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1.
Cell ; 186(26): 5876-5891.e20, 2023 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-38134877

RESUMEN

Harmonizing cell types across the single-cell community and assembling them into a common framework is central to building a standardized Human Cell Atlas. Here, we present CellHint, a predictive clustering tree-based tool to resolve cell-type differences in annotation resolution and technical biases across datasets. CellHint accurately quantifies cell-cell transcriptomic similarities and places cell types into a relationship graph that hierarchically defines shared and unique cell subtypes. Application to multiple immune datasets recapitulates expert-curated annotations. CellHint also reveals underexplored relationships between healthy and diseased lung cell states in eight diseases. Furthermore, we present a workflow for fast cross-dataset integration guided by harmonized cell types and cell hierarchy, which uncovers underappreciated cell types in adult human hippocampus. Finally, we apply CellHint to 12 tissues from 38 datasets, providing a deeply curated cross-tissue database with ∼3.7 million cells and various machine learning models for automatic cell annotation across human tissues.


Asunto(s)
Perfilación de la Expresión Génica , Transcriptoma , Humanos , Bases de Datos Factuales , Análisis de la Célula Individual
2.
Nature ; 616(7955): 143-151, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36991123

RESUMEN

The relationship between the human placenta-the extraembryonic organ made by the fetus, and the decidua-the mucosal layer of the uterus, is essential to nurture and protect the fetus during pregnancy. Extravillous trophoblast cells (EVTs) derived from placental villi infiltrate the decidua, transforming the maternal arteries into high-conductance vessels1. Defects in trophoblast invasion and arterial transformation established during early pregnancy underlie common pregnancy disorders such as pre-eclampsia2. Here we have generated a spatially resolved multiomics single-cell atlas of the entire human maternal-fetal interface including the myometrium, which enables us to resolve the full trajectory of trophoblast differentiation. We have used this cellular map to infer the possible transcription factors mediating EVT invasion and show that they are preserved in in vitro models of EVT differentiation from primary trophoblast organoids3,4 and trophoblast stem cells5. We define the transcriptomes of the final cell states of trophoblast invasion: placental bed giant cells (fused multinucleated EVTs) and endovascular EVTs (which form plugs inside the maternal arteries). We predict the cell-cell communication events contributing to trophoblast invasion and placental bed giant cell formation, and model the dual role of interstitial EVTs and endovascular EVTs in mediating arterial transformation during early pregnancy. Together, our data provide a comprehensive analysis of postimplantation trophoblast differentiation that can be used to inform the design of experimental models of the human placenta in early pregnancy.


Asunto(s)
Multiómica , Primer Trimestre del Embarazo , Trofoblastos , Femenino , Humanos , Embarazo , Movimiento Celular , Placenta/irrigación sanguínea , Placenta/citología , Placenta/fisiología , Primer Trimestre del Embarazo/fisiología , Trofoblastos/citología , Trofoblastos/metabolismo , Trofoblastos/fisiología , Decidua/irrigación sanguínea , Decidua/citología , Relaciones Materno-Fetales/fisiología , Análisis de la Célula Individual , Miometrio/citología , Miometrio/fisiología , Diferenciación Celular , Organoides/citología , Organoides/fisiología , Células Madre/citología , Transcriptoma , Factores de Transcripción/metabolismo , Comunicación Celular
3.
Eur J Immunol ; 54(1): e2350633, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37799110

RESUMEN

In COVID-19, hyperinflammatory and dysregulated immune responses contribute to severity. Patients with pre-existing autoimmune conditions can therefore be at increased risk of severe COVID-19 and/or associated sequelae, yet SARS-CoV-2 infection in this group has been little studied. Here, we performed single-cell analysis of peripheral blood mononuclear cells from patients with three major autoimmune diseases (rheumatoid arthritis, psoriasis, or multiple sclerosis) during SARS-CoV-2 infection. We observed compositional differences between the autoimmune disease groups coupled with altered patterns of gene expression, transcription factor activity, and cell-cell communication that substantially shape the immune response under SARS-CoV-2 infection. While enrichment of HLA-DRlow CD14+ monocytes was observed in all three autoimmune disease groups, type-I interferon signaling as well as inflammatory T cell and monocyte responses varied widely between the three groups of patients. Our results reveal disturbed immune responses to SARS-CoV-2 in patients with pre-existing autoimmunity, highlighting important considerations for disease treatment and follow-up.


