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1.
Cell ; 186(3): 621-645.e33, 2023 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-36736301

RESUMEN

Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/ß-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/ß immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/ß. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/ß-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/ß-dependent antiviral immunity.


Asunto(s)
COVID-19 , Mycobacterium , Niño , Humanos , Interferón gamma , SARS-CoV-2 , Interferón-alfa , Factor 1 Regulador del Interferón
2.
Cell ; 184(14): 3812-3828.e30, 2021 07 08.
Artículo en Inglés | MEDLINE | ID: mdl-34214472

RESUMEN

We study a patient with the human papilloma virus (HPV)-2-driven "tree-man" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4+ T cells. T cell development is barely affected, and T cells respond to CD3 and CD2, but not CD28, costimulation. Although the patients do not display HPV-2- and HPV-4-reactive CD4+ T cells in vitro, they make antibodies specific for both viruses in vivo. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell CD28 co-activation pathway. Surprisingly, human CD28-dependent T cell responses are largely redundant for protective immunity.


Asunto(s)
Antígenos CD28/deficiencia , Patrón de Herencia/genética , Papillomaviridae/fisiología , Piel/virología , Linfocitos T/inmunología , Adulto , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Antígenos CD28/genética , Antígenos CD28/metabolismo , Linfocitos T CD4-Positivos/inmunología , Niño , Endopeptidasas/metabolismo , Femenino , Genes Recesivos , Células HEK293 , Homocigoto , Humanos , Inmunidad Humoral , Memoria Inmunológica , Células Jurkat , Queratinocitos/patología , Masculino , Ratones Endogámicos C57BL , Oncogenes , Papiloma/patología , Papiloma/virología , Linaje , Señales de Clasificación de Proteína , ARN Mensajero/genética , ARN Mensajero/metabolismo
3.
Cell ; 183(7): 1826-1847.e31, 2020 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-33296702

RESUMEN

Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of Mycobacterium-non reactive classic TH1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αß T and non-classic CD4+ αß TH1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8+ αß T, and CD4+ αß TH1∗ cells unable to compensate for this deficit.


Asunto(s)
Inmunidad Adaptativa , Inmunidad Innata , Interferón gamma/inmunología , Mycobacterium/inmunología , Proteínas de Dominio T Box/metabolismo , Secuencia de Aminoácidos , Secuencia de Bases , Linaje de la Célula , Preescolar , Cromatina/metabolismo , Islas de CpG/genética , Metilación de ADN/genética , Células Dendríticas/metabolismo , Epigénesis Genética , Femenino , Homocigoto , Humanos , Mutación INDEL/genética , Lactante , Interferón gamma/metabolismo , Células Asesinas Naturales/citología , Células Asesinas Naturales/metabolismo , Mutación con Pérdida de Función/genética , Masculino , Infecciones por Mycobacterium/genética , Infecciones por Mycobacterium/inmunología , Infecciones por Mycobacterium/microbiología , Linaje , Proteínas de Dominio T Box/química , Proteínas de Dominio T Box/deficiencia , Proteínas de Dominio T Box/genética , Linfocitos T Colaboradores-Inductores/inmunología , Transcriptoma/genética
4.
Brain ; 146(2): 492-506, 2023 02 13.
Artículo en Inglés | MEDLINE | ID: mdl-35943854

RESUMEN

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood-brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood-brain barrier disruption.


Asunto(s)
Sustancia Blanca , Persona de Mediana Edad , Humanos , Anciano , Sustancia Blanca/diagnóstico por imagen , Estudio de Asociación del Genoma Completo/métodos , Encéfalo/diagnóstico por imagen , Metilación de ADN/genética , Imagen por Resonancia Magnética , Epigénesis Genética , Proteína-Arginina N-Metiltransferasas , Proteínas Represoras
5.
Mol Biol Evol ; 37(1): 2-10, 2020 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-31504792

RESUMEN

Recent reports have identified differences in the mutational spectra across human populations. Although some of these reports have been replicated in other cohorts, most have been reported only in the 1000 Genomes Project (1kGP) data. While investigating an intriguing putative population stratification within the Japanese population, we identified a previously unreported batch effect leading to spurious mutation calls in the 1kGP data and to the apparent population stratification. Because the 1kGP data are used extensively, we find that the batch effects also lead to incorrect imputation by leading imputation servers and a small number of suspicious GWAS associations. Lower quality data from the early phases of the 1kGP thus continue to contaminate modern studies in hidden ways. It may be time to retire or upgrade such legacy sequencing data.


