RESUMO
Infection with SARS-CoV-2 results in clinical outcomes ranging from silent or benign infection in most individuals to critical pneumonia and death in a few. Genetic studies in patients have established that critical cases can result from inborn errors of TLR3- or TLR7-dependent type I interferon immunity, or from preexisting autoantibodies neutralizing primarily IFN-α and/or IFN-ω. These findings are consistent with virological studies showing that multiple SARS-CoV-2 proteins interfere with pathways of induction of, or response to, type I interferons. They are also congruent with cellular studies and mouse models that found that type I interferons can limit SARS-CoV-2 replication in vitro and in vivo, while their absence or diminution unleashes viral growth. Collectively, these findings point to insufficient type I interferon during the first days of infection as a general mechanism underlying critical COVID-19 pneumonia, with implications for treatment and directions for future research.
Assuntos
COVID-19 , Interferon Tipo I , Camundongos , Humanos , Animais , Interferons/farmacologia , SARS-CoV-2RESUMO
Alphaviruses are emerging and reemerging viruses that cause disease syndromes ranging from incapacitating arthritis to potentially fatal encephalitis. While infection by arthritogenic and encephalitic alphaviruses results in distinct clinical manifestations, both virus groups induce robust innate and adaptive immune responses. However, differences in cellular tropism, type I interferon induction, immune cell recruitment, and B and T cell responses result in differential disease progression and outcome. In this review, we discuss aspects of immune responses that contribute to protective or pathogenic outcomes after alphavirus infection.
Assuntos
Infecções por Alphavirus , Alphavirus , Interferon Tipo I , Infecções por Alphavirus/patologia , Animais , Humanos , Imunidade , TropismoRESUMO
DNA has been known to be a potent immune stimulus for more than half a century. However, the underlying molecular mechanisms of DNA-triggered immune response have remained elusive until recent years. Cyclic GMP-AMP synthase (cGAS) is a major cytoplasmic DNA sensor in various types of cells that detect either invaded foreign DNA or aberrantly located self-DNA. Upon sensing of DNA, cGAS catalyzes the formation of cyclic GMP-AMP (cGAMP), which in turn activates the ER-localized adaptor protein MITA (also named STING) to elicit the innate immune response. The cGAS-MITA axis not only plays a central role in host defense against pathogen-derived DNA but also acts as a cellular stress response pathway by sensing aberrantly located self-DNA, which is linked to the pathogenesis of various human diseases. In this review, we summarize the spatial and temporal mechanisms of host defense to cytoplasmic DNA mediated by the cGAS-MITA axis and discuss the association of malfunctions of this axis with autoimmune and other diseases.
Assuntos
DNA/imunologia , Imunidade Inata , Animais , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Autoimunidade , Biomarcadores , Citoplasma/imunologia , Citoplasma/metabolismo , Suscetibilidade a Doenças , Interações Hospedeiro-Patógeno/imunologia , Humanos , Evasão da Resposta Imune , Interferon Tipo I/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Nucleotidiltransferases/metabolismoRESUMO
Recognition of foreign nucleic acids is the primary mechanism by which a type I interferon-mediated antiviral response is triggered. Given that human cells are replete with DNA and RNA, this evolutionary strategy poses an inherent biological challenge, i.e., the fundamental requirement to reliably differentiate self-nucleic acids from nonself nucleic acids. We suggest that the group of Mendelian inborn errors of immunity referred to as the type I interferonopathies relate to a breakdown of self/nonself discrimination, with the associated mutant genotypes involving molecules playing direct or indirect roles in nucleic acid signaling. This perspective begs the question as to the sources of self-derived nucleic acids that drive an inappropriate immune response. Resolving this question will provide fundamental insights into immune tolerance, antiviral signaling, and complex autoinflammatory disease states. Here we develop these ideas, discussing type I interferonopathies within the broader framework of nucleic acid-driven inflammation.