Asunto(s)
Enfermedades Autoinmunes , COVID-19 , Humanos , SARS-CoV-2 , Leucocitos Mononucleares , Multiómica , Autoinmunidad , Análisis de la Célula Individual
4.
Cancer Discov ; 14(4): 573-578, 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38571432

RESUMEN

SUMMARY: Traditional endpoints such as progression-free survival and overall survival do not fully capture the pharmacologic and pharmacodynamic effects of a therapeutic intervention. Incorporating mechanism-driven biomarkers and validated surrogate proximal endpoints can provide orthogonal readouts of anti-tumor activity and delineate the relative contribution of treatment components on an individual level, highlighting the limitation of solely relying on aggregated readouts from clinical trials to facilitate go/no-go decisions for precision therapies.


Asunto(s)
Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Medicina de Precisión , Biomarcadores , Oncología Médica , Supervivencia sin Progresión
5.
Cell Syst ; 15(5): 425-444.e9, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38703772

RESUMEN

The placenta is a selective maternal-fetal barrier that provides nourishment and protection from infections. However, certain pathogens can attach to and even cross the placenta, causing pregnancy complications with potential lifelong impacts on the child's health. Here, we profiled at the single-cell level the placental responses to three pathogens associated with intrauterine complications-Plasmodium falciparum, Listeria monocytogenes, and Toxoplasma gondii. We found that upon exposure to the pathogens, all placental lineages trigger inflammatory responses that may compromise placental function. Additionally, we characterized the responses of fetal macrophages known as Hofbauer cells (HBCs) to each pathogen and propose that they are the probable niche for T. gondii. Finally, we revealed how P. falciparum adapts to the placental microenvironment by modulating protein export into the host erythrocyte and nutrient uptake pathways. Altogether, we have defined the cellular networks and signaling pathways mediating acute placental inflammatory responses that could contribute to pregnancy complications.


Asunto(s)
Placenta , Análisis de la Célula Individual , Humanos , Femenino , Embarazo , Placenta/microbiología , Placenta/inmunología , Análisis de la Célula Individual/métodos , Plasmodium falciparum , Listeria monocytogenes/patogenicidad , Listeria monocytogenes/fisiología , Toxoplasma/patogenicidad , Macrófagos/microbiología , Macrófagos/inmunología , Macrófagos/metabolismo , Toxoplasmosis/inmunología , Toxoplasmosis/metabolismo , Inflamación
6.
Cancer Discov ; 13(7): 1513-1515, 2023 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-37416990

RESUMEN

SUMMARY: Negrao and colleagues showed that coalterations in three genes-KEAP1, SMARCA4, and CDKN2A- correlated to poor clinical outcomes in patients with KRASG12C-mutated non-small cell lung cancer treated with sotorasib or adagrasib. Their study highlights how pooling high-resolution real-world genomic data with clinical outcomes can potentially facilitate risk-stratified precision therapies. See related article by Negrao et al., p. 1556 (2).


