RESUMEN
Neurotropic RNA viruses continue to emerge and are increasingly linked to diseases of the central nervous system (CNS) despite viral clearance. Indeed, the overall mortality of viral encephalitis in immunocompetent individuals is low, suggesting efficient mechanisms of virologic control within the CNS. Both immune and neural cells participate in this process, which requires extensive innate immune signaling between resident and infiltrating cells, including microglia and monocytes, that regulate the effector functions of antiviral T and B cells as they gain access to CNS compartments. While these interactions promote viral clearance via mainly neuroprotective mechanisms, they may also promote neuropathology and, in some cases, induce persistent alterations in CNS physiology and function that manifest as neurologic and psychiatric diseases. This review discusses mechanisms of RNA virus clearance and neurotoxicity during viral encephalitis with a focus on the cytokines essential for immune and neural cell inflammatory responses and interactions. Understanding neuroimmune communications in the setting of viral infections is essential for the development of treatments that augment neuroprotective processes while limiting ongoing immunopathological processes that cause ongoing CNS disease.
Asunto(s)
Encéfalo/inmunología , Inmunidad Innata , Microglía/fisiología , Infecciones por Virus ARN/inmunología , Virus ARN/fisiología , Animales , Barrera Hematoencefálica , Encéfalo/virología , Humanos , Inflamación Neurogénica , NeuroinmunomodulaciónRESUMEN
Each of us is a story. Mine is a story of doing science for 60 years, and I am honored to be asked to tell it. Even though this autobiography was written for the Annual Review of Immunology, I have chosen to describe my whole career in science because the segment that was immunology is so intertwined with all else I was doing. This article is an elongation and modification of a talk I gave at my 80th birthday celebration at Caltech on March 23, 2018.
Asunto(s)
Alergia e Inmunología/historia , FN-kappa B/metabolismo , Virus ARN/fisiología , Virosis/inmunología , Animales , Modelos Animales de Enfermedad , Reordenamiento Génico , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Ratones , Proteínas Tirosina Quinasas/metabolismo , Transcripción Reversa , Estados UnidosRESUMEN
A major challenge in understanding SARS-CoV-2 evolution is interpreting the antigenic and functional effects of emerging mutations in the viral spike protein. Here, we describe a deep mutational scanning platform based on non-replicative pseudotyped lentiviruses that directly quantifies how large numbers of spike mutations impact antibody neutralization and pseudovirus infection. We apply this platform to produce libraries of the Omicron BA.1 and Delta spikes. These libraries each contain â¼7,000 distinct amino acid mutations in the context of up to â¼135,000 unique mutation combinations. We use these libraries to map escape mutations from neutralizing antibodies targeting the receptor-binding domain, N-terminal domain, and S2 subunit of spike. Overall, this work establishes a high-throughput and safe approach to measure how â¼105 combinations of mutations affect antibody neutralization and spike-mediated infection. Notably, the platform described here can be extended to the entry proteins of many other viruses.
Asunto(s)
COVID-19 , Virus ARN , Humanos , SARS-CoV-2/genética , Mutación , Anticuerpos Neutralizantes , Anticuerpos AntiviralesRESUMEN
High-throughput RNA sequencing offers broad opportunities to explore the Earth RNA virome. Mining 5,150 diverse metatranscriptomes uncovered >2.5 million RNA virus contigs. Analysis of >330,000 RNA-dependent RNA polymerases (RdRPs) shows that this expansion corresponds to a 5-fold increase of the known RNA virus diversity. Gene content analysis revealed multiple protein domains previously not found in RNA viruses and implicated in virus-host interactions. Extended RdRP phylogeny supports the monophyly of the five established phyla and reveals two putative additional bacteriophage phyla and numerous putative additional classes and orders. The dramatically expanded phylum Lenarviricota, consisting of bacterial and related eukaryotic viruses, now accounts for a third of the RNA virome. Identification of CRISPR spacer matches and bacteriolytic proteins suggests that subsets of picobirnaviruses and partitiviruses, previously associated with eukaryotes, infect prokaryotic hosts.
