ABSTRACT
Antituberculosis drugs, mostly developed over 60 years ago, combined with a poorly effective vaccine, have failed to eradicate tuberculosis. More worryingly, multiresistant strains of Mycobacterium tuberculosis (MTB) are constantly emerging. Innovative strategies are thus urgently needed to improve tuberculosis treatment. Recently, host-directed therapy has emerged as a promising strategy to be used in adjunct with existing or future antibiotics, by improving innate immunity or limiting immunopathology. Here, using high-content imaging, we identified novel 1,2,4-oxadiazole-based compounds, which allow human macrophages to control MTB replication. Genome-wide gene expression analysis revealed that these molecules induced zinc remobilization inside cells, resulting in bacterial zinc intoxication. More importantly, we also demonstrated that, upon treatment with these novel compounds, MTB became even more sensitive to antituberculosis drugs, in vitro and in vivo, in a mouse model of tuberculosis. Manipulation of heavy metal homeostasis holds thus great promise to be exploited to develop host-directed therapeutic interventions.
Subject(s)
Antitubercular Agents , Disease Models, Animal , Macrophages , Mycobacterium tuberculosis , Oxadiazoles , Tuberculosis , Zinc , Animals , Oxadiazoles/pharmacology , Humans , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Mycobacterium tuberculosis/drug effects , Zinc/metabolism , Macrophages/drug effects , Macrophages/metabolism , Mice , Tuberculosis/drug therapy , Mice, Inbred C57BL , Female , Drug SynergismABSTRACT
Humans display remarkable interindividual variation in their immune response to identical challenges. Yet, our understanding of the genetic and epigenetic factors contributing to such variation remains limited. Here we performed in-depth genetic, epigenetic and transcriptional profiling on primary macrophages derived from individuals of European and African ancestry before and after infection with influenza A virus. We show that baseline epigenetic profiles are strongly predictive of the transcriptional response to influenza A virus across individuals. Quantitative trait locus (QTL) mapping revealed highly coordinated genetic effects on gene regulation, with many cis-acting genetic variants impacting concomitantly gene expression and multiple epigenetic marks. These data reveal that ancestry-associated differences in the epigenetic landscape can be genetically controlled, even more than gene expression. Lastly, among QTL variants that colocalized with immune-disease loci, only 7% were gene expression QTL, while the remaining genetic variants impact epigenetic marks, stressing the importance of considering molecular phenotypes beyond gene expression in disease-focused studies.
Subject(s)
Influenza, Human , Humans , Influenza, Human/genetics , Individuality , Quantitative Trait Loci/genetics , Chromosome Mapping , Epigenesis, GeneticABSTRACT
Primary sclerosing cholangitis (PSC) is an immune-mediated disease of the bile ducts that co-occurs with inflammatory bowel disease (IBD) in almost 90% of cases. Colorectal cancer is a major complication of patients with PSC and IBD, and these patients are at a much greater risk compared to patients with IBD without concomitant PSC. Combining flow cytometry, bulk and single-cell transcriptomics, and T and B cell receptor repertoire analysis of right colon tissue from 65 patients with PSC, 108 patients with IBD and 48 healthy individuals we identified a unique adaptive inflammatory transcriptional signature associated with greater risk and shorter time to dysplasia in patients with PSC. This inflammatory signature is characterized by antigen-driven interleukin-17A (IL-17A)+ forkhead box P3 (FOXP3)+ CD4 T cells that express a pathogenic IL-17 signature, as well as an expansion of IgG-secreting plasma cells. These results suggest that the mechanisms that drive the emergence of dysplasia in PSC and IBD are distinct and provide molecular insights that could guide prevention of colorectal cancer in individuals with PSC.
Subject(s)
Cholangitis, Sclerosing , Colorectal Neoplasms , Inflammatory Bowel Diseases , Humans , Cholangitis, Sclerosing/complications , Cholangitis, Sclerosing/pathology , Inflammation/complications , Inflammatory Bowel Diseases/complications , Inflammatory Bowel Diseases/pathology , Colorectal Neoplasms/pathologyABSTRACT
Influenza A virus (IAV) infections are frequent every year and result in a range of disease severity. Here, we wanted to explore the potential contribution of transposable elements (TEs) to the variable human immune response. Transcriptome profiling in monocyte-derived macrophages from 39 individuals following IAV infection revealed significant inter-individual variation in viral load post-infection. Using transposase-accessible chromatin using sequencing (ATAC-seq), we identified a set of TE families with either enhanced or reduced accessibility upon infection. Of the enhanced families, 15 showed high variability between individuals and had distinct epigenetic profiles. Motif analysis showed an association with known immune regulators (e.g., BATFs, FOSs/JUNs, IRFs, STATs, NFkBs, NFYs, and RELs) in stably enriched families and with other factors in variable families, including KRAB-ZNFs. We showed that TEs and host factors regulating TEs were predictive of viral load post-infection. Our findings shed light on the role TEs and KRAB-ZNFs may play in inter-individual variation in immunity.