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Proteína 1 Asociada A ECH Tipo Kelch , Neoplasias Pulmonares/genética , Factor 2 Relacionado con NF-E2 , Genómica , Medición de Riesgo , ADN Helicasas , Proteínas Nucleares/genética , Factores de Transcripción
7.
Cell Rep ; 42(11): 113419, 2023 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-37952150

RESUMEN

Plasmodium parasites contribute to one of the highest global infectious disease burdens. To achieve this success, the parasite has evolved a range of specialized subcellular compartments to extensively remodel the host cell for its survival. The information to fully understand these compartments is likely hidden in the so far poorly characterized Plasmodium species spatial proteome. To address this question, we determined the steady-state subcellular location of more than 12,000 parasite proteins across five different species by extensive subcellular fractionation of erythrocytes infected by Plasmodium falciparum, Plasmodium knowlesi, Plasmodium yoelii, Plasmodium berghei, and Plasmodium chabaudi. This comparison of the pan-species spatial proteomes and their expression patterns indicates increasing species-specific proteins associated with the more external compartments, supporting host adaptations and post-transcriptional regulation. The spatial proteome offers comprehensive insight into the different human, simian, and rodent Plasmodium species, establishing a powerful resource for understanding species-specific host adaptation processes in the parasite.


Asunto(s)
Malaria , Proteómica , Humanos , Malaria/parasitología , Proteoma/metabolismo , Plasmodium berghei/metabolismo , Eritrocitos/parasitología
8.
Nat Commun ; 13(1): 4067, 2022 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-35831417

RESUMEN

Plasmodium falciparum has developed extensive mechanisms to evade host immune clearance. Currently, most of our understanding is based on in vitro studies of individual parasite variant surface antigens and how this relates to the processes in vivo is not well-understood. Here, we have used a humanized mouse model to identify parasite factors important for in vivo growth. We show that upregulation of the specific PfEMP1, VAR2CSA, provides the parasite with protection from macrophage phagocytosis and clearance in the humanized mice. Furthermore, parasites adapted to thrive in the humanized mice show reduced NK cell-mediated killing through interaction with the immune inhibitory receptor, LILRB1. Taken together, these findings reveal new insights into the molecular and cellular mechanisms that the parasite utilizes to coordinate immune escape in vivo. Identification and targeting of these specific parasite variant surface antigens crucial for immune evasion provides a unique approach for therapy.


Asunto(s)
Malaria Falciparum , Plasmodium falciparum , Animales , Antígenos de Protozoos , Antígenos de Superficie/metabolismo , Eritrocitos/parasitología , Malaria Falciparum/parasitología , Ratones , Plasmodium falciparum/metabolismo , Proteínas Protozoarias/metabolismo
9.
Nat Genet ; 53(12): 1698-1711, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34857954

RESUMEN

The endometrium, the mucosal lining of the uterus, undergoes dynamic changes throughout the menstrual cycle in response to ovarian hormones. We have generated dense single-cell and spatial reference maps of the human uterus and three-dimensional endometrial organoid cultures. We dissect the signaling pathways that determine cell fate of the epithelial lineages in the lumenal and glandular microenvironments. Our benchmark of the endometrial organoids reveals the pathways and cell states regulating differentiation of the secretory and ciliated lineages both in vivo and in vitro. In vitro downregulation of WNT or NOTCH pathways increases the differentiation efficiency along the secretory and ciliated lineages, respectively. We utilize our cellular maps to deconvolute bulk data from endometrial cancers and endometriotic lesions, illuminating the cell types dominating in each of these disorders. These mechanistic insights provide a platform for future development of treatments for common conditions including endometriosis and endometrial carcinoma.


Asunto(s)
Endometrio/fisiología , Ciclo Menstrual , Diferenciación Celular , Linaje de la Célula , Microambiente Celular , Neoplasias Endometriales/patología , Endometrio/embriología , Endometrio/patología , Femenino , Hormonas Esteroides Gonadales/metabolismo , Humanos , Técnicas In Vitro , Organoides , Receptores Notch/metabolismo , Transducción de Señal , Análisis Espacio-Temporal , Técnicas de Cultivo de Tejidos , Transcriptoma , Útero/patología , Proteínas Wnt/metabolismo
10.
Front Immunol ; 11: 2070, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33013876

