RESUMEN
The innate immune response is a rapid response to pathogens or danger signals. It is precisely activated not only to efficiently eliminate pathogens but also to avoid excessive inflammation and tissue damage. cis-Regulatory element-associated chromatin architecture shaped by epigenetic factors, which we define as the epiregulome, endows innate immune cells with specialized phenotypes and unique functions by establishing cell-specific gene expression patterns, and it also contributes to resolution of the inflammatory response. In this review, we focus on two aspects: (a) how niche signals during lineage commitment or following infection and pathogenic stress program epiregulomes by regulating gene expression levels, enzymatic activities, or gene-specific targeting of chromatin modifiers and (b) how the programed epiregulomes in turn mediate regulation of gene-specific expression, which contributes to controlling the development of innate cells, or the response to infection and inflammation, in a timely manner. We also discuss the effects of innate immunometabolic rewiring on epiregulomes and speculate on several future challenges to be encountered during the exploration of the master regulators of epiregulomes in innate immunity and inflammation.
Asunto(s)
Inmunidad Innata , Inflamación , Animales , Epigénesis Genética , Humanos , Inmunidad Innata/genética , Inflamación/genéticaRESUMEN
Detection of double-stranded RNAs (dsRNAs) is a central mechanism of innate immune defense in many organisms. We here discuss several families of dsRNA-binding proteins involved in mammalian antiviral innate immunity. These include RIG-I-like receptors, protein kinase R, oligoadenylate synthases, adenosine deaminases acting on RNA, RNA interference systems, and other proteins containing dsRNA-binding domains and helicase domains. Studies suggest that their functions are highly interdependent and that their interdependence could offer keys to understanding the complex regulatory mechanisms for cellular dsRNA homeostasis and antiviral immunity. This review aims to highlight their interconnectivity, as well as their commonalities and differences in their dsRNA recognition mechanisms.
Asunto(s)
Inmunidad Innata/genética , ARN Bicatenario/genética , Virosis/inmunología , 2',5'-Oligoadenilato Sintetasa/metabolismo , Animales , Proteína 58 DEAD Box/metabolismo , Humanos , Inmunomodulación , Mamíferos , Nucleótido Desaminasas/metabolismo , Interferencia de ARN , eIF-2 Quinasa/metabolismoRESUMEN
According to the endosymbiotic theory, most of the DNA of the original bacterial endosymbiont has been lost or transferred to the nucleus, leaving a much smaller (â¼16 kb in mammals), circular molecule that is the present-day mitochondrial DNA (mtDNA). The ability of mtDNA to escape mitochondria and integrate into the nuclear genome was discovered in budding yeast, along with genes that regulate this process. Mitochondria have emerged as key regulators of innate immunity, and it is now recognized that mtDNA released into the cytoplasm, outside of the cell, or into circulation activates multiple innate immune signaling pathways. Here, we first review the mechanisms through which mtDNA is released into the cytoplasm, including several inducible mitochondrial pores and defective mitophagy or autophagy. Next, we cover how the different forms of released mtDNA activate specific innate immune nucleic acid sensors and inflammasomes. Finally, we discuss how intracellular and extracellular mtDNA release, including circulating cell-free mtDNA that promotes systemic inflammation, are implicated in human diseases, bacterial and viral infections, senescence and aging.
Asunto(s)
ADN Mitocondrial , Mitocondrias , Animales , Humanos , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Inmunidad Innata/genética , Envejecimiento/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Mamíferos/genéticaRESUMEN
Cyclic GMP-AMP synthase (cGAS) is an enzyme in human cells that controls an immune response to cytosolic DNA. Upon binding DNA, cGAS synthesizes a nucleotide signal 2'3'-cGAMP that activates STING-dependent downstream immunity. Here, we discover that cGAS-like receptors (cGLRs) constitute a major family of pattern recognition receptors in innate immunity. Building on recent analysis in Drosophila, we identify >3,000 cGLRs present in nearly all metazoan phyla. A forward biochemical screening of 150 animal cGLRs reveals a conserved mechanism of signaling including response to dsDNA and dsRNA ligands and synthesis of isomers of the nucleotide signals cGAMP, c-UMP-AMP, and c-di-AMP. Combining structural biology and in vivo analysis in coral and oyster animals, we explain how synthesis of distinct nucleotide signals enables cells to control discrete cGLR-STING signaling pathways. Our results reveal cGLRs as a widespread family of pattern recognition receptors and establish molecular rules that govern nucleotide signaling in animal immunity.
