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1.
J Exp Med ; 218(4)2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33544838

RESUMO

Yellow fever virus (YFV) live attenuated vaccine can, in rare cases, cause life-threatening disease, typically in patients with no previous history of severe viral illness. Autosomal recessive (AR) complete IFNAR1 deficiency was reported in one 12-yr-old patient. Here, we studied seven other previously healthy patients aged 13 to 80 yr with unexplained life-threatening YFV vaccine-associated disease. One 13-yr-old patient had AR complete IFNAR2 deficiency. Three other patients vaccinated at the ages of 47, 57, and 64 yr had high titers of circulating auto-Abs against at least 14 of the 17 individual type I IFNs. These antibodies were recently shown to underlie at least 10% of cases of life-threatening COVID-19 pneumonia. The auto-Abs were neutralizing in vitro, blocking the protective effect of IFN-α2 against YFV vaccine strains. AR IFNAR1 or IFNAR2 deficiency and neutralizing auto-Abs against type I IFNs thus accounted for more than half the cases of life-threatening YFV vaccine-associated disease studied here. Previously healthy subjects could be tested for both predispositions before anti-YFV vaccination.


Assuntos
Anticorpos Neutralizantes/imunologia , Autoanticorpos/imunologia , Doenças Autoimunes , Doenças Genéticas Inatas , Interferon-alfa , Receptor de Interferon alfa e beta , Vacina contra Febre Amarela , Vírus da Febre Amarela , Adolescente , Adulto , Idoso , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , /imunologia , Feminino , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Células HEK293 , Humanos , Interferon-alfa/genética , Interferon-alfa/imunologia , Masculino , Pessoa de Meia-Idade , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/imunologia , /imunologia , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Vacina contra Febre Amarela/efeitos adversos , Vacina contra Febre Amarela/genética , Vacina contra Febre Amarela/imunologia , Vírus da Febre Amarela/genética , Vírus da Febre Amarela/imunologia
2.
Cell ; 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33296702

RESUMO

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.

3.
Science ; 370(6515)2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-32972995

RESUMO

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.


Assuntos
Infecções por Coronavirus/genética , Infecções por Coronavirus/imunologia , Interferon Tipo I/imunologia , Mutação com Perda de Função , Pneumonia Viral/genética , Pneumonia Viral/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Infecções Assintomáticas , Betacoronavirus , Criança , Pré-Escolar , Feminino , Loci Gênicos , Predisposição Genética para Doença , Humanos , Lactente , Fator Regulador 7 de Interferon/deficiência , Fator Regulador 7 de Interferon/genética , Masculino , Pessoa de Meia-Idade , Pandemias , Receptor de Interferon alfa e beta/deficiência , Receptor de Interferon alfa e beta/genética , Receptor 3 Toll-Like/deficiência , Receptor 3 Toll-Like/genética , Adulto Jovem
4.
Science ; 370(6515)2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-32972996

RESUMO

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-ω (IFN-ω) (13 patients), against the 13 types of IFN-α (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.


Assuntos
Autoanticorpos/sangue , Infecções por Coronavirus/imunologia , Interferon Tipo I/imunologia , Interferon alfa-2/imunologia , Pneumonia Viral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , Infecções Assintomáticas , Betacoronavirus , Estudos de Casos e Controles , Estado Terminal , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Pandemias
5.
J Clin Invest ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32960813

RESUMO

Inborn errors of TLR3-dependent IFN-α/ß- and -λ-mediated immunity in the central nervous system (CNS) can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-α/ß and -λ are unknown. We report a child homozygous for a genomic deletion of the entire coding sequence and part of the 3'UTR of the last exon of IFNAR1, who died from HSE at the age of two years. An older cousin died following vaccination against measles, mumps and rubella at 12 months of age, and another 17-year-old cousin homozygous for the same variant has had other, less severe viral illnesses. The encoded IFNAR1 protein is expressed on the cell surface but is truncated and cannot interact with the tyrosine kinase TYK2. The patient's fibroblasts and EBV-B cells did not respond to IFN-α2b or IFN-ß, in terms of STAT1, STAT2 and STAT3 phosphorylation, or the genome-wide induction of IFN-stimulated genes. The patient's fibroblasts were susceptible to viruses, including HSV-1, even in the presence of exogenous IFN-α2b or IFN-ß. HSE is therefore a consequence of inherited complete IFNAR1 deficiency. This viral disease occurred in natural conditions, unlike those previously reported in other patients with IFNAR1 or IFNAR2 deficiency. This experiment of Nature indicates that IFN-α/ß are essential for anti-HSV-1 immunity in the CNS.

