RESUMEN
Environmental signals shape host physiology and fitness. Microbiota-derived cues are required to program conventional dendritic cells (cDCs) during the steady state so that they can promptly respond and initiate adaptive immune responses when encountering pathogens. However, the molecular underpinnings of microbiota-guided instructive programs are not well understood. Here, we report that the indigenous microbiota controls constitutive production of type I interferons (IFN-I) by plasmacytoid DCs. Using genome-wide analysis of transcriptional and epigenetic regulomes of cDCs from germ-free and IFN-I receptor (IFNAR)-deficient mice, we found that tonic IFNAR signaling instructs a specific epigenomic and metabolic basal state that poises cDCs for future pathogen combat. However, such beneficial biological function comes with a trade-off. Instructed cDCs can prime T cell responses against harmless peripheral antigens when removing roadblocks of peripheral tolerance. Our data provide fresh insights into the evolutionary trade-offs that come with successful adaptation of vertebrates to their microbial environment.
Asunto(s)
Células Dendríticas/inmunología , Interferón Tipo I/inmunología , Microbiota/inmunología , Inmunidad Adaptativa/inmunología , Inmunidad Adaptativa/fisiología , Animales , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/microbiología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Microbiota/fisiología , Receptor de Interferón alfa y beta/metabolismo , Transducción de Señal/inmunologíaRESUMEN
There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.
Asunto(s)
Células Epiteliales Alveolares/metabolismo , Enterocitos/metabolismo , Células Caliciformes/metabolismo , Interferón Tipo I/metabolismo , Mucosa Nasal/citología , Peptidil-Dipeptidasa A/genética , Adolescente , Células Epiteliales Alveolares/inmunología , Enzima Convertidora de Angiotensina 2 , Animales , Betacoronavirus/fisiología , COVID-19 , Línea Celular , Células Cultivadas , Niño , Infecciones por Coronavirus/virología , Enterocitos/inmunología , Células Caliciformes/inmunología , Infecciones por VIH/inmunología , Humanos , Gripe Humana/inmunología , Interferón Tipo I/inmunología , Pulmón/citología , Pulmón/patología , Macaca mulatta , Ratones , Mycobacterium tuberculosis , Mucosa Nasal/inmunología , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/virología , Receptores Virales/genética , SARS-CoV-2 , Serina Endopeptidasas/metabolismo , Análisis de la Célula Individual , Tuberculosis/inmunología , Regulación hacia ArribaRESUMEN
Traumatic brain injury (TBI) and cerebrovascular injury are leading causes of disability and mortality worldwide. Systemic infections often accompany these disorders and can worsen outcomes. Recovery after brain injury depends on innate immunity, but the effect of infections on this process is not well understood. Here, we demonstrate that systemically introduced microorganisms and microbial products interfered with meningeal vascular repair after TBI in a type I interferon (IFN-I)-dependent manner, with sequential infections promoting chronic disrepair. Mechanistically, we discovered that MDA5-dependent detection of an arenavirus encountered after TBI disrupted pro-angiogenic myeloid cell programming via induction of IFN-I signaling. Systemic viral infection similarly blocked restorative angiogenesis in the brain parenchyma after intracranial hemorrhage, leading to chronic IFN-I signaling, blood-brain barrier leakage and a failure to restore cognitive-motor function. Our findings reveal a common immunological mechanism by which systemic infections deviate reparative programming after central nervous system injury and offer a new therapeutic target to improve recovery.