Assuntos
Antígenos Virais/imunologia , Autoantígenos/imunologia , Doenças do Sistema Imunitário/imunologia , Ácidos Nucleicos/imunologia , Viroses/imunologia , Animais , Humanos , Doenças do Sistema Imunitário/genética , Tolerância Imunológica , Imunidade Inata , Interferon Tipo I/metabolismo , Viroses/genéticaRESUMO
Human T cell leukemia virus type 1 (HTLV-1), also known as human T lymphotropic virus type 1, was the first exogenous human retrovirus discovered. Unlike the distantly related lentivirus HIV-1, HTLV-1 causes disease in only 5-10% of infected people, depending on their ethnic origin. But whereas HIV-1 infection and the consequent diseases can be efficiently contained in most cases by antiretroviral drug treatment, there is no satisfactory treatment for the malignant or inflammatory diseases caused by HTLV-1. The purpose of the present article is to review recent advances in the understanding of the mechanisms by which the virus persists in vivo and causes disabling or fatal diseases.
Assuntos
Infecções por HTLV-I/imunologia , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/fisiologia , Animais , Suscetibilidade a Doenças , Infecções por HTLV-I/complicações , Infecções por HTLV-I/epidemiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade , Imunidade Celular , Interferon Tipo I/metabolismo , Leucemia-Linfoma de Células T do Adulto/etiologia , Leucemia-Linfoma de Células T do Adulto/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Proteínas Virais Reguladoras e Acessórias/genética , Proteínas Virais Reguladoras e Acessórias/imunologia , Proteínas Virais Reguladoras e Acessórias/metabolismo , Latência Viral/imunologiaRESUMO
Flaviviruses such as dengue (DENV), yellow fever (YFV), West Nile (WNV), and Zika (ZIKV) are human pathogens of global significance. In particular, DENV causes the most prevalent mosquito-borne viral diseases in humans, and ZIKV emerged from obscurity into the spotlight in 2016 as the etiologic agent of congenital Zika syndrome. Owing to the recent emergence of ZIKV as a global pandemic threat, the roles of the immune system during ZIKV infections are as yet unclear. In contrast, decades of DENV research implicate a dual role for the immune system in protection against and pathogenesis of DENV infection. As DENV and ZIKV are closely related, knowledge based on DENV studies has been used to prioritize investigation of ZIKV immunity and pathogenesis, and to accelerate ZIKV diagnostic, therapeutic, and vaccine design. This review discusses the following topics related to innate and adaptive immune responses to DENV and ZIKV: the interferon system as the key mechanism of host defense and viral target for immune evasion, antibody-mediated protection versus antibody-dependent enhancement, and T cell-mediated protection versus original T cell antigenic sin. Understanding the mechanisms that regulate the balance between immune-mediated protection and pathogenesis during DENV and ZIKV infections is critical toward development of safe and effective DENV and ZIKV therapeutics and vaccines.
Assuntos
Vírus da Dengue/fisiologia , Dengue/imunologia , Interações Hospedeiro-Patógeno/imunologia , Infecção por Zika virus/imunologia , Zika virus/fisiologia , Imunidade Adaptativa , Animais , Dengue/metabolismo , Dengue/prevenção & controle , Dengue/virologia , Humanos , Imunidade Inata , Interferon Tipo I/metabolismo , Tropismo Viral , Vacinas Virais/imunologia , Infecção por Zika virus/metabolismo , Infecção por Zika virus/prevenção & controle , Infecção por Zika virus/virologiaRESUMO
Protective immune responses to viral infection are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. The existence of these sensors raises fundamental questions about self/nonself discrimination because of the abundance of self-DNA and self-RNA that occupy these same compartments. Recent advances have revealed that enzymes that metabolize or modify endogenous nucleic acids are essential for preventing inappropriate activation of the innate antiviral response. In this review, we discuss rare human diseases caused by dysregulated nucleic acid sensing, focusing primarily on intracellular sensors of nucleic acids. We summarize lessons learned from these disorders, we rationalize the existence of these diseases in the context of evolution, and we propose that this framework may also apply to a number of more common autoimmune diseases for which the underlying genetics and mechanisms are not yet fully understood.