RESUMEN

During pregnancy, the placenta forms the anatomical barrier between the mother and developing fetus. Infectious agents can potentially breach the placental barrier resulting in pathogenic transmission from mother to fetus. Innate immune responses, orchestrated by maternal and fetal cells at the decidual-placental interface, are the first line of defense to avoid vertical transmission. Here, we outline the anatomy of the human placenta and uterine lining, the decidua, and discuss the potential capacity of pathogen pattern recognition and other host defense strategies present in the innate immune cells at the placental-decidual interface. We consider major congenital infections that access the placenta from hematogenous or decidual route. Finally, we highlight the challenges in studying human placental responses to pathogens and vertical transmission using current experimental models and identify gaps in knowledge that need to be addressed. We further propose novel experimental strategies to address such limitations.


Asunto(s)
Decidua/inmunología , Infecciones/inmunología , Placenta/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunidad Innata , Transmisión Vertical de Enfermedad Infecciosa , Embarazo
11.
Commun Biol ; 3(1): 351, 2020 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-32620892

RESUMEN

The genomes of Plasmodium spp. encode a number of different multigene families that are thought to play a critical role for survival. However, with the exception of the P. falciparum var genes, very little is known about the biological roles of any of the other multigene families. Using the recently developed Selection Linked Integration method, we have been able to activate the expression of a single member of a multigene family of our choice in Plasmodium spp. from its endogenous promoter. We demonstrate the usefulness of this approach by activating the expression of a unique var, rifin and stevor in P. falciparum as well as yir in P. yoelii. Characterization of the selected parasites reveals differences between the different families in terms of mutual exclusive control, co-regulation, and host adaptation. Our results further support the application of the approach for the study of multigene families in Plasmodium and other organisms.


Asunto(s)
Eritrocitos/metabolismo , Regulación de la Expresión Génica , Malaria Falciparum/genética , Familia de Multigenes , Plasmodium falciparum/genética , Proteínas Protozoarias/metabolismo , Animales , Eritrocitos/parasitología , Humanos , Malaria Falciparum/parasitología , Ratones , Proteínas Protozoarias/genética
12.
EBioMedicine ; 48: 442-452, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31521613

RESUMEN

BACKGROUND: The transcriptome of Plasmodium falciparum clinical isolates varies according to strain, mosquito bites, disease severity and clinical history. Therefore, it remains a challenge to directly interpret the parasite's transcriptomic information into a more general biological signature in a natural human malaria infection. These confounding variations can be potentially overcome with parasites derived from controlled-human malaria infection (CHMI) studies. METHODS: We performed CHMI studies in healthy and immunologically naïve volunteers receiving the same P. falciparum strain ((Sanaria® PfSPZ Challenge (NF54)), but with different sporozoite dosage and route of infection. Parasites isolated from these volunteers at the day of patency were subjected to in vitro culture for several generations and synchronized ring-stage parasites were subjected to transcriptome profiling. FINDINGS: We observed clear deviations between CHMI-derived parasites from volunteer groups receiving different PfSPZ dose and route. CHMI-derived parasites and the pre-mosquito strain used for PfSPZ generation showed significant transcriptional variability for gene clusters associated with malaria pathogenesis, immune evasion and transmission. These transcriptional variation signature clusters were also observed in the transcriptome of P. falciparum isolates from acute clinical infections. INTERPRETATION: Our work identifies a previously unrecognized transcriptional pattern in malaria infections in a non-immune background. Significant transcriptome heterogeneity exits between parasites derived from human infections and the pre-mosquito strain, implying that the malaria parasites undergo a change in functional state to adapt to its host environment. Our work also highlights the potential use of transcriptomics data from CHMI study advance our understanding of malaria parasite adaptation and transmission in humans. FUND: This work is supported by German Israeli Foundation, German ministry for education and research, MOE Tier 1 from the Singapore Ministry of Education Academic Research Fund, Singapore Ministry of Health's National Medical Research Council, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA and the German Centre for Infection Research (Deutsches Zentrum für Infektionsforschung-DZIF).