ABSTRACT
Resident-tissue macrophages (RTMs) arise from embryonic precursors1,2, yet the developmental signals that shape their longevity remain largely unknown. Here we demonstrate in mice genetically deficient in 12-lipoxygenase and 15-lipoxygenase (Alox15-/- mice) that neonatal neutrophil-derived 12-HETE is required for self-renewal and maintenance of alveolar macrophages (AMs) during lung development. Although the seeding and differentiation of AM progenitors remained intact, the absence of 12-HETE led to a significant reduction in AMs in adult lungs and enhanced senescence owing to increased prostaglandin E2 production. A compromised AM compartment resulted in increased susceptibility to acute lung injury induced by lipopolysaccharide and to pulmonary infections with influenza A virus or SARS-CoV-2. Our results highlight the complexity of prenatal RTM programming and reveal their dependency on in trans eicosanoid production by neutrophils for lifelong self-renewal.
Subject(s)
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid , Cell Self Renewal , Macrophages, Alveolar , Neutrophils , Animals , Mice , 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid/metabolism , Acute Lung Injury , Animals, Newborn , Arachidonate 12-Lipoxygenase/deficiency , Arachidonate 15-Lipoxygenase/deficiency , COVID-19 , Influenza A virus , Lipopolysaccharides , Lung/cytology , Lung/virology , Macrophages, Alveolar/cytology , Macrophages, Alveolar/metabolism , Neutrophils/metabolism , Orthomyxoviridae Infections , Prostaglandins E , SARS-CoV-2 , Disease SusceptibilityABSTRACT
There is growing recognition that regionalization of bacterial colonization and immunity along the intestinal tract has an important role in health and disease. Yet, the mechanisms underlying intestinal regionalization and its dysregulation in disease are not well understood. This study found that regional epithelial expression of the transcription factor GATA4 controls bacterial colonization and inflammatory tissue immunity in the proximal small intestine by regulating retinol metabolism and luminal IgA. Furthermore, in mice without jejunal GATA4 expression, the commensal segmented filamentous bacteria promoted pathogenic inflammatory immune responses that disrupted barrier function and increased mortality upon Citrobacter rodentium infection. In celiac disease patients, low GATA4 expression was associated with metabolic alterations, mucosal Actinobacillus, and increased IL-17 immunity. Taken together, these results reveal broad impacts of GATA4-regulated intestinal regionalization on bacterial colonization and tissue immunity, highlighting an elaborate interdependence of intestinal metabolism, immunity, and microbiota in homeostasis and disease.
Subject(s)
Enterobacteriaceae Infections , GATA4 Transcription Factor , Gastrointestinal Microbiome , Intestinal Mucosa , Animals , Humans , Mice , Actinobacillus , Gastrointestinal Microbiome/immunology , GATA4 Transcription Factor/metabolism , Immunity, Mucosal , Interleukin-17/immunology , Interleukin-17/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/microbiology , Intestine, Small , SymbiosisABSTRACT
BACKGROUND: Severe combined immunodeficiency (SCID) comprises rare inherited disorders of immunity that require definitive treatment through hematopoietic cell transplantation (HCT) or gene therapy for survival. Despite successes of allogeneic HCT, many SCID patients experience incomplete immune reconstitution, persistent T-cell lymphopenia, and poor long-term outcomes. OBJECTIVE: We hypothesized that CD4+ T-cell lymphopenia could be associated with a state of T-cell exhaustion in previously transplanted SCID patients. METHODS: We analyzed markers of exhaustion in blood samples from 61 SCID patients at a median of 10.4 years after HCT. RESULTS: Compared to post-HCT SCID patients with normal CD4+ T-cell counts, those with poor T-cell reconstitution showed lower frequency of naive CD45RA+/CCR7+ T cells, recent thymic emigrants, and TCR excision circles. They also had a restricted TCR repertoire, increased expression of inhibitory receptors (PD-1, 2B4, CD160, BTLA, CTLA-4), and increased activation markers (HLA-DR, perforin) on their total and naive CD8+ T cells, suggesting T-cell exhaustion and aberrant activation, respectively. The exhaustion score of CD8+ T cells was inversely correlated with CD4+ T-cell count, recent thymic emigrants, TCR excision circles, and TCR diversity. Exhaustion scores were higher among recipients of unconditioned HCT, especially when further in time from HCT. Patients with fewer CD4+ T cells showed a transcriptional signature of exhaustion. CONCLUSIONS: Recipients of unconditioned HCT for SCID may develop late post-HCT T-cell exhaustion as a result of diminished production of T-lineage cells. Elevated expression of inhibitory receptors on their T cells may be a biomarker of poor long-term T-cell reconstitution.
Subject(s)
Hematopoietic Stem Cell Transplantation , Lymphopenia , Severe Combined Immunodeficiency , Humans , CD8-Positive T-Lymphocytes , T-Cell Exhaustion , Receptors, Antigen, T-CellABSTRACT
A precise biological mechanism by which cadmium acts as a developmental toxicant is unknown but is suggested to include an epigenetic basis. In prior work, we analyzed CpG island methylation levels within gene promoters (n=16,421) in leukocytes collected from mothers and their infants from a pregnancy cohort in Durham County, North Carolina. The CpG methylation levels were examined in relationship to prenatal exposure to cadmium and/or cotinine to identify genes and pathways influenced by in utero exposure. In the present article, we provide an enhanced description of the data collection and processing to facilitate cross-study comparisons. Data are available within the Gene Expression Omnibus database (GSE67976).