RESUMEN
There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection.
Asunto(s)
Células Epiteliales Alveolares/metabolismo , Enterocitos/metabolismo , Células Caliciformes/metabolismo , Interferón Tipo I/metabolismo , Mucosa Nasal/citología , Peptidil-Dipeptidasa A/genética , Adolescente , Células Epiteliales Alveolares/inmunología , Enzima Convertidora de Angiotensina 2 , Animales , Betacoronavirus/fisiología , COVID-19 , Línea Celular , Células Cultivadas , Niño , Infecciones por Coronavirus/virología , Enterocitos/inmunología , Células Caliciformes/inmunología , Infecciones por VIH/inmunología , Humanos , Gripe Humana/inmunología , Interferón Tipo I/inmunología , Pulmón/citología , Pulmón/patología , Macaca mulatta , Ratones , Mycobacterium tuberculosis , Mucosa Nasal/inmunología , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/virología , Receptores Virales/genética , SARS-CoV-2 , Serina Endopeptidasas/metabolismo , Análisis de la Célula Individual , Tuberculosis/inmunología , Regulación hacia ArribaRESUMEN
The human gut microbiome contains many bacterial strains of the same species ('strain-level variants'). Describing strains in a biologically meaningful way rather than purely taxonomically is an important goal but challenging due to the genetic complexity of strain-level variation. Here, we measured patterns of co-evolution across >7,000 strains spanning the bacterial tree-of-life. Using these patterns as a prior for studying hundreds of gut commensal strains that we isolated, sequenced, and metabolically profiled revealed widespread structure beneath the phylogenetic level of species. Defining strains by their co-evolutionary signatures enabled predicting their metabolic phenotypes and engineering consortia from strain genome content alone. Our findings demonstrate a biologically relevant organization to strain-level variation and motivate a new schema for describing bacterial strains based on their evolutionary history.
RESUMEN
Central to anti-tumor immunity are dendritic cells (DCs), which stimulate long-lived protective T cell responses. Recent studies have demonstrated that DCs can achieve a state of hyperactivation, which is associated with inflammasome activities within living cells. Herein, we report that hyperactive DCs have an enhanced ability to migrate to draining lymph nodes and stimulate potent cytotoxic T lymphocyte (CTL) responses. This enhanced migratory activity is dependent on the chemokine receptor CCR7 and is associated with a unique transcriptional program that is not observed in conventionally activated or pyroptotic DCs. We show that hyperactivating stimuli are uniquely capable of inducing durable CTL-mediated anti-tumor immunity against tumors that are sensitive or resistant to PD-1 inhibition. These protective responses are intrinsic to the cDC1 subset of DCs, depend on the inflammasome-dependent cytokine IL-1ß, and enable tumor lysates to serve as immunogens. If these activities are verified in humans, hyperactive DCs may impact immunotherapy.