Metabolic regulation of host defense against influenza virus infection through sensing oxaloacetate
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PROVIDER: PRJNA1080471 | ENA |
REPOSITORIES: ENA
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Project description:Metabolic pathways instructing the cellular fate and function, however, the exact roles of metabolites in host immune responses remain undefined. Using unbiased metabolomics and pharmacological inhibition analysis, we report natural metabolic intermediate, oxaloacetate (OAA) primes effective broad-spectrum innate immunity against viral infection. OAA serves as an immune signal, rather than alters the metabolic flux to prompt antiviral immunity. Malate dehydrogenase 1 (MDH1) senses OAA to undergo dimerization, thus functions as a scaffold to recruit transcription factor ETS2 for phosphorylation by kinase TAOK1 at serine 313. Phosphorylated ETS2 is involved in the transcriptional regulation of TANK-binding kinase 1 (TBK1). OAA deficiency caused by genetic ablation and enzymatic inhibition of the ATP-citrate lyase (ACLY) decreases the antiviral immune responses through MDH1-TAOK1-ETS2-TBK1 pathway in vivo, and makes mice more susceptible to lethal viral infection. Taken together, our findings delineate an OAA-initiated immunometabolic circuit that links metabolic pathway and antiviral immune responses.
2025-07-19 | GSE259217 | GEO
Project description:Exosomes are extracellular vesicles secreted by cells that have an important biological function in intercellular communication by transferring biologically active proteins, lipids, and RNAs to neighbouring or distant cells. While a role for exosomes in antimicrobial defence has recently emerged, currently very little is known regarding the nature and functional relevance of exosomes generated in vivo, particularly during an active viral infection. Here, we characterised exosomes released into the airways during influenza virus infection. We show that these vesicles dynamically change in protein composition over the course of infection, increasing expression of host proteins with known anti-influenza activity, and viral proteins with the potential to trigger host immune responses. We show that exosomes released into the airways during influenza virus infection trigger pulmonary inflammation and carry viral antigen that can be utilized by antigen presenting cells to drive the induction of a cellular immune response. Moreover, we show that attachment factors for influenza virus, namely α2,3 and α2,6-linked sialic acids, are present on the surface of airway exosomes and these vesicles have the ability to neutralize influenza virus, thereby preventing the virus from binding and entering target cells. These data reveal a novel role for airway exosomes in the antiviral innate immune defence against influenza virus infection.
2020-06-03 | PXD018389 | Pride
Project description:Innate immune sensing of influenza virus through IFI16 promote pyroptosis.
| PRJNA687234 | ENA
Project description:Metabolic pathways determine cellular fate and function, however, the exact roles of metabolites in host immune responses against virus infection remain undefined. Here, we report that the metabolic pathways of oxaloacetate (OAA) are integrated with antiviral responses and OAA serves as a fundamental “cornerstone” to prime effective host resistance to the infection of influenza virus. MDH1 senses cellular OAA to undergo dimerization, thus functions as a scaffold to recruit the transcription factor ETS2 for phosphorylation by the kinase TAOK1 at serine 313. The phosphorylated ETS2 translocates into the nucleus and sustains the appropriate expression of TBK1 to provide broad-spectrum antiviral activity. OAA deficiency caused by ACLY genetic ablation decreases the antiviral immunity through MDH1–TAOK1–ETS2–TBK1 pathway in vivo, and makes mice more susceptible to lethal H1N1 virus infection. Our results uncover a previously unknown signaling pathway to maintain immune homeostasis by sensing cellular OAA, which links metabolism and antiviral innate immunity.
2025-07-18 | GSE297098 | GEO
Project description:Ca2+ release-activated Ca2+ entry is a potent host innate immune defence against influenza A virus
| PRJNA494313 | ENA
Project description:The innate immune response is the first line of defense against pathogens, and factors that control this cellular response represent targets for treating both infectious and inflammatory diseases. Here, we reveal a novel role for the human helicase SETX, also previously implicated in amyotrophic lateral sclerosis (ALS4) and ataxia with oculomotor apraxia (AOA2), in controlling the magnitude of the antiviral response. Cells depleted for SETX and AOA2 patient-derived SETX-null cells show increased expression of antiviral mediators in response to infection. Mechanistically, this effect is achieved through SETX-mediated inhibition of RNAPII transcription of antiviral genes, and depends on SETX helicase activity. Our results suggest that SETX helps maintain the delicate balance between controlling viral infection and avoiding the potentially detrimental effects of an excessive antiviral response. More broadly, the observation that SETX can regulate the transcriptional activity of specific genes may have important implications for disorders where SETX function is compromised. A549 cells that were transfected with either control non-targeting or SETX-specific siRNAs were infected with the Influenza A virus (A/PR/8/34(ΔNS1) strain) at a multiplicity of infection (MOI) of 3 for 4 hours. Nuclei were then extracted and used to prepare Global Run-On Sequencing (GRO-seq) libraries.