Asunto(s)
Proyecto Genoma Humano , Artefactos , Estudio de Asociación del Genoma Completo , Humanos , Japón , Mutación
6.
Circ Res ; 124(4): 553-563, 2019 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-30582441

RESUMEN

RATIONALE: Familial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, nonsyndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease phenotype. Rare genetic variants have been identified as important contributors to the risk of congenital heart disease, but relatively small numbers of TOF cases have been studied to date. OBJECTIVE: We used whole exome sequencing to assess the prevalence of unique, deleterious variants in the largest cohort of nonsyndromic TOF patients reported to date. METHODS AND RESULTS: Eight hundred twenty-nine TOF patients underwent whole exome sequencing. The presence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database and a scaled combined annotation-dependent depletion score of ≥20. The clustering of variants in 2 genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5×10-8) after correction for multiple comparisons. NOTCH1 was most frequently found to harbor unique, deleterious variants. Thirty-one changes were observed in 37 probands (4.5%; 95% CI, 3.2%-6.1%) and included 7 loss-of-function variants 22 missense variants and 2 in-frame indels. Sanger sequencing of the unaffected parents of 7 cases identified 5 de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y, and p.N1875S) were subjected to functional evaluation, and 2 showed a reduction in Jagged1-induced NOTCH signaling. FLT4 variants were found in 2.4% (95% CI, 1.6%-3.8%) of TOF patients, with 21 patients harboring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other candidates, including RYR1, ZFPM1, CAMTA2, DLX6, and PCM1. CONCLUSIONS: The NOTCH1 locus is the most frequent site of genetic variants predisposing to nonsyndromic TOF, followed by FLT4. Together, variants in these genes are found in almost 7% of TOF patients.


Asunto(s)
Exoma , Tasa de Mutación , Tetralogía de Fallot/genética , Autoantígenos/genética , Proteínas de Unión al Calcio/genética , Proteínas de Ciclo Celular/genética , Proteínas de Homeodominio/genética , Humanos , Mutación con Pérdida de Función , Mutación Missense , Proteínas Nucleares/genética , Receptor Notch1/genética , Transactivadores/genética , Factores de Transcripción/genética , Receptor 3 de Factores de Crecimiento Endotelial Vascular/genética
7.
NPJ Genom Med ; 9(1): 8, 2024 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-38326393

RESUMEN

Whole genome sequencing (WGS) at high-depth (30X) allows the accurate discovery of variants in the coding and non-coding DNA regions and helps elucidate the genetic underpinnings of human health and diseases. Yet, due to the prohibitive cost of high-depth WGS, most large-scale genetic association studies use genotyping arrays or high-depth whole exome sequencing (WES). Here we propose a cost-effective method which we call "Whole Exome Genome Sequencing" (WEGS), that combines low-depth WGS and high-depth WES with up to 8 samples pooled and sequenced simultaneously (multiplexed). We experimentally assess the performance of WEGS with four different depth of coverage and sample multiplexing configurations. We show that the optimal WEGS configurations are 1.7-2.0 times cheaper than standard WES (no-plexing), 1.8-2.1 times cheaper than high-depth WGS, reach similar recall and precision rates in detecting coding variants as WES, and capture more population-specific variants in the rest of the genome that are difficult to recover when using genotype imputation methods. We apply WEGS to 862 patients with peripheral artery disease and show that it directly assesses more known disease-associated variants than a typical genotyping array and thousands of non-imputable variants per disease-associated locus.

8.
Cell Rep ; 43(4): 113988, 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38517886

RESUMEN

The basal breast cancer subtype is enriched for triple-negative breast cancer (TNBC) and displays consistent large chromosomal deletions. Here, we characterize evolution and maintenance of chromosome 4p (chr4p) loss in basal breast cancer. Analysis of The Cancer Genome Atlas data shows recurrent deletion of chr4p in basal breast cancer. Phylogenetic analysis of a panel of 23 primary tumor/patient-derived xenograft basal breast cancers reveals early evolution of chr4p deletion. Mechanistically we show that chr4p loss is associated with enhanced proliferation. Gene function studies identify an unknown gene, C4orf19, within chr4p, which suppresses proliferation when overexpressed-a member of the PDCD10-GCKIII kinase module we name PGCKA1. Genome-wide pooled overexpression screens using a barcoded library of human open reading frames identify chromosomal regions, including chr4p, that suppress proliferation when overexpressed in a context-dependent manner, implicating network interactions. Together, these results shed light on the early emergence of complex aneuploid karyotypes involving chr4p and adaptive landscapes shaping breast cancer genomes.