Asunto(s)
Antiinfecciosos/inmunología , Lesiones Traumáticas del Encéfalo/inmunología , Sistema Nervioso Central/inmunología , Inmunidad Innata/inmunología , Animales , Barrera Hematoencefálica/inmunología , Encéfalo/inmunología , Modelos Animales de Enfermedad , Femenino , Interferón Tipo I/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/inmunologíaRESUMEN
Efficient immune responses against viral infection are determined by sufficient activation of nucleic acid sensor-mediated innate immunity1,2. Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains an ongoing global pandemic. It is an urgent challenge to clarify the innate recognition mechanism to control this virus. Here we show that retinoic acid-inducible gene-I (RIG-I) sufficiently restrains SARS-CoV-2 replication in human lung cells in a type I/III interferon (IFN)-independent manner. RIG-I recognizes the 3' untranslated region of the SARS-CoV-2 RNA genome via the helicase domains, but not the C-terminal domain. This new mode of RIG-I recognition does not stimulate its ATPase, thereby aborting the activation of the conventional mitochondrial antiviral-signaling protein-dependent pathways, which is in accordance with lack of cytokine induction. Nevertheless, the interaction of RIG-I with the viral genome directly abrogates viral RNA-dependent RNA polymerase mediation of the first step of replication. Consistently, genetic ablation of RIG-I allows lung cells to produce viral particles that expressed the viral spike protein. By contrast, the anti-SARS-CoV-2 activity was restored by all-trans retinoic acid treatment through upregulation of RIG-I protein expression in primary lung cells derived from patients with chronic obstructive pulmonary disease. Thus, our findings demonstrate the distinctive role of RIG-I as a restraining factor in the early phase of SARS-CoV-2 infection in human lung cells.
Asunto(s)
COVID-19/inmunología , Proteína 58 DEAD Box/inmunología , Pulmón/inmunología , Receptores Inmunológicos/inmunología , SARS-CoV-2/inmunología , Células A549 , Animales , Línea Celular , Línea Celular Tumoral , Chlorocebus aethiops , Perros , Células HEK293 , Humanos , Interferón Tipo I/inmunología , Interferones/inmunología , Pulmón/virología , Células de Riñón Canino Madin Darby , Enfermedad Pulmonar Obstructiva Crónica/inmunología , ARN Polimerasa Dependiente del ARN/inmunología , Células Sf9 , Transducción de Señal/inmunología , Células Vero , Proteínas Virales/inmunología , Interferón lambdaRESUMEN
A central paradigm of immunity is that interferon (IFN)-mediated antiviral responses precede pro-inflammatory ones, optimizing host protection and minimizing collateral damage1,2. Here, we report that for coronavirus disease 2019 (COVID-19) this paradigm does not apply. By investigating temporal IFN and inflammatory cytokine patterns in 32 moderate-to-severe patients with COVID-19 hospitalized for pneumonia and longitudinally followed for the development of respiratory failure and death, we reveal that IFN-λ and type I IFN production were both diminished and delayed, induced only in a fraction of patients as they became critically ill. On the contrary, pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6 and IL-8 were produced before IFNs in all patients and persisted for a prolonged time. This condition was reflected in blood transcriptomes wherein prominent IFN signatures were only seen in critically ill patients who also exhibited augmented inflammation. By comparison, in 16 patients with influenza (flu) hospitalized for pneumonia with similar clinicopathological characteristics to those of COVID-19 and 24 nonhospitalized patients with flu with milder symptoms, IFN-λ and type I IFN were robustly induced earlier, at higher levels and independently of disease severity, whereas pro-inflammatory cytokines were only acutely produced. Notably, higher IFN-λ concentrations in patients with COVID-19 correlated with lower viral load in bronchial aspirates and faster viral clearance and a higher IFN-λ to type I IFN ratio correlated with improved outcome for critically ill patients. Moreover, altered cytokine patterns in patients with COVID-19 correlated with longer hospitalization and higher incidence of critical disease and mortality compared to flu. These data point to an untuned antiviral response in COVID-19, contributing to persistent viral presence, hyperinflammation and respiratory failure.
Asunto(s)
COVID-19/inmunología , Inmunidad/inmunología , Gripe Humana/inmunología , Interferón Tipo I/inmunología , Interferones/inmunología , SARS-CoV-2/inmunología , Antivirales/inmunología , Antivirales/metabolismo , COVID-19/genética , COVID-19/virología , Citocinas/genética , Citocinas/inmunología , Progresión de la Enfermedad , Expresión Génica/genética , Expresión Génica/inmunología , Perfilación de la Expresión Génica/métodos , Humanos , Inmunidad/genética , Inflamación/genética , Inflamación/inmunología , Gripe Humana/genética , Interferón Tipo I/genética , Interferones/genética , Tiempo de Internación , Pronóstico , SARS-CoV-2/fisiología , Carga Viral/genética , Carga Viral/inmunología , Interferón lambdaRESUMEN
Memory B cells (MBCs) are key providers of long-lived immunity against infectious disease, yet in chronic viral infection, they do not produce effective protection. How chronic viral infection disrupts MBC development and whether such changes are reversible remain unknown. Through single-cell (sc)ATAC-seq and scRNA-seq during acute versus chronic lymphocytic choriomeningitis viral infection, we identified a memory subset enriched for interferon (IFN)-stimulated genes (ISGs) during chronic infection that was distinct from the T-bet+ subset normally associated with chronic infection. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic MBCs, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing phenotypic changes in the dominating MBC subset, with a decrease in the ISG subset and an increase in CD11c+CD80+ cells. However, timing was critical, with MBCs resistant to intervention at 4 weeks post-infection. Together, our research identifies a key mechanism to instruct MBC identity during viral infection.