Assuntos
Doenças Autoimunes do Sistema Nervoso/imunologia , Autoimunidade , Lúpus Eritematoso Sistêmico/imunologia , Malformações do Sistema Nervoso/imunologia , Ácidos Nucleicos/imunologia , Viroses/imunologia , Animais , Humanos , Imunidade Inata , Interferon Tipo I/metabolismo , Receptores Toll-Like/metabolismoRESUMO
Microglia are brain-resident macrophages that shape neural circuit development and are implicated in neurodevelopmental diseases. Multiple microglial transcriptional states have been defined, but their functional significance is unclear. Here, we identify a type I interferon (IFN-I)-responsive microglial state in the developing somatosensory cortex (postnatal day 5) that is actively engulfing whole neurons. This population expands during cortical remodeling induced by partial whisker deprivation. Global or microglial-specific loss of the IFN-I receptor resulted in microglia with phagolysosomal dysfunction and an accumulation of neurons with nuclear DNA damage. IFN-I gain of function increased neuronal engulfment by microglia in both mouse and zebrafish and restricted the accumulation of DNA-damaged neurons. Finally, IFN-I deficiency resulted in excess cortical excitatory neurons and tactile hypersensitivity. These data define a role for neuron-engulfing microglia during a critical window of brain development and reveal homeostatic functions of a canonical antiviral signaling pathway in the brain.
Assuntos
Encéfalo , Interferon Tipo I , Microglia , Animais , Camundongos , Interferon Tipo I/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Peixe-Zebra , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimentoRESUMO
Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to immune checkpoint blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING-dependent type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.
Assuntos
Linfócitos T CD8-Positivos , Proteínas de Ligação a DNA , Interferon Tipo I , Proteínas de Membrana , Neoplasias , Transdução de Sinais , Fatores de Transcrição , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Exodesoxirribonucleases/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Mutação , Neoplasias/imunologia , Neoplasias/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Fatores de Transcrição/metabolismo , Masculino , Quimiocinas/genética , Quimiocinas/metabolismoRESUMO
Mycobacterium tuberculosis (Mtb) causes 1.6 million deaths annually. Active tuberculosis correlates with a neutrophil-driven type I interferon (IFN) signature, but the cellular mechanisms underlying tuberculosis pathogenesis remain poorly understood. We found that interstitial macrophages (IMs) and plasmacytoid dendritic cells (pDCs) are dominant producers of type I IFN during Mtb infection in mice and non-human primates, and pDCs localize near human Mtb granulomas. Depletion of pDCs reduces Mtb burdens, implicating pDCs in tuberculosis pathogenesis. During IFN-driven disease, we observe abundant DNA-containing neutrophil extracellular traps (NETs) described to activate pDCs. Cell-type-specific disruption of the type I IFN receptor suggests that IFNs act on IMs to inhibit Mtb control. Single-cell RNA sequencing (scRNA-seq) indicates that type I IFN-responsive cells are defective in their response to IFNγ, a cytokine critical for Mtb control. We propose that pDC-derived type I IFNs act on IMs to permit bacterial replication, driving further neutrophil recruitment and active tuberculosis disease.