Asunto(s)
Neoplasias de la Mama , Redes Reguladoras de Genes , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Animales , Ratones , Cromosomas Humanos Par 4/genética , Proliferación Celular/genética , Aberraciones Cromosómicas , Línea Celular Tumoral , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología
9.
J Exp Med ; 220(2)2023 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-36515678

RESUMEN

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.


Asunto(s)
Antígenos CD28 , Proteínas de Microfilamentos , Humanos , Antígenos CD28/metabolismo , Proteínas de Microfilamentos/genética , Mutación/genética , Fenotipo , Linfocitos T CD4-Positivos
10.
Nat Med ; 29(4): 950-962, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37069360

RESUMEN

Perivascular space (PVS) burden is an emerging, poorly understood, magnetic resonance imaging marker of cerebral small vessel disease, a leading cause of stroke and dementia. Genome-wide association studies in up to 40,095 participants (18 population-based cohorts, 66.3 ± 8.6 yr, 96.9% European ancestry) revealed 24 genome-wide significant PVS risk loci, mainly in the white matter. These were associated with white matter PVS already in young adults (N = 1,748; 22.1 ± 2.3 yr) and were enriched in early-onset leukodystrophy genes and genes expressed in fetal brain endothelial cells, suggesting early-life mechanisms. In total, 53% of white matter PVS risk loci showed nominally significant associations (27% after multiple-testing correction) in a Japanese population-based cohort (N = 2,862; 68.3 ± 5.3 yr). Mendelian randomization supported causal associations of high blood pressure with basal ganglia and hippocampal PVS, and of basal ganglia PVS and hippocampal PVS with stroke, accounting for blood pressure. Our findings provide insight into the biology of PVS and cerebral small vessel disease, pointing to pathways involving extracellular matrix, membrane transport and developmental processes, and the potential for genetically informed prioritization of drug targets.


Asunto(s)
Enfermedades de los Pequeños Vasos Cerebrales , Accidente Cerebrovascular , Humanos , Células Endoteliales/patología , Estudio de Asociación del Genoma Completo , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/genética , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Imagen por Resonancia Magnética/métodos , Genómica
11.
Genet Epidemiol ; 35(6): 526-35, 2011 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-21769930

RESUMEN

The study of the genetic component of early-onset diseases requires investigation into parental genetic effects, particularly those mediated by the mother who can influence the offspring's risk of disease through the effects of her genes acting directly on the intrauterine milieu or indirectly through maternal-gene child-gene interaction effects. An important source of bias that can arise in feto-maternal association testing is the possibility of confounding due to mating asymmetry (MA). However, there is little information on the levels of MA present in human populations and the impact on maternal association testing. In this study, we developed a novel approach to measuring MA and, using HapMap mate-pairs of European and African descent, carried out a genome-wide investigation and characterization of MA. We further investigated the impact of observed levels of MA on maternal association tests through simulation experiments. For the first time, we showed that non-negligible levels of MA are detected in human populations, such that subtle genotype frequency differences between individuals mating in the population are sufficient to induce spurious maternal genotype associations. Though the underlying mechanisms driving the asymmetry within these populations remain elusive, our findings provide consequential evidence for the occurrence of MA in humans and highlight the importance of controlling for MA in maternal association testing.


Asunto(s)
Estudio de Asociación del Genoma Completo , Epidemiología Molecular/métodos , África , Europa (Continente) , Femenino , Predisposición Genética a la Enfermedad , Genética de Población , Genoma , Genotipo , Proyecto Mapa de Haplotipos , Humanos , Masculino , Modelos Genéticos , Modelos Estadísticos , Tamaño de la Muestra
12.
Acta Neuropathol ; 124(3): 439-47, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22661320

