RESUMEN
Globally, about 36.7 million people were living with HIV infection at the end of 2015. The most frequent infection co-occurring with HIV-1 is Mycobacterium tuberculosis-374,000 deaths per annum are attributable to HIV-tuberculosis, 75% of those occurring in Africa. HIV-1 infection increases the risk of tuberculosis by a factor of up to 26 and alters its clinical presentation, complicates diagnosis and treatment, and worsens outcome. Although HIV-1-induced depletion of CD4+ T cells underlies all these effects, more widespread immune deficits also contribute to susceptibility and pathogenesis. These defects present a challenge to understand and ameliorate, but also an opportunity to learn and optimize mechanisms that normally protect people against tuberculosis. The most effective means to prevent and ameliorate tuberculosis in HIV-1-infected people is antiretroviral therapy, but this may be complicated by pathological immune deterioration that in turn requires more effective host-directed anti-inflammatory therapies to be derived.
Asunto(s)
Coinfección , Infecciones por VIH/inmunología , VIH-1/inmunología , Interacciones Huésped-Patógeno/inmunología , Inmunidad , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Animales , Terapia Antirretroviral Altamente Activa , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Progresión de la Enfermedad , Variación Genética , Infecciones por VIH/diagnóstico , Infecciones por VIH/terapia , Infecciones por VIH/virología , VIH-1/genética , Humanos , Tuberculosis/diagnóstico , Tuberculosis/microbiología , Tuberculosis/terapia , Replicación ViralRESUMEN
While CD4+ T cell depletion is key to disease progression in people living with HIV and SIV-infected macaques, the mechanisms underlying this depletion remain incompletely understood, with most cell death involving uninfected cells. In contrast, SIV infection of "natural" hosts such as sooty mangabeys does not cause CD4+ depletion and AIDS despite high-level viremia. Here, we report that the CARD8 inflammasome is activated immediately after HIV entry by the viral protease encapsulated in incoming virions. Sensing of HIV protease activity by CARD8 leads to rapid pyroptosis of quiescent cells without productive infection, while T cell activation abolishes CARD8 function and increases permissiveness to infection. In humanized mice reconstituted with CARD8-deficient cells, CD4+ depletion is delayed despite high viremia. Finally, we discovered loss-of-function mutations in CARD8 from "natural hosts," which may explain the peculiarly non-pathogenic nature of these infections. Our study suggests that CARD8 drives CD4+ T cell depletion during pathogenic HIV/SIV infections.
Asunto(s)
Infecciones por VIH , Inflamasomas , Síndrome de Inmunodeficiencia Adquirida del Simio , Animales , Humanos , Ratones , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Progresión de la Enfermedad , Infecciones por VIH/patología , Inflamasomas/metabolismo , Proteínas de Neoplasias/metabolismo , Síndrome de Inmunodeficiencia Adquirida del Simio/patología , Virus de la Inmunodeficiencia de los Simios/fisiología , Viremia , VIH/fisiologíaRESUMEN
Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.
Asunto(s)
Síndrome Post Agudo de COVID-19 , Serotonina , Humanos , COVID-19/complicaciones , Progresión de la Enfermedad , Inflamación , Síndrome Post Agudo de COVID-19/sangre , Síndrome Post Agudo de COVID-19/patología , Serotonina/sangre , VirosisRESUMEN
Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Analysis of spatial multi-omic data from 31 human colorectal specimens enabled phylogeographic mapping of tumor evolution that revealed individualized progression trajectories and accompanying microenvironmental and clonal alterations. Phylogeographic mapping ordered genetic events, classified tumors by their evolutionary dynamics, and placed clonal regions along global pseudotemporal progression trajectories encompassing the chromosomal instability (CIN+) and hypermutated (HM) pathways. Integrated single-cell and spatial transcriptomic data revealed recurring epithelial programs and infiltrating immune states along progression pseudotime. We discovered an immune exclusion signature (IEX), consisting of extracellular matrix regulators DDR1, TGFBI, PAK4, and DPEP1, that charts with CIN+ tumor progression, is associated with reduced cytotoxic cell infiltration, and shows prognostic value in independent cohorts. This spatial multi-omic atlas provides insights into colorectal tumor-microenvironment co-evolution, serving as a resource for stratification and targeted treatments.