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Bacteriófagos , Virus ARN , Bacteriófagos/genética , ARN Polimerasas Dirigidas por ADN/genética , Genoma Viral , Filogenia , ARN , Virus ARN/genética , ARN Polimerasa Dependiente del ARN/genética , ViromaRESUMEN
NLRP6 is important in host defense by inducing functional outcomes including inflammasome activation and interferon production. Here, we show that NLRP6 undergoes liquid-liquid phase separation (LLPS) upon interaction with double-stranded RNA (dsRNA) in vitro and in cells, and an intrinsically disordered poly-lysine sequence (K350-354) of NLRP6 is important for multivalent interactions, phase separation, and inflammasome activation. Nlrp6-deficient or Nlrp6K350-354A mutant mice show reduced inflammasome activation upon mouse hepatitis virus or rotavirus infection, and in steady state stimulated by intestinal microbiota, implicating NLRP6 LLPS in anti-microbial immunity. Recruitment of ASC via helical assembly solidifies NLRP6 condensates, and ASC further recruits and activates caspase-1. Lipoteichoic acid, a known NLRP6 ligand, also promotes NLRP6 LLPS, and DHX15, a helicase in NLRP6-induced interferon signaling, co-forms condensates with NLRP6 and dsRNA. Thus, LLPS of NLRP6 is a common response to ligand stimulation, which serves to direct NLRP6 to distinct functional outcomes depending on the cellular context.
Asunto(s)
Inflamasomas/metabolismo , Virus ARN/fisiología , Receptores de Superficie Celular/metabolismo , Secuencia de Aminoácidos , Animales , Proteínas Adaptadoras de Señalización CARD/metabolismo , Hepatocitos/virología , Intestinos/virología , Proteínas Intrínsecamente Desordenadas/química , Lipopolisacáridos/metabolismo , Hígado/virología , Ratones , Polilisina/metabolismo , Unión Proteica , ARN Bicatenario/metabolismo , Receptores de Superficie Celular/química , Transducción de Señal , Ácidos Teicoicos/metabolismoRESUMEN
RNA viruses are among the most prevalent pathogens and are a major burden on society. Although RNA viruses have been studied extensively, little is known about the processes that occur during the first several hours of infection because of a lack of sensitive assays. Here we develop a single-molecule imaging assay, virus infection real-time imaging (VIRIM), to study translation and replication of individual RNA viruses in live cells. VIRIM uncovered a striking heterogeneity in replication dynamics between cells and revealed extensive coordination between translation and replication of single viral RNAs. Furthermore, using VIRIM, we identify the replication step of the incoming viral RNA as a major bottleneck of successful infection and identify host genes that are responsible for inhibition of early virus replication. Single-molecule imaging of virus infection is a powerful tool to study virus replication and virus-host interactions that may be broadly applicable to RNA viruses.
Asunto(s)
Biosíntesis de Proteínas , Virus ARN/fisiología , Replicación Viral/fisiología , Línea Celular Tumoral , Supervivencia Celular , Células HEK293 , Interacciones Huésped-Patógeno , Humanos , Interferones/metabolismo , Transporte de ARN , ARN Viral/genética , Reproducibilidad de los Resultados , Imagen Individual de Molécula , Factores de TiempoRESUMEN
Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/inmunología , Neumonía Viral/inmunología , Virus ARN/inmunología , Animales , COVID-19 , Células Cultivadas , Quimiocinas/genética , Quimiocinas/inmunología , Infecciones por Coronavirus/genética , Modelos Animales de Enfermedad , Interacciones Huésped-Patógeno , Humanos , Inmunidad Innata , Inflamación/virología , Interferones/genética , Interferones/inmunología , Pandemias , Neumonía Viral/genética , Virus ARN/clasificación , SARS-CoV-2 , Transcripción GenéticaRESUMEN
Hantaviruses are rodent-borne viruses causing serious zoonotic outbreaks worldwide for which no treatment is available. Hantavirus particles are pleomorphic and display a characteristic square surface lattice. The envelope glycoproteins Gn and Gc form heterodimers that further assemble into tetrameric spikes, the lattice building blocks. The glycoproteins, which are the sole targets of neutralizing antibodies, drive virus entry via receptor-mediated endocytosis and endosomal membrane fusion. Here we describe the high-resolution X-ray structures of the heterodimer of Gc and the Gn head and of the homotetrameric Gn base. Docking them into an 11.4-Å-resolution cryoelectron tomography map of the hantavirus surface accounted for the complete extramembrane portion of the viral glycoprotein shell and allowed a detailed description of the surface organization of these pleomorphic virions. Our results, which further revealed a built-in mechanism controlling Gc membrane insertion for fusion, pave the way for immunogen design to protect against pathogenic hantaviruses.