RESUMEN

Pediatric glioblastomas (GBM) including diffuse intrinsic pontine gliomas (DIPG) are devastating brain tumors with no effective therapy. Here, we investigated clinical and biological impacts of histone H3.3 mutations. Forty-two DIPGs were tested for H3.3 mutations. Wild-type versus mutated (K27M-H3.3) subgroups were compared for HIST1H3B, IDH, ATRX and TP53 mutations, copy number alterations and clinical outcome. K27M-H3.3 occurred in 71 %, TP53 mutations in 77 % and ATRX mutations in 9 % of DIPGs. ATRX mutations were more frequent in older children (p < 0.0001). No G34V/R-H3.3, IDH1/2 or H3.1 mutations were identified. K27M-H3.3 DIPGs showed specific copy number changes, including all gains/amplifications of PDGFRA and MYC/PVT1 loci. Notably, all long-term survivors were H3.3 wild type and this group of patients had better overall survival. K27M-H3.3 mutation defines clinically and biologically distinct subgroups and is prevalent in DIPG, which will impact future therapeutic trial design. K27M- and G34V-H3.3 have location-based incidence (brainstem/cortex) and potentially play distinct roles in pediatric GBM pathogenesis. K27M-H3.3 is universally associated with short survival in DIPG, while patients wild-type for H3.3 show improved survival. Based on prognostic and therapeutic implications, our findings argue for H3.3-mutation testing at diagnosis, which should be rapidly integrated into the clinical decision-making algorithm, particularly in atypical DIPG.


Asunto(s)
Neoplasias del Tronco Encefálico/genética , Glioma/genética , Histonas/genética , Puente/patología , Adolescente , Neoplasias del Tronco Encefálico/mortalidad , Neoplasias del Tronco Encefálico/patología , Niño , Preescolar , Femenino , Perfilación de la Expresión Génica , Glioma/mortalidad , Glioma/patología , Humanos , Lactante , Masculino , Mutación , Pronóstico , Tasa de Supervivencia
13.
Sci Adv ; 8(22): eabm2510, 2022 06 03.
Artículo en Inglés | MEDLINE | ID: mdl-35648852

RESUMEN

Despite the availability of highly efficacious vaccines, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lacks effective drug treatment, which results in a high rate of mortality. To address this therapeutic shortcoming, we applied a systems biology approach to the study of patients hospitalized with severe COVID. We show that, at the time of hospital admission, patients who were equivalent on the clinical ordinal scale displayed significant differential monocyte epigenetic and transcriptomic attributes between those who would survive and those who would succumb to COVID-19. We identified messenger RNA metabolism, RNA splicing, and interferon signaling pathways as key host responses overactivated by patients who would not survive. Those pathways are prime drug targets to reduce mortality of critically ill patients with COVID-19, leading us to identify tacrolimus, zotatifin, and nintedanib as three strong candidates for treatment of severely ill patients at the time of hospital admission.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , Antivirales/farmacología , Antivirales/uso terapéutico , Humanos , SARS-CoV-2 , Biología de Sistemas
14.
Cell Genom ; 2(5)2022 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-35720974

RESUMEN

The precisionFDA Truth Challenge V2 aimed to assess the state of the art of variant calling in challenging genomic regions. Starting with FASTQs, 20 challenge participants applied their variant-calling pipelines and submitted 64 variant call sets for one or more sequencing technologies (Illumina, PacBio HiFi, and Oxford Nanopore Technologies). Submissions were evaluated following best practices for benchmarking small variants with updated Genome in a Bottle benchmark sets and genome stratifications. Challenge submissions included numerous innovative methods, with graph-based and machine learning methods scoring best for short-read and long-read datasets, respectively. With machine learning approaches, combining multiple sequencing technologies performed particularly well. Recent developments in sequencing and variant calling have enabled benchmarking variants in challenging genomic regions, paving the way for the identification of previously unknown clinically relevant variants.

15.
Nat Commun ; 12(1): 2627, 2021 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-33976190

RESUMEN

The kidney and upper urinary tract develop through reciprocal interactions between the ureteric bud and the surrounding mesenchyme. Ureteric bud branching forms the arborized collecting duct system of the kidney, while ureteric tips promote nephron formation from dedicated progenitor cells. While nephron progenitor cells are relatively well characterized, the origin of ureteric bud progenitors has received little attention so far. It is well established that the ureteric bud is induced from the nephric duct, an epithelial duct derived from the intermediate mesoderm of the embryo. However, the cell state transitions underlying the progression from intermediate mesoderm to nephric duct and ureteric bud remain unknown. Here we show that nephric duct morphogenesis results from the coordinated organization of four major progenitor cell populations. Using single cell RNA-seq and Cluster RNA-seq, we show that these progenitors emerge in time and space according to a stereotypical pattern. We identify the transcription factors Tfap2a/b and Gata3 as critical coordinators of this progenitor cell progression. This study provides a better understanding of the cellular origin of the renal collecting duct system and associated urinary tract developmental diseases, which may inform guided differentiation of functional kidney tissue.