Asunto(s)
Epigénesis Genética , Interferón Tipo I , Coriomeningitis Linfocítica , Virus de la Coriomeningitis Linfocítica , Células B de Memoria , Animales , Interferón Tipo I/metabolismo , Interferón Tipo I/inmunología , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/virología , Ratones , Virus de la Coriomeningitis Linfocítica/inmunología , Células B de Memoria/inmunología , Ratones Endogámicos C57BL , Receptor de Interferón alfa y beta/genética , Memoria Inmunológica/inmunología , Enfermedad Crónica , Subgrupos de Linfocitos B/inmunología , Análisis de la Célula IndividualRESUMEN
Naive CD4+ T cells in specific pathogen-free (SPF) mice are characterized by transcriptional heterogeneity and subpopulations distinguished by the expression of quiescence, the extracellular matrix (ECM) and cytoskeleton, type I interferon (IFN-I) response, memory-like, and T cell receptor (TCR) activation genes. We demonstrate that this constitutive heterogeneity, including the presence of the IFN-I response cluster, is commensal independent insofar as being identical in germ-free and SPF mice. By contrast, Nippostrongylus brasiliensis infection altered this constitutive heterogeneity. Naive T cell-intrinsic transcriptional changes acquired during helminth infection correlated with and accounted for decreased immunization response to an unrelated antigen. These compositional and functional changes were dependent variables of helminth infection, as they disappeared at the established time point of its clearance in mice. Collectively, our results indicate that the naive T cell pool is subject to dynamic transcriptional changes in response to certain environmental cues, which in turn permutes the magnitude of the immune response.
Asunto(s)
Linfocitos T CD4-Positivos , Nippostrongylus , Animales , Ratones , Linfocitos T CD4-Positivos/inmunología , Nippostrongylus/inmunología , Infecciones por Strongylida/inmunología , Infecciones por Strongylida/parasitología , Organismos Libres de Patógenos Específicos , Transcripción Genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Helmintiasis/inmunología , Interferón Tipo I/metabolismo , Interferón Tipo I/inmunología , Ratones Endogámicos C57BL , Activación de Linfocitos/inmunologíaRESUMEN
Prolonged activation of the type I interferon (IFN-I) pathway leads to autoimmune diseases such as systemic lupus erythematosus (SLE). Metabolic regulation of cytokine signaling is critical for cellular homeostasis. Through metabolomics analyses of IFN-ß-activated macrophages and an IFN-stimulated-response-element reporter screening, we identified spermine as a metabolite brake for Janus kinase (JAK) signaling. Spermine directly bound to the FERM and SH2 domains of JAK1 to impair JAK1-cytokine receptor interaction, thus broadly suppressing JAK1 phosphorylation triggered by cytokines IFN-I, IFN-II, interleukin (IL)-2, and IL-6. Peripheral blood mononuclear cells (PBMCs) from individuals with SLE showing decreased spermine concentrations exhibited enhanced IFN-I and lupus gene signatures. Spermine treatment attenuated autoimmune pathogenesis in SLE and psoriasis mice and reduced IFN-I signaling in monocytes from individuals with SLE. We synthesized a spermine derivative (spermine derivative 1 [SD1]) and showed that it had a potent immunosuppressive function. Our findings reveal spermine as a metabolic checkpoint for cellular homeostasis and a potential immunosuppressive molecule for controlling autoimmune disease.