6.
Proc Natl Acad Sci U S A ; 117(24): 13626-13636, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32487729

RESUMO

Humans homozygous or hemizygous for variants predicted to cause a loss of function (LoF) of the corresponding protein do not necessarily present with overt clinical phenotypes. We report here 190 autosomal genes with 207 predicted LoF variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups. No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as LoF. Of the 179 remaining variants in 166 genes, only 11 alleles in 11 genes had previously been confirmed experimentally to be LoF. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes). The 41 dispensable olfactory receptor genes displayed a relaxation of selective constraints similar to that observed for other olfactory receptor genes. The 125 dispensable nonolfactory receptor genes also displayed a relaxation of selective constraints consistent with greater redundancy. Sixty-two of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Of the 179 LoF variants, 68 could be tested for two neutrality statistics, and 8 displayed robust signals of positive selection. These latter variants included a known FUT2 variant that confers resistance to intestinal viruses, and an APOL3 variant involved in resistance to parasitic infections. Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted LoF alleles reveals both redundancies and advantages of such deficiencies for human survival.


Assuntos
Genética Humana , Mutação com Perda de Função , Alelos , Apolipoproteínas L/genética , Fucosiltransferases/genética , Variação Genética , Homozigoto , Humanos , Proteínas/genética , Cromossomos Sexuais/genética
8.
J Exp Med ; 217(6)2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32207811

RESUMO

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

9.
J Clin Invest ; 130(6): 3158-3171, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32163377

RESUMO

Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to clinical disease caused by the Bacille Calmette-Guérin (BCG) vaccine and environmental mycobacteria. The known genetic etiologies of MSMD are inborn errors of IFN-γ immunity due to mutations of 15 genes controlling the production of or response to IFN-γ. Since the first MSMD-causing mutations were reported in 1996, biallelic mutations in the genes encoding IFN-γ receptor 1 (IFN-γR1) and IFN-γR2 have been reported in many patients of diverse ancestries. Surprisingly, mutations of the gene encoding the IFN-γ cytokine itself have not been reported, raising the remote possibility that there might be other agonists of the IFN-γ receptor. We describe 2 Lebanese cousins with MSMD, living in Kuwait, who are both homozygous for a small deletion within the IFNG gene (c.354_357del), causing a frameshift that generates a premature stop codon (p.T119Ifs4*). The mutant allele is loss of expression and loss of function. We also show that the patients' herpesvirus Saimiri-immortalized T lymphocytes did not produce IFN-γ, a phenotype that can be rescued by retrotransduction with WT IFNG cDNA. The blood T and NK lymphocytes from these patients also failed to produce and secrete detectable amounts of IFN-γ. Finally, we show that human IFNG has evolved under stronger negative selection than IFNGR1 or IFNGR2, suggesting that it is less tolerant to heterozygous deleterious mutations than IFNGR1 or IFNGR2. This may account for the rarity of patients with autosomal-recessive, complete IFN-γ deficiency relative to patients with complete IFN-γR1 and IFN-γR2 deficiencies.

10.
J Exp Med ; 216(9): 2057-2070, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31270247

RESUMO

Vaccination against measles, mumps, and rubella (MMR) and yellow fever (YF) with live attenuated viruses can rarely cause life-threatening disease. Severe illness by MMR vaccines can be caused by inborn errors of type I and/or III interferon (IFN) immunity (mutations in IFNAR2, STAT1, or STAT2). Adverse reactions to the YF vaccine have remained unexplained. We report two otherwise healthy patients, a 9-yr-old boy in Iran with severe measles vaccine disease at 1 yr and a 14-yr-old girl in Brazil with viscerotropic disease caused by the YF vaccine at 12 yr. The Iranian patient is homozygous and the Brazilian patient compound heterozygous for loss-of-function IFNAR1 variations. Patient-derived fibroblasts are susceptible to viruses, including the YF and measles virus vaccine strains, in the absence or presence of exogenous type I IFN. The patients' fibroblast phenotypes are rescued with WT IFNAR1 Autosomal recessive, complete IFNAR1 deficiency can result in life-threatening complications of vaccination with live attenuated measles and YF viruses in previously healthy individuals.