Asunto(s)
Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/ultraestructura , Orthohantavirus/química , Glicoproteínas/química , Glicoproteínas/ultraestructura , Orthohantavirus/metabolismo , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/fisiología , Conformación Proteica , Virus ARN , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/ultraestructura , Virión , Internalización del VirusRESUMEN
RNA viruses are a major human health threat. The life cycles of many highly pathogenic RNA viruses like influenza A virus (IAV) and Lassa virus depends on host mRNA, because viral polymerases cleave 5'-m7G-capped host transcripts to prime viral mRNA synthesis ("cap-snatching"). We hypothesized that start codons within cap-snatched host transcripts could generate chimeric human-viral mRNAs with coding potential. We report the existence of this mechanism of gene origination, which we named "start-snatching." Depending on the reading frame, start-snatching allows the translation of host and viral "untranslated regions" (UTRs) to create N-terminally extended viral proteins or entirely novel polypeptides by genetic overprinting. We show that both types of chimeric proteins are made in IAV-infected cells, generate T cell responses, and contribute to virulence. Our results indicate that during infection with IAV, and likely a multitude of other human, animal and plant viruses, a host-dependent mechanism allows the genesis of hybrid genes.
Asunto(s)
Caperuzas de ARN/genética , Infecciones por Virus ARN/genética , Proteínas Recombinantes de Fusión/genética , Regiones no Traducidas 5'/genética , Animales , Bovinos , Línea Celular , Cricetinae , Perros , Humanos , Virus de la Influenza A/metabolismo , Ratones , Proteínas Mutantes Quiméricas/genética , Proteínas Mutantes Quiméricas/metabolismo , Sistemas de Lectura Abierta/genética , Caperuzas de ARN/metabolismo , Infecciones por Virus ARN/metabolismo , Virus ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Viral/metabolismo , ARN Polimerasa Dependiente del ARN/genética , ARN Polimerasa Dependiente del ARN/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Transcripción Genética/genética , Proteínas Virales/metabolismo , Replicación Viral/genéticaRESUMEN
In this issue, Enard and Petrov present intriguing results on the possibility of genetic traces left behind in our genomes from adaptation to past viral epidemics that may have been initiated by interaction with Neanderthal archaic hominins. The work highlights how powerful infectious agents can act as a selective force to shape our genetic makeup.
Asunto(s)
Hominidae/genética , Hombre de Neandertal/genética , Virus ARN , Animales , Genoma , HumanosRESUMEN
Neanderthals and modern humans interbred at least twice in the past 100,000 years. While there is evidence that most introgressed DNA segments from Neanderthals to modern humans were removed by purifying selection, less is known about the adaptive nature of introgressed sequences that were retained. We hypothesized that interbreeding between Neanderthals and modern humans led to (1) the exposure of each species to novel viruses and (2) the exchange of adaptive alleles that provided resistance against these viruses. Here, we find that long, frequent-and more likely adaptive-segments of Neanderthal ancestry in modern humans are enriched for proteins that interact with viruses (VIPs). We found that VIPs that interact specifically with RNA viruses were more likely to belong to introgressed segments in modern Europeans. Our results show that retained segments of Neanderthal ancestry can be used to detect ancient epidemics.
Asunto(s)
Hibridación Genética/genética , Hombre de Neandertal/genética , Virus ARN/genética , Alelos , Animales , Evolución Biológica , Genoma Humano/genética , Haplotipos , Hominidae/genética , Humanos , Filogenia , Virus ARN/patogenicidad , Selección Genética/genéticaRESUMEN
We know less about viruses than any other lifeform. Fortunately, metagenomics has led to a massive expansion in the known diversity of the virosphere. Here, we discuss how metagenomics has changed our understanding of RNA viruses and present some of the remaining challenges, including characterization of the "dark matter" of divergent viral genomes.