Asunto(s)
Autoinmunidad , Citocinas , Lupus Eritematoso Sistémico , Transducción de Señal , Espermina , Animales , Espermina/metabolismo , Espermina/farmacología , Humanos , Transducción de Señal/efectos de los fármacos , Ratones , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/metabolismo , Citocinas/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Janus Quinasa 1/metabolismo , Fosforilación , Interferón Tipo I/metabolismo , Interferón Tipo I/inmunología , Psoriasis/inmunología , Psoriasis/metabolismo , Ratones Endogámicos C57BL , Quinasas Janus/metabolismo , Femenino , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismoRESUMEN
Although mouse infection models have been extensively used to study the host response to Mycobacterium tuberculosis, their validity in revealing determinants of human tuberculosis (TB) resistance and disease progression has been heavily debated. Here, we show that the modular transcriptional signature in the blood of susceptible mice infected with a clinical isolate of M. tuberculosis resembles that of active human TB disease, with dominance of a type I interferon response and neutrophil activation and recruitment, together with a loss in B lymphocyte, natural killer and T cell effector responses. In addition, resistant but not susceptible strains of mice show increased lung B cell, natural killer and T cell effector responses in the lung upon infection. Notably, the blood signature of active disease shared by mice and humans is also evident in latent TB progressors before diagnosis, suggesting that these responses both predict and contribute to the pathogenesis of progressive M. tuberculosis infection.
Asunto(s)
Transcriptoma/inmunología , Tuberculosis/inmunología , Animales , Linfocitos B/inmunología , Linfocitos B/microbiología , Humanos , Interferón Tipo I/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/microbiología , Pulmón/inmunología , Pulmón/microbiología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Mycobacterium tuberculosis/inmunología , Linfocitos T/inmunología , Linfocitos T/microbiología , Tuberculosis/microbiologíaRESUMEN
Although animal models have been evaluated for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, none have fully recapitulated the lung disease phenotypes seen in humans who have been hospitalized. Here, we evaluate transgenic mice expressing the human angiotensin I-converting enzyme 2 (ACE2) receptor driven by the cytokeratin-18 (K18) gene promoter (K18-hACE2) as a model of SARS-CoV-2 infection. Intranasal inoculation of SARS-CoV-2 in K18-hACE2 mice results in high levels of viral infection in lungs, with spread to other organs. A decline in pulmonary function occurs 4 days after peak viral titer and correlates with infiltration of monocytes, neutrophils and activated T cells. SARS-CoV-2-infected lung tissues show a massively upregulated innate immune response with signatures of nuclear factor-κB-dependent, type I and II interferon signaling, and leukocyte activation pathways. Thus, the K18-hACE2 model of SARS-CoV-2 infection shares many features of severe COVID-19 infection and can be used to define the basis of lung disease and test immune and antiviral-based countermeasures.
Asunto(s)
Betacoronavirus/inmunología , Infecciones por Coronavirus/patología , Inmunidad Innata/inmunología , Peptidil-Dipeptidasa A/genética , Neumonía Viral/patología , Neumonía/patología , Enzima Convertidora de Angiotensina 2 , Animales , COVID-19 , Chlorocebus aethiops , Infecciones por Coronavirus/inmunología , Modelos Animales de Enfermedad , Femenino , Humanos , Interferón Tipo I/inmunología , Interferón gamma/inmunología , Queratina-18/genética , Leucocitos/inmunología , Activación de Linfocitos/inmunología , Masculino , Ratones , Ratones Transgénicos , Monocitos/inmunología , FN-kappa B/inmunología , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Pandemias , Neumonía/genética , Neumonía/virología , Neumonía Viral/inmunología , Regiones Promotoras Genéticas/genética , SARS-CoV-2 , Linfocitos T/inmunología , Células Vero , Replicación Viral/inmunologíaRESUMEN
In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ effector-GNLY (granulysin), CD8+ effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.