Asunto(s)
Perfilación de la Expresión Génica , Malaria Falciparum/parasitología , Plasmodium falciparum/genética , Transcriptoma , Interacciones Huésped-Parásitos , Humanos , Carga de Parásitos
13.
Cell Host Microbe ; 23(3): 407-420.e8, 2018 03 14.
Artículo en Inglés | MEDLINE | ID: mdl-29503181

RESUMEN

Heterochromatin-dependent gene silencing is central to the adaptation and survival of Plasmodium falciparum malaria parasites, allowing clonally variant gene expression during blood infection in humans. By assessing genome-wide heterochromatin protein 1 (HP1) occupancy, we present a comprehensive analysis of heterochromatin landscapes across different Plasmodium species, strains, and life cycle stages. Common targets of epigenetic silencing include fast-evolving multi-gene families encoding surface antigens and a small set of conserved HP1-associated genes with regulatory potential. Many P. falciparum heterochromatic genes are marked in a strain-specific manner, increasing the parasite's adaptive capacity. Whereas heterochromatin is strictly maintained during mitotic proliferation of asexual blood stage parasites, substantial heterochromatin reorganization occurs in differentiating gametocytes and appears crucial for the activation of key gametocyte-specific genes and adaptation of erythrocyte remodeling machinery. Collectively, these findings provide a catalog of heterochromatic genes and reveal conserved and specialized features of epigenetic control across the genus Plasmodium.


Asunto(s)
Proteínas Cromosómicas no Histona/genética , Proteínas Cromosómicas no Histona/metabolismo , Epigénesis Genética/genética , Epigenómica , Perfilación de la Expresión Génica , Heterocromatina/genética , Plasmodium/genética , Plasmodium/fisiología , Adaptación Fisiológica/genética , Adaptación Fisiológica/fisiología , Animales , Variación Antigénica/genética , Antígenos de Protozoos/genética , Proliferación Celular , Homólogo de la Proteína Chromobox 5 , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Silenciador del Gen , Interacciones Huésped-Parásitos/genética , Interacciones Huésped-Parásitos/fisiología , Humanos , Estadios del Ciclo de Vida/genética , Estadios del Ciclo de Vida/fisiología , Malaria Falciparum/parasitología , Ratones , Ratones Endogámicos BALB C , Parásitos/genética , Filogenia , Plasmodium/clasificación , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Diferenciación Sexual
15.
EBioMedicine ; 7: 255-66, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-27322479

RESUMEN

The genome sequence available for different Plasmodium species is a valuable resource for understanding malaria parasite biology. However, comparative genomics on its own cannot fully explain all the species-specific differences which suggests that other genomic aspects such as regulation of gene expression play an important role in defining species-specific characteristics. Here, we developed a comprehensive approach to measure transcriptional changes of the evolutionary conserved syntenic orthologs during the intraerythrocytic developmental cycle across six Plasmodium species. We show significant transcriptional constraint at the mid-developmental stage of Plasmodium species while the earliest stages of parasite development display the greatest transcriptional variation associated with critical functional processes. Modeling of the evolutionary relationship based on changes in transcriptional profile reveal a phylogeny pattern of the Plasmodium species that strictly follows its mammalian hosts. In addition, the work shows that transcriptional conserved orthologs represent potential future targets for anti-malaria intervention as they would be expected to carry out key essential functions within the parasites. This work provides an integrated analysis of orthologous transcriptome, which aims to provide insights into the Plasmodium evolution thereby establishing a framework to explore complex pathways and drug discovery in Plasmodium species with broad host range.