Asunto(s)
Variación Genética , Genoma Viral/genética , Metagenómica/métodos , Virus/genética , Evolución Molecular , Filogenia , Virus ARN/clasificación , Virus ARN/genética , Virus/clasificaciónRESUMEN
The helicase RIG-I initiates an antiviral immune response after recognition of pathogenic RNA. TRIM25, an E3 ubiquitin ligase, mediates K63-linked ubiquitination of RIG-I, which is crucial for RIG-I downstream signaling and the antiviral innate immune response. The components and mode of the RIG-I-initiated innate signaling remain to be fully understood. Here we identify a novel long noncoding RNA (Lnczc3h7a) that binds to TRIM25 and promotes RIG-I-mediated antiviral innate immune responses. Depletion of Lnczc3h7a impairs RIG-I signaling and the antiviral innate response to RNA viruses in vitro and in vivo. Mechanistically, Lnczc3h7a binds to both TRIM25 and activated RIG-I, serving as a molecular scaffold for stabilization of the RIG-I-TRIM25 complex at the early stage of viral infection. Lnczc3h7a facilitates TRIM25-mediated K63-linked ubiquitination of RIG-I and thus promotes downstream signaling transduction. Our findings reveal that host RNAs can enhance the response of innate immune sensors to foreign RNAs, ensuring effective antiviral defense.
Asunto(s)
Proteína 58 DEAD Box/genética , Proteínas de Unión al ADN/genética , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Inmunidad Innata/genética , ARN Largo no Codificante/genética , Factores de Transcripción/genética , Animales , Línea Celular , Humanos , Macrófagos Peritoneales/inmunología , Macrófagos Peritoneales/metabolismo , Macrófagos Peritoneales/virología , Ratones , Modelos Biológicos , Interferencia de ARN , Virus ARN/inmunología , Transducción de Señal , Virosis/genética , Virosis/inmunología , Virosis/metabolismo , Virosis/virologíaRESUMEN
Type I interferons (IFNs) are critical cytokines in the host defense against invading pathogens. Sustained production of IFNs, however, is detrimental to the host, as it provokes autoimmune diseases. Thus, the expression of IFNs is tightly controlled. We report that the mRNA 5' cap-binding protein 4EHP plays a key role in regulating type I IFN concomitant with controlling virus replication, both in vitro and in vivo. Mechanistically, 4EHP suppresses IFN-ß production by effecting the miR-34a-induced translational silencing of Ifnb1 mRNA. miR-34a is upregulated by both RNA virus infection and IFN-ß induction, prompting a negative feedback regulatory mechanism that represses IFN-ß expression via 4EHP. These findings demonstrate the direct involvement of 4EHP in virus-induced host response, underscoring a critical translational silencing mechanism mediated by 4EHP and miR-34a to impede sustained IFN production. This study highlights an intrinsic regulatory function for miRNA and the translation machinery in maintaining host homeostasis.
Asunto(s)
Factor 4E Eucariótico de Iniciación/inmunología , Inmunidad Innata , MicroARNs/inmunología , Biosíntesis de Proteínas/inmunología , Infecciones por Virus ARN/inmunología , Virus ARN/inmunología , Animales , Factor 4E Eucariótico de Iniciación/genética , Células HEK293 , Humanos , Interferón beta/genética , Interferón beta/inmunología , Ratones , Ratones Transgénicos , MicroARNs/genética , Infecciones por Virus ARN/genética , Virus ARN/genéticaRESUMEN
Viral RNA-dependent RNA polymerases (RdRps) are a target for broad-spectrum antiviral therapeutic agents. Recently, we demonstrated that incorporation of the T-1106 triphosphate, a pyrazine-carboxamide ribonucleotide, into nascent RNA increases pausing and backtracking by the poliovirus RdRp. Here, by monitoring enterovirus A-71 RdRp dynamics during RNA synthesis using magnetic tweezers, we identify the "backtracked" state as an intermediate used by the RdRp for copy-back RNA synthesis and homologous recombination. Cell-based assays and RNA sequencing (RNA-seq) experiments further demonstrate that the pyrazine-carboxamide ribonucleotide stimulates these processes during infection. These results suggest that pyrazine-carboxamide ribonucleotides do not induce lethal mutagenesis or chain termination but function by promoting template switching and formation of defective viral genomes. We conclude that RdRp-catalyzed intra- and intermolecular template switching can be induced by pyrazine-carboxamide ribonucleotides, defining an additional mechanistic class of antiviral ribonucleotides with potential for broad-spectrum activity.