Asunto(s)
Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Interferón Tipo I/metabolismo , Neumonía Viral/inmunología , Receptores Inmunológicos/metabolismo , Adolescente , Adulto , Anciano , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación de Linfocitos T/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , COVID-19 , Estudios de Cohortes , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/virología , Femenino , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/inmunología , Proteínas Ligadas a GPI/metabolismo , Humanos , Interferón Tipo I/genética , Interferón Tipo I/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/sangre , Neumonía Viral/diagnóstico , Neumonía Viral/virología , RNA-Seq , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Análisis de la Célula IndividualRESUMEN
A fundamental challenge in immunology is to decipher the principles governing immune responses at the whole-organism scale. Here, using a comparative infection model, we observe immune signal propagation within and between organs to obtain a dynamic map of immune processes at the organism level. We uncover two inter-organ mechanisms of protective immunity mediated by soluble and cellular factors. First, analyzing ligand-receptor connectivity across tissues reveals that type I IFNs trigger a whole-body antiviral state, protecting the host within hours after skin vaccination. Second, combining parabiosis, single-cell analyses, and gene knockouts, we uncover a multi-organ web of tissue-resident memory T cells that functionally adapt to their environment to stop viral spread across the organism. These results have implications for manipulating tissue-resident memory T cells through vaccination and open up new lines of inquiry for the analysis of immune responses at the organism level.
Asunto(s)
Memoria Inmunológica , Interferón Tipo I/inmunología , Virus Vaccinia/fisiología , Vaccinia/inmunología , Vaccinia/prevención & control , Vacunas Virales/inmunología , Administración Cutánea , Animales , Femenino , Perfilación de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , Especificidad de Órganos , Organismos Libres de Patógenos Específicos , Linfocitos T/inmunología , Vacunas Virales/administración & dosificaciónRESUMEN
N6-methyladenosine (m6A) is the most common mRNA modification. Recent studies have revealed that depletion of m6A machinery leads to alterations in the propagation of diverse viruses. These effects were proposed to be mediated through dysregulated methylation of viral RNA. Here we show that following viral infection or stimulation of cells with an inactivated virus, deletion of the m6A 'writer' METTL3 or 'reader' YTHDF2 led to an increase in the induction of interferon-stimulated genes. Consequently, propagation of different viruses was suppressed in an interferon-signaling-dependent manner. Significantly, the mRNA of IFNB, the gene encoding the main cytokine that drives the type I interferon response, was m6A modified and was stabilized following repression of METTL3 or YTHDF2. Furthermore, we show that m6A-mediated regulation of interferon genes was conserved in mice. Together, our findings uncover the role m6A serves as a negative regulator of interferon response by dictating the fast turnover of interferon mRNAs and consequently facilitating viral propagation.
Asunto(s)
Adenosina/análogos & derivados , Interacciones Huésped-Patógeno/genética , Inmunidad Innata/genética , Interferón Tipo I/genética , ARN Mensajero/metabolismo , Adenosina/metabolismo , Animales , Línea Celular Tumoral , Citomegalovirus/inmunología , Modelos Animales de Enfermedad , Femenino , Fibroblastos , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/virología , Interacciones Huésped-Patógeno/inmunología , Humanos , Subtipo H1N1 del Virus de la Influenza A/inmunología , Gripe Humana/inmunología , Gripe Humana/virología , Interferón Tipo I/inmunología , Masculino , Metilación , Metiltransferasas/genética , Metiltransferasas/inmunología , Metiltransferasas/metabolismo , Ratones , Ratones Endogámicos ICR , Ratones Noqueados , Muromegalovirus/inmunología , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/inmunología , Proteínas de Unión al ARN/metabolismoRESUMEN
Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER) signaling adaptor that is essential for the type I interferon response to DNA pathogens. Aberrant activation of STING is linked to the pathology of autoimmune and autoinflammatory diseases. The rate-limiting step for the activation of STING is its translocation from the ER to the ER-Golgi intermediate compartment. Here, we found that deficiency in the Ca2+ sensor stromal interaction molecule 1 (STIM1) caused spontaneous activation of STING and enhanced expression of type I interferons under resting conditions in mice and a patient with combined immunodeficiency. Mechanistically, STIM1 associated with STING to retain it in the ER membrane, and coexpression of full-length STIM1 or a STING-interacting fragment of STIM1 suppressed the function of dominant STING mutants that cause autoinflammatory diseases. Furthermore, deficiency in STIM1 strongly enhanced the expression of type I interferons after viral infection and prevented the lethality of infection with a DNA virus in vivo. This work delineates a STIM1-STING circuit that maintains the resting state of the STING pathway.