Assuntos
Padrões de Herança/genética , Vacina contra Sarampo/efeitos adversos , Receptor de Interferon alfa e beta/deficiência , Vacina contra Febre Amarela/efeitos adversos , Adolescente , Alelos , Criança , Feminino , Humanos , Imunidade , Lactente , Interferon Tipo I/metabolismo , Masculino , Vacina contra Sarampo/imunologia , Proteínas Mutantes/metabolismo , Mutação/genética , Linhagem , Receptor de Interferon alfa e beta/genética , Transdução de Sinais , Vacina contra Febre Amarela/imunologia
11.
Proc Natl Acad Sci U S A ; 116(21): 10430-10434, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31068474

RESUMO

The human genetic basis of tuberculosis (TB) has long remained elusive. We recently reported a high level of enrichment in homozygosity for the common TYK2 P1104A variant in a heterogeneous cohort of patients with TB from non-European countries in which TB is endemic. This variant is homozygous in ∼1/600 Europeans and ∼1/5,000 people from other countries outside East Asia and sub-Saharan Africa. We report a study of this variant in the UK Biobank cohort. The frequency of P1104A homozygotes was much higher in patients with TB (6/620, 1%) than in controls (228/114,473, 0.2%), with an odds ratio (OR) adjusted for ancestry of 5.0 [95% confidence interval (CI): 1.96-10.31, P = 2 × 10-3]. Conversely, we did not observe enrichment for P1104A heterozygosity, or for TYK2 I684S or V362F homozygosity or heterozygosity. Moreover, it is unlikely that more than 10% of controls were infected with Mycobacterium tuberculosis, as 97% were of European genetic ancestry, born between 1939 and 1970, and resided in the United Kingdom. Had all of them been infected, the OR for developing TB upon infection would be higher. These findings suggest that homozygosity for TYK2 P1104A may account for ∼1% of TB cases in Europeans.


Assuntos
TYK2 Quinase/genética , Tuberculose/genética , África ao Sul do Saara , Estudos de Casos e Controles , Estudos de Coortes , Extremo Oriente , Feminino , Variação Genética/genética , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/patogenicidade , Razão de Chances , Reino Unido
12.
Sci Immunol ; 3(30)2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30578351

RESUMO

Hundreds of patients with autosomal recessive, complete IL-12p40 or IL-12Rß1 deficiency have been diagnosed over the last 20 years. They typically suffer from invasive mycobacteriosis and, occasionally, from mucocutaneous candidiasis. Susceptibility to these infections is thought to be due to impairments of IL-12-dependent IFN-γ immunity and IL-23-dependent IL-17A/IL-17F immunity, respectively. We report here patients with autosomal recessive, complete IL-12Rß2 or IL-23R deficiency, lacking responses to IL-12 or IL-23 only, all of whom, unexpectedly, display mycobacteriosis without candidiasis. We show that αß T, γδ T, B, NK, ILC1, and ILC2 cells from healthy donors preferentially produce IFN-γ in response to IL-12, whereas NKT cells and MAIT cells preferentially produce IFN-γ in response to IL-23. We also show that the development of IFN-γ-producing CD4+ T cells, including, in particular, mycobacterium-specific TH1* cells (CD45RA-CCR6+), is dependent on both IL-12 and IL-23. Last, we show that IL12RB1, IL12RB2, and IL23R have similar frequencies of deleterious variants in the general population. The comparative rarity of symptomatic patients with IL-12Rß2 or IL-23R deficiency, relative to IL-12Rß1 deficiency, is, therefore, due to lower clinical penetrance. There are fewer symptomatic IL-23R- and IL-12Rß2-deficient than IL-12Rß1-deficient patients, not because these genetic disorders are rarer, but because the isolated absence of IL-12 or IL-23 is, in part, compensated by the other cytokine for the production of IFN-γ, thereby providing some protection against mycobacteria. These experiments of nature show that human IL-12 and IL-23 are both required for optimal IFN-γ-dependent immunity to mycobacteria, both individually and much more so cooperatively.


Assuntos
Imunidade Inata/imunologia , Interferon gama/imunologia , Interleucina-12/imunologia , Interleucina-23/imunologia , Infecções por Mycobacterium não Tuberculosas/imunologia , Mycobacterium/imunologia , Humanos , Interleucina-12/deficiência , Interleucina-12/genética , Interleucina-23/deficiência , Interleucina-23/genética , Linhagem
13.
Nat Commun ; 9(1): 373, 2018 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-29371626

RESUMO

While our knowledge about the roles of microbes and viruses in the ocean has increased tremendously due to recent advances in genomics and metagenomics, research on marine microbial eukaryotes and zooplankton has benefited much less from these new technologies because of their larger genomes, their enormous diversity, and largely unexplored physiologies. Here, we use a metatranscriptomics approach to capture expressed genes in open ocean Tara Oceans stations across four organismal size fractions. The individual sequence reads cluster into 116 million unigenes representing the largest reference collection of eukaryotic transcripts from any single biome. The catalog is used to unveil functions expressed by eukaryotic marine plankton, and to assess their functional biogeography. Almost half of the sequences have no similarity with known proteins, and a great number belong to new gene families with a restricted distribution in the ocean. Overall, the resource provides the foundations for exploring the roles of marine eukaryotes in ocean ecology and biogeochemistry.