Asunto(s)
Pirazinas/química , Virus ARN/genética , ARN Viral/genética , ARN Polimerasa Dependiente del ARN/genética , Recombinación Genética , Ribonucleótidos/química , Animales , Antivirales , Catálisis , Células Cultivadas , Técnicas Genéticas , Genoma , Genoma Viral , Recombinación Homóloga , Humanos , Cinética , Ratones , Ratones Transgénicos , Simulación de Dinámica Molecular , Mutagénesis , Nucleótidos/genética , Conformación Proteica , ARN/química , ARN Polimerasa Dependiente del ARN/metabolismo , RNA-Seq , Transgenes , VirulenciaRESUMEN
The mammalian cytoplasmic multi-tRNA synthetase complex (MSC) is a depot system that regulates non-translational cellular functions. Here we found that the MSC component glutamyl-prolyl-tRNA synthetase (EPRS) switched its function following viral infection and exhibited potent antiviral activity. Infection-specific phosphorylation of EPRS at Ser990 induced its dissociation from the MSC, after which it was guided to the antiviral signaling pathway, where it interacted with PCBP2, a negative regulator of mitochondrial antiviral signaling protein (MAVS) that is critical for antiviral immunity. This interaction blocked PCBP2-mediated ubiquitination of MAVS and ultimately suppressed viral replication. EPRS-haploid (Eprs+/-) mice showed enhanced viremia and inflammation and delayed viral clearance. This stimulus-inducible activation of MAVS by EPRS suggests an unexpected role for the MSC as a regulator of immune responses to viral infection.
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Aminoacil-ARNt Sintetasas/metabolismo , Resistencia a la Enfermedad/inmunología , Interacciones Huésped-Patógeno/inmunología , Virosis/inmunología , Virosis/metabolismo , Aminoacil-ARNt Sintetasas/química , Aminoacil-ARNt Sintetasas/genética , Animales , Antivirales/farmacología , Modelos Animales de Enfermedad , Inmunidad Innata , Ratones , Ratones Noqueados , Péptidos/farmacología , Fosforilación , Unión Proteica , Infecciones por Virus ARN/inmunología , Infecciones por Virus ARN/metabolismo , Infecciones por Virus ARN/virología , Virus ARN/efectos de los fármacos , Virus ARN/inmunología , Proteínas de Unión al ARN/metabolismo , Transducción de Señal , Ubiquitinación , Virosis/virología , Replicación ViralRESUMEN
Interferon-inducible human oligoadenylate synthetase-like (OASL) and its mouse ortholog, Oasl2, enhance RNA-sensor RIG-I-mediated type I interferon (IFN) induction and inhibit RNA virus replication. Here, we show that OASL and Oasl2 have the opposite effect in the context of DNA virus infection. In Oasl2-/- mice and OASL-deficient human cells, DNA viruses such as vaccinia, herpes simplex, and adenovirus induced increased IFN production, which resulted in reduced virus replication and pathology. Correspondingly, ectopic expression of OASL in human cells inhibited IFN induction through the cGAS-STING DNA-sensing pathway. cGAS was necessary for the reduced DNA virus replication observed in OASL-deficient cells. OASL directly and specifically bound to cGAS independently of double-stranded DNA, resulting in a non-competitive inhibition of the second messenger cyclic GMP-AMP production. Our findings define distinct mechanisms by which OASL differentially regulates host IFN responses during RNA and DNA virus infection and identify OASL as a negative-feedback regulator of cGAS.