Asunto(s)
Inmunidad Innata , Nucleotidiltransferasas , Humanos , Animales , Nucleotidiltransferasas/metabolismo , Inmunidad Innata/genética , Transducción de Señal/genética , ADN/metabolismo , Receptores de Reconocimiento de PatronesRESUMEN
SARS-CoV-2 variants of concern (VOCs) emerged during the COVID-19 pandemic. Here, we used unbiased systems approaches to study the host-selective forces driving VOC evolution. We discovered that VOCs evolved convergent strategies to remodel the host by modulating viral RNA and protein levels, altering viral and host protein phosphorylation, and rewiring virus-host protein-protein interactions. Integrative computational analyses revealed that although Alpha, Beta, Gamma, and Delta ultimately converged to suppress interferon-stimulated genes (ISGs), Omicron BA.1 did not. ISG suppression correlated with the expression of viral innate immune antagonist proteins, including Orf6, N, and Orf9b, which we mapped to specific mutations. Later Omicron subvariants BA.4 and BA.5 more potently suppressed innate immunity than early subvariant BA.1, which correlated with Orf6 levels, although muted in BA.4 by a mutation that disrupts the Orf6-nuclear pore interaction. Our findings suggest that SARS-CoV-2 convergent evolution overcame human adaptive and innate immune barriers, laying the groundwork to tackle future pandemics.
Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/virología , Inmunidad Innata/genética , Pandemias , SARS-CoV-2/genéticaRESUMEN
In the decade since the discovery of the innate immune cyclic GMP-AMP synthase (cGAS)-2'3'-cyclic GMP-AMP (cGAMP)-stimulator of interferon genes (STING) pathway, its proper activation and dysregulation have been rapidly implicated in many aspects of human disease. Understanding the biochemical, cellular, and regulatory mechanisms of this pathway is critical to developing therapeutic strategies that either harness it to boost defense or inhibit it to prevent unwanted inflammation. In this review, we first discuss how the second messenger cGAMP is synthesized by cGAS in response to double-stranded DNA and cGAMP's subsequent activation of cell-type-dependent STING signaling cascades with differential physiological consequences. We then review how cGAMP as an immunotransmitter mediates tightly controlled cell-cell communication by being exported from producing cells and imported into responding cells via cell-type-specific transporters. Finally, we review mechanisms by which thecGAS-cGAMP-STING pathway responds to different sources of mislocalized double-stranded DNA in pathogen defense, cancer, and autoimmune diseases.
Asunto(s)
Proteínas de la Membrana , Nucleótidos Cíclicos , ADN/genética , Humanos , Inmunidad Innata/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Nucleótidos Cíclicos/genética , Nucleotidiltransferasas/genéticaRESUMEN
The lymphocyte family has expanded significantly in recent years to include not only the adaptive lymphocytes (T cells, B cells) and NK cells, but also several additional innate lymphoid cell (ILC) types. ILCs lack clonally distributed antigen receptors characteristic of adaptive lymphocytes and instead respond exclusively to signaling via germline-encoded receptors. ILCs resemble T cells more closely than any other leukocyte lineage at the transcriptome level and express many elements of the core T cell transcriptional program, including Notch, Gata3, Tcf7, and Bcl11b. We present our current understanding of the shared and distinct transcriptional regulatory mechanisms involved in the development of adaptive T lymphocytes and closely related ILCs. We discuss the possibility that a core set of transcriptional regulators common to ILCs and T cells establish enhancers that enable implementation of closely aligned effector pathways. Studies of the transcriptional regulation of lymphopoiesis will support the development of novel therapeutic approaches to correct early lymphoid developmental defects and aberrant lymphocyte function.
