus (EBV) causes infectious mononucleosis, triggers multiple sclerosis and is associated with 200,000 cancers/year. EBV colonizes the B-cell compartment and periodically reactivates, inducing expression of 80 viral proteins. Yet much remains unknown about how EBV remodels host cells and dismantles key antiviral responses. We therefore created a proteomic map of EBV-host and EBV-EBV interactions in B-cells undergoing EBV replication, uncovering conserved herpesvirus versus EBV-specific host cell targets. The EBV-encoded G-protein coupled receptor BILF1 associated with MAVS and the UFM1 E3 ligase UFL1. Whereas UFMylation of 14-3-3 proteins drives RIG-I/MAVS signaling, BILF1-directed MAVS UFMylation instead triggered MAVS packaging into mitochondrial-derived vesicles and lysosomal proteolysis. In the absence of BILF1, EBV replication activated the NLRP3 inflammasome, which impaired viral replication and triggered pyroptosis. Our results provide a viral protein interaction network resource, reveal a UFM1-dependent pathway for selective degradation of mitochondrial cargo and highlight BILF1 as a novel therapeutic target.
2023-07-20 | PXD041336 | Pride
Project description:Transcriptional profiling of Mycobacterium smegmatis comparing the effects of wild type levels of CarD expression with CarD depletion. Transcriptional profile of the mgm1701 control strain was compared with that of mgm1703, a strain where CarD transcription is regulated by a Tet-On system. Both strains were grown in the absence of anhydrotetracline for 13 hours in nutrient rich broth to allow for depletion of CarD transcription in mgm1703.
2009-07-01 | GSE15437 | GEO
Project description:The unprecedented 2013-16 outbreak of Ebola virus (EBOV) in West Africa resulted in over 11,300 human deaths. Host resistance to EBOV is thought to involve RIG-I-like receptor (RLR) signaling through the adaptor protein, mitochondrial antiviral signaling (MAVS), but role of RLR-MAVS in orchestrating anti-EBOV responses in vivo is not known. Here, we apply a systems approach to MAVS-deficient mice infected with either wild-type or mouse-adapted EBOV. MAVS controlled EBOV replication through expression of IFNα, IFN-stimulated genes, and regulation of inflammatory responses in the spleen, and prevented cell death in the liver, with macrophages implicated as a major cell-type influencing host resistance. A dominant role for RLR signaling in macrophages was confirmed following conditional deletion of MAVS in LysM+ myeloid cells. These findings reveal tissue-specific transcriptional pathways controlled by RLR signaling in resistance to EBOV, and suggest that EBOV adaptation to cause disease in mice is linked in part to increased antagonism of RLR-dependent signaling.
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