Asunto(s)
2',5'-Oligoadenilato Sintetasa/metabolismo , Infecciones por Virus ADN/inmunología , Virus ADN/fisiología , Infecciones por Virus ARN/inmunología , Virus ARN/inmunología , 2',5'-Oligoadenilato Sintetasa/genética , Animales , AMP Cíclico/metabolismo , Humanos , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nucleotidiltransferasas/metabolismo , ARN Interferente Pequeño/genética , Transducción de Señal , Células THP-1 , Replicación ViralRESUMEN
RIG-I is a critical RNA virus sensor that serves to initiate antiviral innate immunity. However, posttranslational regulation of RIG-I signaling remains to be fully understood. We report here that RNA viruses, but not DNA viruses or bacteria, specifically upregulate lectin family member Siglecg expression in macrophages by RIG-I- or NF-κB-dependent mechanisms. Siglec-G-induced recruitment of SHP2 and the E3 ubiquitin ligase c-Cbl to RIG-I leads to RIG-I degradation via K48-linked ubiquitination at Lys813 by c-Cbl. By increasing type I interferon production, targeted inactivation of Siglecg protects mice against lethal RNA virus infection. Taken together, our data reveal a negative feedback loop of RIG-I signaling and identify a Siglec-G-mediated immune evasion pathway exploited by RNA viruses with implication in antiviral applications. These findings also provide insights into the functions and crosstalk of Siglec-G, a known adaptive response regulator, in innate immunity.
Asunto(s)
ARN Helicasas DEAD-box/metabolismo , Infecciones por Bacterias Gramnegativas/inmunología , Inmunidad Innata , Lectinas/metabolismo , Infecciones por Virus ARN/inmunología , Receptores de Antígenos de Linfocitos B/metabolismo , Animales , Proteína 58 DEAD Box , ARN Helicasas DEAD-box/química , Células Dendríticas/inmunología , Bacterias Gramnegativas/metabolismo , Factor 3 Regulador del Interferón/metabolismo , Lectinas/genética , Lisina/metabolismo , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogénicas c-cbl/metabolismo , Virus ARN/metabolismo , Receptores de Antígenos de Linfocitos B/genética , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico , UbiquitinaciónRESUMEN
Public databases contain a planetary collection of nucleic acid sequences, but their systematic exploration has been inhibited by a lack of efficient methods for searching this corpus, which (at the time of writing) exceeds 20 petabases and is growing exponentially1. Here we developed a cloud computing infrastructure, Serratus, to enable ultra-high-throughput sequence alignment at the petabase scale. We searched 5.7 million biologically diverse samples (10.2 petabases) for the hallmark gene RNA-dependent RNA polymerase and identified well over 105 novel RNA viruses, thereby expanding the number of known species by roughly an order of magnitude. We characterized novel viruses related to coronaviruses, hepatitis delta virus and huge phages, respectively, and analysed their environmental reservoirs. To catalyse the ongoing revolution of viral discovery, we established a free and comprehensive database of these data and tools. Expanding the known sequence diversity of viruses can reveal the evolutionary origins of emerging pathogens and improve pathogen surveillance for the anticipation and mitigation of future pandemics.
Asunto(s)
Nube Computacional , Bases de Datos Genéticas , Virus ARN/genética , Virus ARN/aislamiento & purificación , Alineación de Secuencia/métodos , Virología/métodos , Viroma/genética , Animales , Archivos , Bacteriófagos/enzimología , Bacteriófagos/genética , Biodiversidad , Coronavirus/clasificación , Coronavirus/enzimología , Coronavirus/genética , Evolución Molecular , Virus de la Hepatitis Delta/enzimología , Virus de la Hepatitis Delta/genética , Humanos , Modelos Moleculares , Virus ARN/clasificación , Virus ARN/enzimología , ARN Polimerasa Dependiente del ARN/química , ARN Polimerasa Dependiente del ARN/genética , Programas InformáticosRESUMEN
Deciphering the mechanisms that regulate the sensitivity of pathogen recognition receptors is imperative to understanding infection and inflammation. Here we demonstrate that the RNA triphosphatase dual-specificity phosphatase 11 (DUSP11) acts on both host and virus-derived 5'-triphosphate RNAs rendering them less active in inducing a RIG-I-mediated immune response. Reducing DUSP11 levels alters host triphosphate RNA packaged in extracellular vesicles and induces enhanced RIG-I activation in cells exposed to extracellular vesicles. Virus infection of cells lacking DUSP11 results in a higher proportion of triphosphorylated viral transcripts and attenuated virus replication, which is rescued by reducing RIG-I expression. Consistent with the activity of DUSP11 in the cellular RIG-I response, mice lacking DUSP11 display lower viral loads, greater sensitivity to triphosphorylated RNA, and a signature of enhanced interferon activity in select tissues. Our results reveal the importance of controlling 5'-triphosphate RNA levels to prevent aberrant RIG-I signaling and demonstrate DUSP11 as a key effector of this mechanism.