Asunto(s)
Inmunidad Adaptativa/genética , Linaje de la Célula/genética , Regulación de la Expresión Génica , Inmunidad Innata/genética , Linfocitos/inmunología , Linfocitos/metabolismo , Transcripción Genética , Animales , Diferenciación Celular , Humanos , Linfocitos/citología , Células Progenitoras Linfoides/citología , Células Progenitoras Linfoides/metabolismoRESUMEN
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.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/inmunología , Interferón Tipo I/metabolismo , Neoplasias Pulmonares/inmunología , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Reparación del ADN por Recombinación/genética , Proteínas Represoras/metabolismo , Escape del Tumor/genética , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Femenino , Células HEK293 , Humanos , Inmunidad Innata/genética , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Mutación , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Represoras/genética , Transducción de Señal/genética , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
Asunto(s)
COVID-19/complicaciones , COVID-19/diagnóstico , Convalecencia , Inmunidad Adaptativa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Autoanticuerpos/sangre , Biomarcadores/metabolismo , Proteínas Sanguíneas/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , COVID-19/inmunología , COVID-19/patología , COVID-19/virología , Progresión de la Enfermedad , Femenino , Humanos , Inmunidad Innata/genética , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Factores de Riesgo , SARS-CoV-2/aislamiento & purificación , Transcriptoma , Adulto Joven , Síndrome Post Agudo de COVID-19RESUMEN
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.
Asunto(s)
Epigenómica , Inmunidad/genética , Vacunas contra la Influenza/genética , Vacunas contra la Influenza/inmunología , Análisis de la Célula Individual , Transcripción Genética , Vacunación , Adolescente , Adulto , Antibacterianos/farmacología , Antígenos CD34/metabolismo , Antivirales/farmacología , Reprogramación Celular , Cromatina/metabolismo , Citocinas/biosíntesis , Combinación de Medicamentos , Femenino , Regulación de la Expresión Génica , Histonas/metabolismo , Humanos , Inmunidad Innata/genética , Subtipo H5N1 del Virus de la Influenza A/efectos de los fármacos , Subtipo H5N1 del Virus de la Influenza A/inmunología , Interferón Tipo I/metabolismo , Masculino , Células Mieloides/metabolismo , Polisorbatos/farmacología , Escualeno/farmacología , Receptores Toll-Like/metabolismo , Factor de Transcripción AP-1/metabolismo , Transcriptoma/genética , Adulto Joven , alfa-Tocoferol/farmacologíaRESUMEN
Innate lymphoid cells (ILCs) can quickly switch from a quiescent state to an active state and rapidly produce effector molecules that provide critical early immune protection. How the post-transcriptional machinery processes different stimuli and initiates robust gene expression in ILCs is poorly understood. Here, we show that deletion of the N6-methyladenosine (m6A) writer protein METTL3 has little impact on ILC homeostasis or cytokine-induced ILC1 or ILC3 responses but significantly diminishes ILC2 proliferation, migration and effector cytokine production and results in impaired antihelminth immunity. m6A RNA modification supports an increase in cell size and transcriptional activity in activated ILC2s but not in ILC1s or ILC3s. Among other transcripts, the gene encoding the transcription factor GATA3 is highly m6A methylated in ILC2s. Targeted m6A demethylation destabilizes nascent Gata3 mRNA and abolishes the upregulation of GATA3 and ILC2 activation. Our study suggests a lineage-specific requirement of m6A for ILC2 responses.
Asunto(s)
Inmunidad Innata , Linfocitos , Citocinas/metabolismo , Homeostasis , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Linfocitos/inmunología , ARN/metabolismo , Animales , RatonesRESUMEN
Runx factors are essential for lineage specification of various hematopoietic cells, including T lymphocytes. However, they regulate context-specific genes and occupy distinct genomic regions in different cell types. Here, we show that dynamic Runx binding shifts in mouse early T cell development are mostly not restricted by local chromatin state but regulated by Runx dosage and functional partners. Runx cofactors compete to recruit a limited pool of Runx factors in early T progenitor cells, and a modest increase in Runx protein availability at pre-commitment stages causes premature Runx occupancy at post-commitment binding sites. This increased Runx factor availability results in striking T cell lineage developmental acceleration by selectively activating T cell-identity and innate lymphoid cell programs. These programs are collectively regulated by Runx together with other, Runx-induced transcription factors that co-occupy Runx-target genes and propagate gene network changes.