Assuntos
Organismos Aquáticos , Eucariotos/genética , Células Eucarióticas/metabolismo , Metagenoma , Filogenia , Zooplâncton/genética , Sequência de Aminoácidos , Animais , Atlas como Assunto , Bactérias/classificação , Bactérias/genética , Biodiversidade , Ecossistema , Eucariotos/classificação , Células Eucarióticas/citologia , Metagenômica/métodos , Oceanos e Mares , Fitoplâncton/classificação , Fitoplâncton/genética , Água do Mar , Vírus/classificação , Vírus/genética , Zooplâncton/classificação
14.
Nat Commun ; 9(1): 310, 2018 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-29358710

RESUMO

Single-celled eukaryotes (protists) are critical players in global biogeochemical cycling of nutrients and energy in the oceans. While their roles as primary producers and grazers are well appreciated, other aspects of their life histories remain obscure due to challenges in culturing and sequencing their natural diversity. Here, we exploit single-cell genomics and metagenomics data from the circumglobal Tara Oceans expedition to analyze the genome content and apparent oceanic distribution of seven prevalent lineages of uncultured heterotrophic stramenopiles. Based on the available data, each sequenced genome or genotype appears to have a specific oceanic distribution, principally correlated with water temperature and depth. The genome content provides hypotheses for specialization in terms of cell motility, food spectra, and trophic stages, including the potential impact on their lifestyles of horizontal gene transfer from prokaryotes. Our results support the idea that prominent heterotrophic marine protists perform diverse functions in ocean ecology.

15.
Sci Rep ; 7: 41498, 2017 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-28128359

RESUMO

Pico-sized eukaryotes play key roles in the functioning of marine ecosystems, but we still have a limited knowledge on their ecology and evolution. The MAST-4 lineage is of particular interest, since it is widespread in surface oceans, presents ecotypic differentiation and has defied culturing efforts so far. Single cell genomics (SCG) are promising tools to retrieve genomic information from these uncultured organisms. However, SCG are based on whole genome amplification, which normally introduces amplification biases that limit the amount of genomic data retrieved from a single cell. Here, we increase the recovery of genomic information from two MAST-4 lineages by co-assembling short reads from multiple Single Amplified Genomes (SAGs) belonging to evolutionary closely related cells. We found that complementary genomic information is retrieved from different SAGs, generating co-assembly that features >74% of genome recovery, against about 20% when assembled individually. Even though this approach is not aimed at generating high-quality draft genomes, it allows accessing to the genomic information of microbes that would otherwise remain unreachable. Since most of the picoeukaryotes still remain uncultured, our work serves as a proof-of-concept that can be applied to other taxa in order to extract genomic data and address new ecological and evolutionary questions.


Assuntos
Eucariotos/genética , Genômica , Oceanos e Mares , Análise de Célula Única , Organismos Aquáticos/genética , Sequência de Bases , Genoma , Filogenia , Ribossomos/metabolismo , Análise de Sequência de DNA
16.
Sci Rep ; 6: 37900, 2016 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-27901108

RESUMO

Bathycoccus is a cosmopolitan green micro-alga belonging to the Mamiellophyceae, a class of picophytoplankton that contains important contributors to oceanic primary production. A single species of Bathycoccus has been described while the existence of two ecotypes has been proposed based on metagenomic data. A genome is available for one strain corresponding to the described phenotype. We report a second genome assembly obtained by a single cell genomics approach corresponding to the second ecotype. The two Bathycoccus genomes are divergent enough to be unambiguously distinguishable in whole DNA metagenomic data although they possess identical sequence of the 18S rRNA gene including in the V9 region. Analysis of 122 global ocean whole DNA metagenome samples from the Tara-Oceans expedition reveals that populations of Bathycoccus that were previously identified by 18S rRNA V9 metabarcodes are only composed of these two genomes. Bathycoccus is relatively abundant and widely distributed in nutrient rich waters. The two genomes rarely co-occur and occupy distinct oceanic niches in particular with respect to depth. Metatranscriptomic data provide evidence for gain or loss of highly expressed genes in some samples, suggesting that the gene repertoire is modulated by environmental conditions.


Assuntos
Clorófitas/genética , Metagenoma/genética , Microalgas/genética , Fitoplâncton/genética , Ecótipo , Genômica/métodos , Metagenômica/métodos , Oceanos e Mares , Filogenia , RNA Ribossômico 18S/genética , Água do Mar , Inquéritos e Questionários
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