Catálogo de publicaciones - revistas

<jats:title>Abstract</jats:title><jats:p>COVID-19, which is caused by infection with SARS-CoV-2, is characterized by lung pathology and extrapulmonary complications<jats:sup>1,2</jats:sup>. Type I interferons (IFNs) have an essential role in the pathogenesis of COVID-19 (refs <jats:sup>3–5</jats:sup>). Although rapid induction of type I IFNs limits virus propagation, a sustained increase in the levels of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome<jats:sup>5–17</jats:sup>. Here we show that the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway, which controls immunity to cytosolic DNA, is a critical driver of aberrant type I IFN responses in COVID-19 (ref. <jats:sup>18</jats:sup>). Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature that is primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS–STING activity was detected in lung samples from patients with COVID-19 with prominent tissue destruction, and was associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, infection with SARS-CoV-2 activates cGAS–STING signalling in endothelial cells through mitochondrial DNA release, which leads to cell death and type I IFN production. In mice, pharmacological inhibition of STING reduces severe lung inflammation induced by SARS-CoV-2 and improves disease outcome. Collectively, our study establishes a mechanistic basis of pathological type I IFN responses in COVID-19 and reveals a principle for the development of host-directed therapeutics.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system underpinned by partially understood genetic risk factors and environmental triggers and their undefined interactions<jats:sup>1,2</jats:sup>. Here we investigated the peripheral immune signatures of 61 monozygotic twin pairs discordant for MS to dissect the influence of genetic predisposition and environmental factors. Using complementary multimodal high-throughput and high-dimensional single-cell technologies in conjunction with data-driven computational tools, we identified an inflammatory shift in a monocyte cluster of twins with MS, coupled with the emergence of a population of IL-2 hyper-responsive transitional naive helper T cells as MS-related immune alterations. By integrating data on the immune profiles of healthy monozygotic and dizygotic twin pairs, we estimated the variance in CD25 expression by helper T cells displaying a naive phenotype to be largely driven by genetic and shared early environmental influences. Nonetheless, the expanding helper T cells of twins with MS, which were also elevated in non-twin patients with MS, emerged independent of the individual genetic makeup. These cells expressed central nervous system-homing receptors, exhibited a dysregulated CD25–IL-2 axis, and their proliferative capacity positively correlated with MS severity. Together, our matched-pair analysis of the extended twin approach allowed us to discern genetically and environmentally determined features of an MS-associated immune signature.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects<jats:sup>1–4</jats:sup>. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action<jats:sup>4,5</jats:sup>; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation<jats:sup>6</jats:sup>. We synthesize a photoactive metformin probe and identify PEN2, a subunit of γ-secretase<jats:sup>7</jats:sup>, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase<jats:sup>8</jats:sup>, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of <jats:italic>PEN2</jats:italic> or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of <jats:italic>Pen2</jats:italic> abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of <jats:italic>Pen2</jats:italic> impairs its glucose-lowering effects. Furthermore, knockdown of <jats:italic>pen-2</jats:italic> in <jats:italic>Caenorhabditis elegans</jats:italic> abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.</jats:p>

<jats:title>Abstract</jats:title><jats:p>Combinations of anti-cancer drugs can overcome resistance and provide new treatments<jats:sup>1,2</jats:sup>. The number of possible drug combinations vastly exceeds what could be tested clinically. Efforts to systematically identify active combinations and the tissues and molecular contexts in which they are most effective could accelerate the development of combination treatments. Here we evaluate the potency and efficacy of 2,025 clinically relevant two-drug combinations, generating a dataset encompassing 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines. We show that synergy between drugs is rare and highly context-dependent, and that combinations of targeted agents are most likely to be synergistic. We incorporate multi-omic molecular features to identify combination biomarkers and specify synergistic drug combinations and their active contexts, including in basal-like breast cancer, and microsatellite-stable or <jats:italic>KRAS</jats:italic>-mutant colon cancer. Our results show that irinotecan and CHEK1 inhibition have synergistic effects in microsatellite-stable or <jats:italic>KRAS</jats:italic>–<jats:italic>TP53</jats:italic> double-mutant colon cancer cells, leading to apoptosis and suppression of tumour xenograft growth. This study identifies clinically relevant effective drug combinations in distinct molecular subpopulations and is a resource to guide rational efforts to develop combinatorial drug treatments.</jats:p>