Asunto(s)
Redes Reguladoras de Genes , Linfocitos T , Ratones , Animales , Linfocitos T/metabolismo , Inmunidad Innata/genética , Linfocitos/metabolismo , Subunidades alfa del Factor de Unión al Sitio Principal/genética , Subunidades alfa del Factor de Unión al Sitio Principal/metabolismo , Diferenciación Celular/genéticaRESUMEN
Innate lymphocytes encompass a diverse array of phenotypic identities with specialized functions. DNA methylation and hydroxymethylation are essential for epigenetic fidelity and fate commitment. The landscapes of these modifications are unknown in innate lymphocytes. Here, we characterized the whole-genome distribution of methyl-CpG and 5-hydroxymethylcytosine (5hmC) in mouse innate lymphoid cell 3 (ILC3), ILC2 and natural killer (NK) cells. We identified differentially methylated regions (DMRs) and differentially hydroxymethylated regions (DHMRs) between ILC and NK cell subsets and correlated them with transcriptional signatures. We associated lineage-determining transcription factors (LDTFs) with demethylation and demonstrated unique patterns of DNA methylation/hydroxymethylation in relationship to open chromatin regions (OCRs), histone modifications and TF-binding sites. We further identified an association between hydroxymethylation and NK cell superenhancers (SEs). Using mice lacking the DNA hydroxymethylase TET2, we showed the requirement for TET2 in optimal production of hallmark cytokines by ILC3s and interleukin-17A (IL-17A) by inflammatory ILC2s. These findings provide a powerful resource for studying innate lymphocyte epigenetic regulation and decode the regulatory logic governing their identity.
Asunto(s)
Metilación de ADN , Inmunidad Innata , Animales , Cromatina/genética , Epigénesis Genética , Inmunidad Innata/genética , Células Asesinas Naturales , Linfocitos , RatonesRESUMEN
Aging is characterized by an increased vulnerability to infection and the development of inflammatory diseases, such as atherosclerosis, frailty, cancer and neurodegeneration. Here, we find that aging is associated with the loss of diurnally rhythmic innate immune responses, including monocyte trafficking from bone marrow to blood, response to lipopolysaccharide and phagocytosis. This decline in homeostatic immune responses was associated with a striking disappearance of circadian gene transcription in aged compared to young tissue macrophages. Chromatin accessibility was significantly greater in young macrophages than in aged macrophages; however, this difference did not explain the loss of rhythmic gene transcription in aged macrophages. Rather, diurnal expression of Kruppel-like factor 4 (Klf4), a transcription factor (TF) well established in regulating cell differentiation and reprogramming, was selectively diminished in aged macrophages. Ablation of Klf4 expression abolished diurnal rhythms in phagocytic activity, recapitulating the effect of aging on macrophage phagocytosis. Examination of individuals harboring genetic variants of KLF4 revealed an association with age-dependent susceptibility to death caused by bacterial infection. Our results indicate that loss of rhythmic Klf4 expression in aged macrophages is associated with disruption of circadian innate immune homeostasis, a mechanism that may underlie age-associated loss of protective immune responses.
Asunto(s)
Relojes Circadianos/genética , Macrófagos/fisiología , Envejecimiento , Animales , Aterosclerosis/genética , Diferenciación Celular/genética , Regulación de la Expresión Génica/genética , Inmunidad Innata/genética , Inflamación/genética , Factor 4 Similar a Kruppel/genética , Factores de Transcripción de Tipo Kruppel/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Monocitos/fisiología , Fagocitosis/genéticaRESUMEN
The mammalian inflammatory response is a rapid and complex physiological reaction to noxious stimuli including microbial pathogens. Although inflammation plays a valuable role in combating infection, its dysregulation often occurs in people and can cause a variety of pathologies, ranging from chronic inflammation, to autoimmunity, to cancer. In recent years, our understanding of both the cellular and molecular networks that regulate inflammation has improved dramatically. Although much of the focus has been on the study of protein regulators of inflammation, recent evidence also points to a critical role for a specific class of noncoding RNAs, called microRNAs (miRNAs), in managing certain features of the inflammatory process. In this review, we discuss recent advances in our understanding of miRNAs and their connection to inflammatory responses. Additionally, we consider the link between perturbations in miRNA levels and the onset of human inflammatory diseases.