Asunto(s)
Interferón Tipo I/inmunología , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Molécula de Interacción Estromal 1/metabolismo , Animales , Preescolar , Chlorocebus aethiops , ADN Viral/inmunología , Modelos Animales de Enfermedad , Retículo Endoplásmico/metabolismo , Fibroblastos , Técnicas de Inactivación de Genes , Células HEK293 , Herpes Simple/inmunología , Herpes Simple/virología , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/inmunología , Humanos , Inmunidad Innata , Células Jurkat , Macrófagos , Masculino , Proteínas de la Membrana/inmunología , Ratones , Ratones Noqueados , Células 3T3 NIH , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Cultivo Primario de Células , Inmunodeficiencia Combinada Grave/sangre , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/inmunología , Molécula de Interacción Estromal 1/genética , Molécula de Interacción Estromal 1/inmunología , Células VeroRESUMEN
Tumor-infiltrating dendritic cells (DCs) assume varied functional states that impact anti-tumor immunity. To delineate the DC states associated with productive anti-tumor T cell immunity, we compared spontaneously regressing and progressing tumors. Tumor-reactive CD8+ T cell responses in Batf3-/- mice lacking type 1 DCs (DC1s) were lost in progressor tumors but preserved in regressor tumors. Transcriptional profiling of intra-tumoral DCs within regressor tumors revealed an activation state of CD11b+ conventional DCs (DC2s) characterized by expression of interferon (IFN)-stimulated genes (ISGs) (ISG+ DCs). ISG+ DC-activated CD8+ T cells ex vivo comparably to DC1. Unlike cross-presenting DC1, ISG+ DCs acquired and presented intact tumor-derived peptide-major histocompatibility complex class I (MHC class I) complexes. Constitutive type I IFN production by regressor tumors drove the ISG+ DC state, and activation of MHC class I-dressed ISG+ DCs by exogenous IFN-ß rescued anti-tumor immunity against progressor tumors in Batf3-/- mice. The ISG+ DC gene signature is detectable in human tumors. Engaging this functional DC state may present an approach for the treatment of human disease.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Interferón Tipo I/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Animales , Antígenos de Neoplasias/inmunología , Antígeno CD11b/inmunología , Reactividad Cruzada , Células Dendríticas/efectos de los fármacos , Interferón beta/administración & dosificación , Interferón beta/farmacología , Ratones , Neoplasias/inmunología , Receptores de Interferón/inmunología , Transducción de Señal/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
Type I interferon (IFN-I) elicits a complex cascade of events in response to microbial infection. Here, we review recent developments illuminating the large number of IFN-I species and describing their unique biologic functions.
Asunto(s)
Infecciones Bacterianas/inmunología , Interferón Tipo I/metabolismo , Virosis/inmunología , Animales , Infecciones Bacterianas/microbiología , Humanos , Interferón Tipo I/química , Interferón Tipo I/inmunología , Receptor de Interferón alfa y beta/metabolismo , Virosis/virologíaRESUMEN
Type 1 interferon (IFN) is a key mediator of organismal responses to pathogens, eliciting prototypical "interferon signature genes" that encode antiviral and inflammatory mediators. For a global view of IFN signatures and regulatory pathways, we performed gene expression and chromatin analyses of the IFN-induced response across a range of immunocyte lineages. These distinguished ISGs by cell-type specificity, kinetics, and sensitivity to tonic IFN and revealed underlying changes in chromatin configuration. We combined 1,398 human and mouse datasets to computationally infer ISG modules and their regulators, validated by genetic analysis in both species. Some ISGs are controlled by Stat1/2 and Irf9 and the ISRE DNA motif, but others appeared dependent on non-canonical factors. This regulatory framework helped to interpret JAK1 blockade pharmacology, different clusters being affected under tonic or IFN-stimulated conditions, and the IFN signatures previously associated with human diseases, revealing unrecognized subtleties in disease footprints, as affected by human ancestry.
