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1.
Nat Commun ; 14(1): 6902, 2023 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-37903791

RESUMO

Human preimplantation development involves extensive remodeling of RNA expression and splicing. However, its transcriptome has been compiled using short-read sequencing data, which fails to capture most full-length mRNAs. Here, we generate an isoform-resolved transcriptome of early human development by performing long- and short-read RNA sequencing on 73 embryos spanning the zygote to blastocyst stages. We identify 110,212 unannotated isoforms transcribed from known genes, including highly conserved protein-coding loci and key developmental regulators. We further identify 17,964 isoforms from 5,239 unannotated genes, which are largely non-coding, primate-specific, and highly associated with transposable elements. These isoforms are widely supported by the integration of published multi-omics datasets, including single-cell 8CLC and blastoid studies. Alternative splicing and gene co-expression network analyses further reveal that embryonic genome activation is associated with splicing disruption and transient upregulation of gene modules. Together, these findings show that the human embryo transcriptome is far more complex than currently known, and will act as a valuable resource to empower future studies exploring development.


Assuntos
Desenvolvimento Embrionário , Transcriptoma , Animais , Humanos , Desenvolvimento Embrionário/genética , Zigoto/metabolismo , Perfilação da Expressão Gênica , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Análise de Sequência de RNA , Processamento Alternativo/genética , Blastocisto/metabolismo
2.
Cell Metab ; 34(5): 761-774.e9, 2022 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-35413274

RESUMO

K. pneumoniae sequence type 258 (Kp ST258) is a major cause of healthcare-associated pneumonia. However, it remains unclear how it causes protracted courses of infection in spite of its expression of immunostimulatory lipopolysaccharide, which should activate a brisk inflammatory response and bacterial clearance. We predicted that the metabolic stress induced by the bacteria in the host cells shapes an immune response that tolerates infection. We combined in situ metabolic imaging and transcriptional analyses to demonstrate that Kp ST258 activates host glutaminolysis and fatty acid oxidation. This response creates an oxidant-rich microenvironment conducive to the accumulation of anti-inflammatory myeloid cells. In this setting, metabolically active Kp ST258 elicits a disease-tolerant immune response. The bacteria, in turn, adapt to airway oxidants by upregulating the type VI secretion system, which is highly conserved across ST258 strains worldwide. Thus, much of the global success of Kp ST258 in hospital settings can be explained by the metabolic activity provoked in the host that promotes disease tolerance.


Assuntos
Infecções por Klebsiella , Klebsiella pneumoniae , Humanos , Infecções por Klebsiella/microbiologia , Estresse Fisiológico
3.
Nat Commun ; 12(1): 1399, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658521

RESUMO

Staphylococcus aureus is a prominent human pathogen that readily adapts to host immune defenses. Here, we show that, in contrast to Gram-negative pathogens, S. aureus induces a distinct airway immunometabolic response dominated by the release of the electrophilic metabolite, itaconate. The itaconate synthetic enzyme, IRG1, is activated by host mitochondrial stress, which is induced by staphylococcal glycolysis. Itaconate inhibits S. aureus glycolysis and selects for strains that re-direct carbon flux to fuel extracellular polysaccharide (EPS) synthesis and biofilm formation. Itaconate-adapted strains, as illustrated by S. aureus isolates from chronic airway infection, exhibit decreased glycolytic activity, high EPS production, and proficient biofilm formation even before itaconate stimulation. S. aureus thus adapts to the itaconate-dominated immunometabolic response by producing biofilms, which are associated with chronic infection of the human airway.


Assuntos
Interações Hospedeiro-Patógeno/fisiologia , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/fisiologia , Staphylococcus aureus/patogenicidade , Succinatos/metabolismo , Adulto , Animais , Biofilmes/crescimento & desenvolvimento , Líquido da Lavagem Broncoalveolar , Metabolismo dos Carboidratos , Fibrose Cística/microbiologia , Regulação Bacteriana da Expressão Gênica , Glicólise/efeitos dos fármacos , Glicólise/fisiologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Hidroliases/metabolismo , Camundongos Endogâmicos C57BL , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Escarro/microbiologia , Infecções Estafilocócicas/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/isolamento & purificação , Estresse Fisiológico , Succinatos/farmacologia , Ácido Succínico/metabolismo , Adulto Jovem
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