Asunto(s)
Nefronas/embriología , Organogénesis/genética , Células Madre/fisiología , Animales , Diferenciación Celular/genética , Embrión de Mamíferos , Femenino , Factor de Transcripción GATA3/metabolismo , Regulación del Desarrollo de la Expresión Génica , Masculino , Ratones , Ratones Transgénicos , Modelos Animales , RNA-Seq , Análisis de la Célula Individual , Factor de Transcripción AP-2/metabolismo
16.
Med ; 2(4): 411-422.e5, 2021 04 09.
Artículo en Inglés | MEDLINE | ID: mdl-33521749

RESUMEN

BACKGROUND: Coronavirus disease 2019 (COVID-19) primarily affects the lungs, but evidence of systemic disease with multi-organ involvement is emerging. Here, we developed a blood test to broadly quantify cell-, tissue-, and organ-specific injury due to COVID-19. METHODS: Our test leverages genome-wide methylation profiling of circulating cell-free DNA in plasma. We assessed the utility of this test to identify subjects with severe disease in two independent, longitudinal cohorts of hospitalized patients. Cell-free DNA profiling was performed on 104 plasma samples from 33 COVID-19 patients and compared to samples from patients with other viral infections and healthy controls. FINDINGS: We found evidence of injury to the lung and liver and involvement of red blood cell progenitors associated with severe COVID-19. The concentration of cell-free DNA correlated with the World Health Organization (WHO) ordinal scale for disease progression and was significantly increased in patients requiring intubation. CONCLUSIONS: This study points to the utility of cell-free DNA as an analyte to monitor and study COVID-19. FUNDING: This work was supported by NIH grants 1DP2AI138242 (to I.D.V.), R01AI146165 (to I.D.V., M.P.C., F.M.M., and J.R.), 1R01AI151059 (to I.D.V.), K08-CA230156 (to W.G.), and R33-AI129455 to C.Y.C., a Synergy award from the Rainin Foundation (to I.D.V.), a SARS-CoV-2 seed grant at Cornell (to I.D.V.), a National Sciences and Engineering Research Council of Canada fellowship PGS-D3 (to A.P.C.), and a Burroughs-Wellcome CAMS Award (to W.G.). D.C.V. is supported by a Fonds de la Recherche en Sante du Quebec Clinical Research Scholar Junior 2 award. C.Y.C. is supported by the California Initiative to Advance Precision Medicine, and the Charles and Helen Schwab Foundation.


Asunto(s)
COVID-19 , Ácidos Nucleicos Libres de Células , Virosis , Humanos , Metilación , SARS-CoV-2/genética
17.
Genome Med ; 13(1): 169, 2021 10 28.
Artículo en Inglés | MEDLINE | ID: mdl-34706766

RESUMEN

BACKGROUND: Québec was the Canadian province most impacted by COVID-19, with 401,462 cases as of September 24th, 2021, and 11,347 deaths due mostly to a very severe first pandemic wave. In April 2020, we assembled the Coronavirus Sequencing in Québec (CoVSeQ) consortium to sequence SARS-CoV-2 genomes in Québec to track viral introduction events and transmission within the province. METHODS: Using genomic epidemiology, we investigated the arrival of SARS-CoV-2 to Québec. We report 2921 high-quality SARS-CoV-2 genomes in the context of > 12,000 publicly available genomes sampled globally over the first pandemic wave (up to June 1st, 2020). By combining phylogenetic and phylodynamic analyses with epidemiological data, we quantify the number of introduction events into Québec, identify their origins, and characterize the spatiotemporal spread of the virus. RESULTS: Conservatively, we estimated approximately 600 independent introduction events, the majority of which happened from spring break until 2 weeks after the Canadian border closed for non-essential travel. Subsequent mass repatriations did not generate large transmission lineages (> 50 sequenced cases), likely due to mandatory quarantine measures in place at the time. Consistent with common spring break and "snowbird" destinations, most of the introductions were inferred to have originated from Europe via the Americas. Once introduced into Québec, viral lineage sizes were overdispersed, with a few lineages giving rise to most infections. Consistent with founder effects, the earliest lineages to arrive tended to spread most successfully. Fewer than 100 viral introductions arrived during spring break, of which 7-12 led to the largest transmission lineages of the first wave (accounting for 52-75% of all sequenced infections). These successful transmission lineages dispersed widely across the province. Transmission lineage size was greatly reduced after March 11th, when a quarantine order for returning travellers was enacted. While this suggests the effectiveness of early public health measures, the biggest transmission lineages had already been ignited prior to this order. CONCLUSIONS: Combined, our results reinforce how, in the absence of tight travel restrictions or quarantine measures, fewer than 100 viral introductions in a week can ensure the establishment of extended transmission chains.