Asunto(s)
Redes Reguladoras de Genes , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Animales , Linfocitos T CD4-Positivos/metabolismo , Conjuntos de Datos como Asunto , Humanos , Quinasas Janus/metabolismo , Ratones , Ratones Endogámicos C57BL , Receptor de Interferón alfa y beta/metabolismoRESUMEN
The sensor RIG-I detects double-stranded RNA derived from RNA viruses. Although RIG-I is also known to have a role in the antiviral response to DNA viruses, physiological RNA species recognized by RIG-I during infection with a DNA virus are largely unknown. Using next-generation RNA sequencing (RNAseq), we found that host-derived RNAs, most prominently 5S ribosomal RNA pseudogene 141 (RNA5SP141), bound to RIG-I during infection with herpes simplex virus 1 (HSV-1). Infection with HSV-1 induced relocalization of RNA5SP141 from the nucleus to the cytoplasm, and virus-induced shutoff of host protein synthesis downregulated the abundance of RNA5SP141-interacting proteins, which allowed RNA5SP141 to bind RIG-I and induce the expression of type I interferons. Silencing of RNA5SP141 strongly dampened the antiviral response to HSV-1 and the related virus Epstein-Barr virus (EBV), as well as influenza A virus (IAV). Our findings reveal that antiviral immunity can be triggered by host RNAs that are unshielded following depletion of their respective binding proteins by the virus.
Asunto(s)
Proteína 58 DEAD Box/inmunología , Herpesvirus Humano 1/inmunología , Inmunidad/inmunología , ARN Ribosómico 5S/inmunología , Animales , Células Cultivadas , Chlorocebus aethiops , Proteína 58 DEAD Box/metabolismo , Expresión Génica/inmunología , Células HEK293 , Herpesvirus Humano 1/fisiología , Interacciones Huésped-Patógeno/inmunología , Humanos , Interferón Tipo I/genética , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Ratones Noqueados , Seudogenes/genética , Transporte de ARN/inmunología , ARN Ribosómico 5S/genética , ARN Ribosómico 5S/metabolismo , Receptores Inmunológicos , Células VeroRESUMEN
Innate immune cells adjust to microbial and inflammatory stimuli through a process termed environmental plasticity, which links a given individual stimulus to a unique activated state. Here, we report that activation of human plasmacytoid predendritic cells (pDCs) with a single microbial or cytokine stimulus triggers cell diversification into three stable subpopulations (P1-P3). P1-pDCs (PD-L1+CD80-) displayed a plasmacytoid morphology and specialization for type I interferon production. P3-pDCs (PD-L1-CD80+) adopted a dendritic morphology and adaptive immune functions. P2-pDCs (PD-L1+CD80+) displayed both innate and adaptive functions. Each subpopulation expressed a specific coding- and long-noncoding-RNA signature and was stable after secondary stimulation. P1-pDCs were detected in samples from patients with lupus or psoriasis. pDC diversification was independent of cell divisions or preexisting heterogeneity within steady-state pDCs but was controlled by a TNF autocrine and/or paracrine communication loop. Our findings reveal a novel mechanism for diversity and division of labor in innate immune cells.
Asunto(s)
Citocinas/inmunología , Células Dendríticas/inmunología , Expresión Génica/inmunología , Inmunidad Innata/inmunología , Inmunidad Adaptativa/inmunología , Antígeno B7-1/inmunología , Antígeno B7-1/metabolismo , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/ultraestructura , Perfilación de la Expresión Génica/métodos , Humanos , Interferón Tipo I/genética , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Lupus Eritematoso Sistémico/inmunología , Microscopía Electrónica de Transmisión , Orthomyxoviridae/inmunología , Psoriasis/inmunologíaRESUMEN
Viral infections during pregnancy are a considerable cause of adverse outcomes and birth defects, and the underlying mechanisms are poorly understood. Among those, cytomegalovirus (CMV) infection stands out as the most common intrauterine infection in humans, putatively causing early pregnancy loss. We employed murine CMV as a model to study the consequences of viral infection on pregnancy outcome and fertility maintenance. Even though pregnant mice successfully controlled CMV infection, we observed highly selective, strong infection of corpus luteum (CL) cells in their ovaries. High infection densities indicated complete failure of immune control in CL cells, resulting in progesterone insufficiency and pregnancy loss. An abundance of gap junctions, absence of vasculature, strong type I interferon (IFN) responses, and interaction of innate immune cells fully protected the ovarian follicles from viral infection. Our work provides fundamental insights into the effect of CMV infection on pregnancy loss and mechanisms protecting fertility.