Asunto(s)
Biología Computacional/métodos , Perfilación de la Expresión Génica/métodos , Malaria/veterinaria , Plasmodium/genética , Animales , Evolución Molecular , Regulación del Desarrollo de la Expresión Génica , Especificidad del Huésped , Malaria/parasitología , Ratones , Filogenia , Plasmodium/clasificación , Plasmodium/fisiología , Especificidad de la Especie , Sintenía
16.
PLoS One ; 9(12): e115243, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25501560

RESUMEN

Polysaccharide (PS) capsules are important virulence determinants for many bacterial pathogens. Bordetella pertussis, the agent of whooping cough, produces a surface associated microcapsule but its role in pertussis pathogenesis remained unknown. Here we showed that the B. pertussis capsule locus is expressed in vivo in murine lungs and that absence of the membrane-associated protein KpsT, involved in the transport of the PS polymers across the envelope, but not the surface-exposed PS capsule itself, affects drastically B. pertussis colonization efficacy in mice. Microarray analysis revealed that absence of KpsT in B. pertussis resulted in global down-regulation of gene expression including key virulence genes regulated by BvgA/S, the master two-component system. Using a BvgS phase-locked mutant, we demonstrated a functional link between KpsT and BvgA/S-mediated signal transduction. Whereas pull-down assays do not support physical interaction between BvgS sensor and any of the capsule locus encoded proteins, absence of KpsT impaired BvgS oligomerization, necessary for BvgS function. Furthermore, complementation studies indicated that instead of KpsT alone, the entire PS capsule transport machinery spanning the cell envelope likely plays a role in BvgS-mediated signal transduction. Our work thus provides the first experimental evidence of a role for a virulence-repressed gene in pertussis pathogenesis.


Asunto(s)
Cápsulas Bacterianas/metabolismo , Bordetella pertussis/patogenicidad , Polisacáridos Bacterianos/metabolismo , Factores de Virulencia de Bordetella/metabolismo , Tos Ferina/microbiología , Animales , Cápsulas Bacterianas/genética , Cápsulas Bacterianas/patología , Bordetella pertussis/genética , Bordetella pertussis/metabolismo , Regulación hacia Abajo , Femenino , Regulación Bacteriana de la Expresión Génica , Ratones , Ratones Endogámicos BALB C , Polisacáridos Bacterianos/genética , Transducción de Señal , Factores de Virulencia de Bordetella/genética , Tos Ferina/patología
17.
Microbes Infect ; 12(3): 238-45, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20005302

RESUMEN

Polysaccharide capsules contribute to the pathogenesis of many bacteria species by providing resistance against various defense mechanisms. The production of a capsule in Bordetella pertussis, the etiologic agent of whooping cough, has remained controversial; earlier studies reported this pathogen as a capsulated microorganism whereas the recent B. pertussis genome analysis revealed the presence of a truncated capsule locus. In this work, using transmission electron microscopy and immunostaining approaches, we provide a formal evidence for the presence of an intact microcapsule produced at the surface of both laboratory strain and clinical isolates of B. pertussis. In agreement with previous studies, we found that the capsule is optimally produced in avirulent phase. Unexpectedly, the presence of the capsule was also detected at the surface of virulent B. pertussis bacteria. Consistently, a substantial transcriptional activity of the capsule operon was detected in virulent phase, suggesting that the capsular polysaccharide may play a role during pertussis pathogenesis. In vitro assays indicated that the presence of the capsule does not affect B. pertussis adherence to mammalian cells and does not further protect the bacterium from phagocytosis, complement-mediated killing or antimicrobial peptide attack.


Asunto(s)
Cápsulas Bacterianas/análisis , Cápsulas Bacterianas/ultraestructura , Bordetella pertussis/fisiología , Animales , Adhesión Bacteriana , Bordetella pertussis/química , Bordetella pertussis/ultraestructura , Línea Celular , Proteínas del Sistema Complemento/inmunología , Células Epiteliales/microbiología , Humanos , Inmunohistoquímica , Macrófagos/inmunología , Ratones , Viabilidad Microbiana , Microscopía Electrónica de Transmisión , Fagocitosis
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