Asunto(s)
COVID-19/transmisión , COVID-19/epidemiología , COVID-19/virología , Canadá/epidemiología , Europa (Continente)/epidemiología , Genoma Viral , Humanos , Epidemiología Molecular , Pandemias , Filogenia , Salud Pública , Quebec/epidemiología , SARS-CoV-2/genética , SARS-CoV-2/aislamiento & purificación , Viaje
18.
Nat Med ; 27(9): 1646-1654, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34183838

RESUMEN

The pathophysiology of adverse events following programmed cell death protein 1 (PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly characterized. We studied a patient with inherited PD-1 deficiency and TB who died of pulmonary autoimmunity. The patient's leukocytes did not express PD-1 or respond to PD-1-mediated suppression. The patient's lymphocytes produced only small amounts of interferon (IFN)-γ upon mycobacterial stimuli, similarly to patients with inborn errors of IFN-γ production who are vulnerable to TB. This phenotype resulted from a combined depletion of Vδ2+ γδ T, mucosal-associated invariant T and CD56bright natural killer lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated and RORγT+ CD4-CD8- double-negative αß T cells, similar to patients with STAT3 gain-of-function mutations who display lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts of STAT3-activating cytokines interleukin (IL)-6 and IL-23 produced by activated T lymphocytes and monocytes, and the STAT3-dependent expression of RORγT by activated T lymphocytes. Our work highlights the indispensable role of human PD-1 in governing both antimycobacterial immunity and self-tolerance, while identifying potentially actionable molecular targets for the diagnostic and therapeutic management of TB and autoimmunity in patients on PD-1 blockade.


Asunto(s)
Autoinmunidad/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Receptor de Muerte Celular Programada 1/genética , Factor de Transcripción STAT3/genética , Tuberculosis/inmunología , Autoinmunidad/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Antígeno CD56/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Niño , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/efectos adversos , Interleucina-23/genética , Interleucina-6/genética , Linfocitos Intraepiteliales/inmunología , Linfocitos Intraepiteliales/patología , Masculino , Mycobacterium tuberculosis/patogenicidad , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Neoplasias/mortalidad , Receptor de Muerte Celular Programada 1/deficiencia , Tuberculosis/genética , Tuberculosis/mortalidad
19.
J Clin Invest ; 131(14)2021 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-34043590

RESUMEN

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.


Asunto(s)
COVID-19/genética , COVID-19/inmunología , Interferón Tipo I/genética , Interferón Tipo I/inmunología , Mutación con Pérdida de Función , SARS-CoV-2 , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Factor 7 Regulador del Interferón/genética , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Receptor Toll-Like 3/genética , Secuenciación del Exoma , Secuenciación Completa del Genoma , Adulto Joven
20.
J Clin Invest ; 131(17)2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-34623332

RESUMEN

We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4+ T cells. In naive CD4+ T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient's naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.


Asunto(s)
Genes rel , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunología , Proteínas Proto-Oncogénicas c-rel/deficiencia , Proteínas Proto-Oncogénicas c-rel/genética , Inmunidad Adaptativa/genética , Inmunidad Adaptativa/inmunología , Niño , Consanguinidad , Femenino , Trasplante de Células Madre Hematopoyéticas , Homocigoto , Interacciones Microbiota-Huesped/genética , Interacciones Microbiota-Huesped/inmunología , Humanos , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Activación de Linfocitos , Linfocitos/clasificación , Linfocitos/inmunología , Mutación , Células Mieloides/inmunología , Enfermedades de Inmunodeficiencia Primaria/terapia , Isoformas de Proteínas
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