Assuntos
Interferon Tipo I , Tuberculose , Humanos , Camundongos , Animais , Macrófagos/microbiologia , Citocinas , Neutrófilos , Células DendríticasRESUMO
Non-small cell lung cancers (NSCLCs) harboring KEAP1 mutations are often resistant to immunotherapy. Here, we show that KEAP1 targets EMSY for ubiquitin-mediated degradation to regulate homologous recombination repair (HRR) and anti-tumor immunity. Loss of KEAP1 in NSCLC induces stabilization of EMSY, producing a BRCAness phenotype, i.e., HRR defects and sensitivity to PARP inhibitors. Defective HRR contributes to a high tumor mutational burden that, in turn, is expected to prompt an innate immune response. Notably, EMSY accumulation suppresses the type I interferon response and impairs innate immune signaling, fostering cancer immune evasion. Activation of the type I interferon response in the tumor microenvironment using a STING agonist results in the engagement of innate and adaptive immune signaling and impairs the growth of KEAP1-mutant tumors. Our results suggest that targeting PARP and STING pathways, individually or in combination, represents a therapeutic strategy in NSCLC patients harboring alterations in KEAP1.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Interferon Tipo I/metabolismo , Neoplasias Pulmonares/imunologia , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Reparo de DNA por Recombinação/genética , Proteínas Repressoras/metabolismo , Evasão Tumoral/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Imunidade Inata/genética , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Mutação , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Transdução de Sinais/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Rare genetic variants in toll-like receptor 7 (TLR7) are known to cause lupus in humans and mice. UNC93B1 is a transmembrane protein that regulates TLR7 localization into endosomes. In the present study, we identify two new variants in UNC93B1 (T314A, located proximally to the TLR7 transmembrane domain, and V117L) in a cohort of east Asian patients with childhood-onset systemic lupus erythematosus. The V117L variant was associated with increased expression of type I interferons and NF-κB-dependent cytokines in patient plasma and immortalized B cells. THP-1 cells expressing the variant UNC93B1 alleles exhibited exaggerated responses to stimulation of TLR7/-8, but not TLR3 or TLR9, which could be inhibited by targeting the downstream signaling molecules, IRAK1/-4. Heterozygous mice expressing the orthologous Unc93b1V117L variant developed a spontaneous lupus-like disease that was more severe in homozygotes and again hyperresponsive to TLR7 stimulation. Together, this work formally identifies genetic variants in UNC93B1 that can predispose to childhood-onset systemic lupus erythematosus.
Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico , Receptor 7 Toll-Like , Lúpus Eritematoso Sistêmico/genética , Humanos , Animais , Receptor 7 Toll-Like/genética , Receptor 7 Toll-Like/metabolismo , Camundongos , Criança , Feminino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Masculino , Idade de Início , Variação Genética , NF-kappa B/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Adolescente , Células THP-1 , Interferon Tipo I/metabolismoRESUMO
The microbiota plays a fundamental role in regulating host immunity. However, the processes involved in the initiation and regulation of immunity to the microbiota remain largely unknown. Here, we show that the skin microbiota promotes the discrete expression of defined endogenous retroviruses (ERVs). Keratinocyte-intrinsic responses to ERVs depended on cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes protein (STING) signaling and promoted the induction of commensal-specific T cells. Inhibition of ERV reverse transcription significantly impacted these responses, resulting in impaired immunity to the microbiota and its associated tissue repair function. Conversely, a lipid-enriched diet primed the skin for heightened ERV- expression in response to commensal colonization, leading to increased immune responses and tissue inflammation. Together, our results support the idea that the host may have co-opted its endogenous virome as a means to communicate with the exogenous microbiota, resulting in a multi-kingdom dialog that controls both tissue homeostasis and inflammation.
Assuntos
Retrovirus Endógenos/fisiologia , Homeostase , Inflamação/microbiologia , Inflamação/patologia , Microbiota , Animais , Bactérias/metabolismo , Cromossomos Bacterianos/genética , Dieta Hiperlipídica , Inflamação/imunologia , Inflamação/virologia , Interferon Tipo I/metabolismo , Queratinócitos/metabolismo , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Nucleotidiltransferases/metabolismo , Retroelementos/genética , Transdução de Sinais , Pele/imunologia , Pele/microbiologia , Linfócitos T/imunologia , Transcrição GênicaRESUMO
Emerging evidence supports that mitochondrial dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis. Here we show that programmed mitochondrial removal, a hallmark of mammalian erythropoiesis, is defective in SLE. Specifically, we demonstrate that during human erythroid cell maturation, a hypoxia-inducible factor (HIF)-mediated metabolic switch is responsible for the activation of the ubiquitin-proteasome system (UPS), which precedes and is necessary for the autophagic removal of mitochondria. A defect in this pathway leads to accumulation of red blood cells (RBCs) carrying mitochondria (Mito+ RBCs) in SLE patients and in correlation with disease activity. Antibody-mediated internalization of Mito+ RBCs induces type I interferon (IFN) production through activation of cGAS in macrophages. Accordingly, SLE patients carrying both Mito+ RBCs and opsonizing antibodies display the highest levels of blood IFN-stimulated gene (ISG) signatures, a distinctive feature of SLE.