Asunto(s)
Inflamación/genética , MicroARNs/genética , Inmunidad Adaptativa/genética , Animales , Autoinmunidad/genética , Enfermedades Transmisibles/genética , Enfermedades Transmisibles/inmunología , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/inmunología , Humanos , Inmunidad Innata/genética , Inflamación/inmunologíaRESUMEN
Dendritic cells (DCs) play a critical role in orchestrating adaptive immune responses due to their unique ability to initiate T cell responses and direct their differentiation into effector lineages. Classical DCs have been divided into two subsets, cDC1 and cDC2, based on phenotypic markers and their distinct abilities to prime CD8 and CD4 T cells. While the transcriptional regulation of the cDC1 subset has been well characterized, cDC2 development and function remain poorly understood. By combining transcriptional and chromatin analyses with genetic reporter expression, we identified two principal cDC2 lineages defined by distinct developmental pathways and transcriptional regulators, including T-bet and RORγt, two key transcription factors known to define innate and adaptive lymphocyte subsets. These novel cDC2 lineages were characterized by distinct metabolic and functional programs. Extending our findings to humans revealed conserved DC heterogeneity and the presence of the newly defined cDC2 subsets in human cancer.
Asunto(s)
Diferenciación Celular/genética , Linaje de la Célula/genética , Heterogeneidad Genética , Neoplasias/inmunología , Inmunidad Adaptativa/genética , Animales , Diferenciación Celular/inmunología , Cromatina/genética , Células Dendríticas/inmunología , Regulación del Desarrollo de la Expresión Génica , Humanos , Inmunidad Innata/genética , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Ratones , Neoplasias/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Transcripción Genética/inmunologíaRESUMEN
Circular RNAs (circRNAs) produced from back-splicing of exons of pre-mRNAs are widely expressed, but current understanding of their functions is limited. These RNAs are stable in general and are thought to have unique structural conformations distinct from their linear RNA cognates. Here, we show that endogenous circRNAs tend to form 16-26 bp imperfect RNA duplexes and act as inhibitors of double-stranded RNA (dsRNA)-activated protein kinase (PKR) related to innate immunity. Upon poly(I:C) stimulation or viral infection, circRNAs are globally degraded by RNase L, a process required for PKR activation in early cellular innate immune responses. Augmented PKR phosphorylation and circRNA reduction are found in peripheral blood mononuclear cells (PBMCs) derived from patients with autoimmune disease systemic lupus erythematosus (SLE). Importantly, overexpression of the dsRNA-containing circRNA in PBMCs or T cells derived from SLE can alleviate the aberrant PKR activation cascade, thus providing a connection between circRNAs and SLE.
Asunto(s)
ARN Circular/metabolismo , ARN Circular/fisiología , eIF-2 Quinasa/metabolismo , Adolescente , Adulto , Enfermedades Autoinmunes/genética , Línea Celular , Endorribonucleasas/metabolismo , Femenino , Humanos , Inmunidad Innata/genética , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/metabolismo , Lupus Eritematoso Sistémico/genética , Persona de Mediana Edad , Fosforilación , ARN/metabolismo , Empalme del ARN/genética , Estabilidad del ARN/fisiología , ARN Circular/genética , ARN Bicatenario/metabolismo , Virosis/metabolismo , eIF-2 Quinasa/inmunologíaRESUMEN
Sub-Saharan Africa currently experiences an unprecedented wave of urbanization, which has important consequences for health and disease patterns. This study aimed to investigate and integrate the immune and metabolic consequences of rural or urban lifestyles and the role of nutritional changes associated with urban living. In a cohort of 323 healthy Tanzanians, urban as compared to rural living was associated with a pro-inflammatory immune phenotype, both at the transcript and protein levels. We identified different food-derived and endogenous circulating metabolites accounting for these differences. Serum from urban dwellers induced reprogramming of innate immune cells with higher tumor necrosis factor production upon microbial re-stimulation in an in vitro model of trained immunity. These data demonstrate important shifts toward an inflammatory phenotype associated with an urban lifestyle and provide new insights into the underlying dietary and metabolic factors, which may affect disease epidemiology in sub-Sahara African countries.