2015-03-30 | E-GEOD-52935 | biostudies-arrayexpress
Project description:We report that IFI16, which was previously identified as a cytosolic DNA sensor, is essential for the activation of programmed cell death pathways in IAV infected cells. We have identified IFI16 as an innate immune sensor of the influenza A virus. We find that IFI16 recognizes viral genomic RNA upon infection. The activation of IFI16, in turn, triggers the production of type I, III interferons, and also other pro-inflammatory cytokines via the STING-TBK1 and Pro-caspase-1 signalling axis, thereby promoting cell death (apoptosis and pyroptosis in IAV infected cells).
2021-12-31 | GSE163705 | GEO
Project description:RIG-I is thought to be the most important sensor of influenza virus infection and plays critical roles in the recognition of cytoplasmic dsRNA and activation of type I IFNs and initiates the innate antiviral immune responses. How the binding of viral RNA to and activation of RIG-I are regulated remains enigmatic. Here, by an affinity proteomics approach with viral RNA as the bait, we found that IFI16, previously identified as a DNA sensor, was significantly induced both in vitro and in vivo during influenza virus infection. Using an IFI16 knockout cells and p204-deficient mice model, we demonstrated that IFI16 enhanced RIG-I-mediated production of type I IFNs and thereby inhibited viral replication during influenza virus infection. Furthermore, we showed that IFI16 regulated the RIG-I signaling by enhancing its transcriptional expression through recruitment of RNA Pol II to the RIG-I promoter. We also verified that IFI16 directly interacted with both viral RNA by HINa domain and associated with RIG-I through its PYRIN domain as well as promoted influenza virus-induced K63-linked polyubiquitination of RIG-I. In addition, we found that IFI16 lost its ability to inhibit viral replication in the absence of RIG-I in virus-infected cells. These results indicate that IFI16 is a key regulator of the RIG-I signaling during antiviral innate immune responses, which highlights a novel mechanism of IFI16 in IAV and other RNA viruses infection, expands our knowledge in antiviral innate immunity, and suggests its possible use as a new strategies to manipulate antiviral responses.
2020-09-09 | GSE157609 | GEO
Project description:RIG-I is thought to be the most important sensor of influenza virus infection and plays critical roles in the recognition of cytoplasmic dsRNA and activation of type I IFNs and initiates the innate antiviral immune responses. How the binding of viral RNA to and activation of RIG-I are regulated remains enigmatic. Here, by an affinity proteomics approach with viral RNA as the bait, we found that IFI16, previously identified as a DNA sensor, was significantly induced both in vitro and in vivo during influenza virus infection. Using an IFI16 knockout cells and p204-deficient mice model, we demonstrated that IFI16 enhanced RIG-I-mediated production of type I IFNs and thereby inhibited viral replication during influenza virus infection. Furthermore, we showed that IFI16 regulated the RIG-I signaling by enhancing its transcriptional expression through recruitment of RNA Pol II to the RIG-I promoter. We also verified that IFI16 directly interacted with both viral RNA by HINa domain and associated with RIG-I through its PYRIN domain as well as promoted influenza virus-induced K63-linked polyubiquitination of RIG-I. In addition, we found that IFI16 lost its ability to inhibit viral replication in the absence of RIG-I in virus-infected cells. These results indicate that IFI16 is a key regulator of the RIG-I signaling during antiviral innate immune responses, which highlights a novel mechanism of IFI16 in IAV and other RNA viruses infection, expands our knowledge in antiviral innate immunity, and suggests its possible use as a new strategies to manipulate antiviral responses.
2020-09-17 | GSE158122 | 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