Assuntos
Interferon Tipo I/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Mitocôndrias/metabolismo , Células Mieloides/metabolismo , Adolescente , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Criança , Pré-Escolar , Eritroblastos/metabolismo , Eritroblastos/ultraestrutura , Eritrócitos/metabolismo , Eritropoese , Humanos , Mitofagia , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina/metabolismoRESUMO
Emerging evidence indicates a fundamental role for the epigenome in immunity. Here, we mapped the epigenomic and transcriptional landscape of immunity to influenza vaccination in humans at the single-cell level. Vaccination against seasonal influenza induced persistently diminished H3K27ac in monocytes and myeloid dendritic cells (mDCs), which was associated with impaired cytokine responses to Toll-like receptor stimulation. Single-cell ATAC-seq analysis revealed an epigenomically distinct subcluster of monocytes with reduced chromatin accessibility at AP-1-targeted loci after vaccination. Similar effects were observed in response to vaccination with the AS03-adjuvanted H5N1 pandemic influenza vaccine. However, this vaccine also stimulated persistently increased chromatin accessibility at interferon response factor (IRF) loci in monocytes and mDCs. This was associated with elevated expression of antiviral genes and heightened resistance to the unrelated Zika and Dengue viruses. These results demonstrate that vaccination stimulates persistent epigenomic remodeling of the innate immune system and reveal AS03's potential as an epigenetic adjuvant.
Assuntos
Epigenômica , Imunidade/genética , Vacinas contra Influenza/genética , Vacinas contra Influenza/imunologia , Análise de Célula Única , Transcrição Gênica , Vacinação , Adolescente , Adulto , Antibacterianos/farmacologia , Antígenos CD34/metabolismo , Antivirais/farmacologia , Reprogramação Celular , Cromatina/metabolismo , Citocinas/biossíntese , Combinação de Medicamentos , Feminino , Regulação da Expressão Gênica , Histonas/metabolismo , Humanos , Imunidade Inata/genética , Virus da Influenza A Subtipo H5N1/efeitos dos fármacos , Virus da Influenza A Subtipo H5N1/imunologia , Interferon Tipo I/metabolismo , Masculino , Células Mieloides/metabolismo , Polissorbatos/farmacologia , Esqualeno/farmacologia , Receptores Toll-Like/metabolismo , Fator de Transcrição AP-1/metabolismo , Transcriptoma/genética , Adulto Jovem , alfa-Tocoferol/farmacologiaRESUMO
TANK binding kinase 1 (TBK1) regulates IFN-I, NF-κB, and TNF-induced RIPK1-dependent cell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discovered four humans, ages 32, 26, 7, and 8 from three unrelated consanguineous families with homozygous loss-of-function mutations in TBK1. All four patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We demonstrate that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-κB. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD.
Assuntos
Inflamação/enzimologia , Proteínas Serina-Treonina Quinases/deficiência , Fator de Necrose Tumoral alfa/farmacologia , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose , Autoimunidade/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Morte Celular/efeitos dos fármacos , Citocinas/metabolismo , Enzima Desubiquitinante CYLD/metabolismo , Feminino , Células HEK293 , Homozigoto , Humanos , Quinase I-kappa B/metabolismo , Imunofenotipagem , Inflamação/patologia , Interferon Tipo I/metabolismo , Interferon gama/metabolismo , Mutação com Perda de Função/genética , Masculino , Linhagem , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptores de Reconhecimento de Padrão/metabolismo , Receptor 3 Toll-Like/metabolismo , Transcriptoma/genética , Vesiculovirus/efeitos dos fármacos , Vesiculovirus/fisiologiaRESUMO
The tumor microenvironment (TME) influences cancer progression and therapy response. Therefore, understanding what regulates the TME immune compartment is vital. Here we show that microbiota signals program mononuclear phagocytes in the TME toward immunostimulatory monocytes and dendritic cells (DCs). Single-cell RNA sequencing revealed that absence of microbiota skews the TME toward pro-tumorigenic macrophages. Mechanistically, we show that microbiota-derived stimulator of interferon genes (STING) agonists induce type I interferon (IFN-I) production by intratumoral monocytes to regulate macrophage polarization and natural killer (NK) cell-DC crosstalk. Microbiota modulation with a high-fiber diet triggered the intratumoral IFN-I-NK cell-DC axis and improved the efficacy of immune checkpoint blockade (ICB). We validated our findings in individuals with melanoma treated with ICB and showed that the predicted intratumoral IFN-I and immune compositional differences between responder and non-responder individuals can be transferred by fecal microbiota transplantation. Our study uncovers a mechanistic link between the microbiota and the innate TME that can be harnessed to improve cancer therapies.