Asunto(s)
Citocinas/sangre , Dieta Saludable , Metabolismo Energético , Inmunidad Innata , Mediadores de Inflamación/sangre , Salud Rural , Salud Urbana , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Citocinas/genética , Metabolismo Energético/genética , Femenino , Humanos , Inmunidad Innata/genética , Masculino , Metaboloma , Persona de Mediana Edad , Estado Nutricional , Valor Nutritivo , Conducta de Reducción del Riesgo , Estaciones del Año , Tanzanía , Transcriptoma , Factor de Necrosis Tumoral alfa/sangre , Urbanización , Adulto JovenRESUMEN
Controlled human infections provide opportunities to study the interaction between the immune system and malaria parasites, which is essential for vaccine development. Here, we compared immune signatures of malaria-naive Europeans and of Africans with lifelong malaria exposure using mass cytometry, RNA sequencing and data integration, before and 5 and 11 days after venous inoculation with Plasmodium falciparum sporozoites. We observed differences in immune cell populations, antigen-specific responses and gene expression profiles between Europeans and Africans and among Africans with differing degrees of immunity. Before inoculation, an activated/differentiated state of both innate and adaptive cells, including elevated CD161+CD4+ T cells and interferon-γ production, predicted Africans capable of controlling parasitemia. After inoculation, the rapidity of the transcriptional response and clusters of CD4+ T cells, plasmacytoid dendritic cells and innate T cells were among the features distinguishing Africans capable of controlling parasitemia from susceptible individuals. These findings can guide the development of a vaccine effective in malaria-endemic regions.
Asunto(s)
Inmunidad Adaptativa/inmunología , Susceptibilidad a Enfermedades/inmunología , Malaria Falciparum/inmunología , Plasmodium falciparum/inmunología , Inmunidad Adaptativa/genética , Adolescente , Adulto , Anticuerpos Antiprotozoarios/sangre , Anticuerpos Antiprotozoarios/inmunología , Antígenos de Protozoos/inmunología , Población Negra/genética , Células Dendríticas/inmunología , Susceptibilidad a Enfermedades/sangre , Susceptibilidad a Enfermedades/parasitología , Femenino , Voluntarios Sanos , Interacciones Huésped-Parásitos/genética , Interacciones Huésped-Parásitos/inmunología , Humanos , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Interferón gamma/metabolismo , Malaria Falciparum/sangre , Malaria Falciparum/parasitología , Masculino , RNA-Seq , Análisis de Sistemas , Linfocitos T/inmunología , Linfocitos T/metabolismo , Población Blanca/genética , Adulto JovenRESUMEN
Cytokine signaling via signal transducer and activator of transcription (STAT) proteins is crucial for optimal antiviral responses of natural killer (NK) cells. However, the pleiotropic effects of both cytokine and STAT signaling preclude the ability to precisely attribute molecular changes to specific cytokine-STAT modules. Here, we employed a multi-omics approach to deconstruct and rebuild the complex interaction of multiple cytokine signaling pathways in NK cells. Proinflammatory cytokines and homeostatic cytokines formed a cooperative axis to commonly regulate global gene expression and to further repress expression induced by type I interferon signaling. These cytokines mediated distinct modes of epigenetic regulation via STAT proteins, and collective signaling best recapitulated global antiviral responses. The most dynamically responsive genes were conserved across humans and mice, which included a cytokine-STAT-induced cross-regulatory program. Thus, an intricate crosstalk exists between cytokine signaling pathways, which governs NK cell responses.