Assuntos
Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Microbiota , Monócitos/metabolismo , Microambiente Tumoral , Akkermansia/efeitos dos fármacos , Akkermansia/fisiologia , Animais , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Fibras na Dieta/farmacologia , Fosfatos de Dinucleosídeos/administração & dosagem , Fosfatos de Dinucleosídeos/farmacologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunomodulação/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Melanoma/imunologia , Melanoma/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microbiota/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Fagócitos/efeitos dos fármacos , Fagócitos/metabolismo , Transcrição Gênica/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacosRESUMO
Plasmacytoid dendritic cells (pDCs) are the main source of type I interferon (IFN-I) during viral infections. Their other functions are debated, due to a lack of tools to identify and target them in vivo without affecting pDC-like cells and transitional DCs (tDCs), which harbor overlapping phenotypes and transcriptomes but a higher efficacy for T cell activation. In the present report, we present a reporter mouse, pDC-Tom, designed through intersectional genetics based on unique Siglech and Pacsin1 coexpression in pDCs. The pDC-Tom mice specifically tagged pDCs and, on breeding with Zbtb46GFP mice, enabled transcriptomic profiling of all splenic DC types, unraveling diverging activation of pDC-like cells versus tDCs during a viral infection. The pDC-Tom mice also revealed initially similar but later divergent microanatomical relocation of splenic IFN+ versus IFN- pDCs during infection. The mouse models and specific gene modules we report here will be useful to delineate the physiological functions of pDCs versus other DC types.
Assuntos
Células Dendríticas , Interferon Tipo I , Animais , Camundongos , Interferon Tipo I/metabolismo , Perfilação da Expressão Gênica , Fenótipo , TranscriptomaRESUMO
The type I interferon (IFN) response is the body's typical immune defense against viruses. Previous studies linked high expression of genes encoding type I IFNs in the brain's choroid plexus to cognitive decline under virus-free conditions in aging and neurodegeneration. Multiple reports have documented persisting cognitive symptoms following recovery from COVID-19. Cumulative evidence shows that the choroid plexus is one of the brain regions most vulnerable to infection with the coronavirus SARS-CoV-2, and manifests increased expression of genes encoding type I IFNs even in the absence of viral traces within the brain. In this Perspective, we propose that the type I IFN defensive immune response to SARS-CoV-2 infection in the choroid plexus poses a risk to cognitive function if not resolved in a timely manner.
Assuntos
COVID-19 , Interferon Tipo I , Humanos , COVID-19/metabolismo , Interferon Tipo I/metabolismo , SARS-CoV-2/fisiologia , Plexo Corióideo/metabolismo , Cognição , Antivirais/metabolismo , Interferons/metabolismoRESUMO
Trained innate immunity, induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Here, we investigated whether anti-tumor immunity can be enhanced through induction of trained immunity. Pre-treatment of mice with ß-glucan, a fungal-derived prototypical agonist of trained immunity, resulted in diminished tumor growth. The anti-tumor effect of ß-glucan-induced trained immunity was associated with transcriptomic and epigenetic rewiring of granulopoiesis and neutrophil reprogramming toward an anti-tumor phenotype; this process required type I interferon signaling irrespective of adaptive immunity in the host. Adoptive transfer of neutrophils from ß-glucan-trained mice to naive recipients suppressed tumor growth in the latter in a ROS-dependent manner. Moreover, the anti-tumor effect of ß-glucan-induced trained granulopoiesis was transmissible by bone marrow transplantation to recipient naive mice. Our findings identify a novel and therapeutically relevant anti-tumor facet of trained immunity involving appropriate rewiring of granulopoiesis.