Asunto(s)
Neoplasias Colorrectales , Inestabilidad de Microsatélites , Microambiente Tumoral , Humanos , Inestabilidad Cromosómica/genética , Neoplasias Colorrectales/patología , Perfilación de la Expresión Génica , Quinasas p21 Activadas/genética , Filogenia , Mutación , Progresión de la Enfermedad , PronósticoRESUMEN
Ductal carcinoma in situ (DCIS) is a common precursor of invasive breast cancer. Our understanding of its genomic progression to recurrent disease remains poor, partly due to challenges associated with the genomic profiling of formalin-fixed paraffin-embedded (FFPE) materials. Here, we developed Arc-well, a high-throughput single-cell DNA-sequencing method that is compatible with FFPE materials. We validated our method by profiling 40,330 single cells from cell lines, a frozen tissue, and 27 FFPE samples from breast, lung, and prostate tumors stored for 3-31 years. Analysis of 10 patients with matched DCIS and cancers that recurred 2-16 years later show that many primary DCIS had already undergone whole-genome doubling and clonal diversification and that they shared genomic lineages with persistent subclones in the recurrences. Evolutionary analysis suggests that most DCIS cases in our cohort underwent an evolutionary bottleneck, and further identified chromosome aberrations in the persistent subclones that were associated with recurrence.
Asunto(s)
Neoplasias de la Mama , Carcinoma Ductal de Mama , Carcinoma Intraductal no Infiltrante , Femenino , Humanos , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/patología , Progresión de la Enfermedad , Genómica/métodos , Análisis de Expresión Génica de una Sola Célula , Línea Celular TumoralRESUMEN
Ductal carcinoma in situ (DCIS) is a pre-invasive lesion that is thought to be a precursor to invasive breast cancer (IBC). To understand the changes in the tumor microenvironment (TME) accompanying transition to IBC, we used multiplexed ion beam imaging by time of flight (MIBI-TOF) and a 37-plex antibody staining panel to interrogate 79 clinically annotated surgical resections using machine learning tools for cell segmentation, pixel-based clustering, and object morphometrics. Comparison of normal breast with patient-matched DCIS and IBC revealed coordinated transitions between four TME states that were delineated based on the location and function of myoepithelium, fibroblasts, and immune cells. Surprisingly, myoepithelial disruption was more advanced in DCIS patients that did not develop IBC, suggesting this process could be protective against recurrence. Taken together, this HTAN Breast PreCancer Atlas study offers insight into drivers of IBC relapse and emphasizes the importance of the TME in regulating these processes.
Asunto(s)
Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Diferenciación Celular , Estudios de Cohortes , Progresión de la Enfermedad , Células Epiteliales/patología , Epitelio/patología , Matriz Extracelular/metabolismo , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/patología , Fenotipo , Análisis de la Célula Individual , Células del Estroma/patología , Microambiente TumoralRESUMEN
Tau (MAPT) drives neuronal dysfunction in Alzheimer disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established interactions of Tau with presynaptic vesicle proteins during activity-dependent Tau secretion and mapped the Tau-binding sites to the cytosolic domains of integral synaptic vesicle proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Tau's interaction with mitochondria proteins, which were downregulated in AD brains of multiple cohorts and correlated with disease severity. These multimodal and dynamic Tau interactomes with exquisite spatial resolution shed light on Tau's role in neuronal function and disease and highlight potential therapeutic targets to block Tau-mediated pathogenesis.
Asunto(s)
Mitocondrias/metabolismo , Degeneración Nerviosa/metabolismo , Mapas de Interacción de Proteínas , Sinapsis/metabolismo , Proteínas tau/metabolismo , Enfermedad de Alzheimer/genética , Aminoácidos/metabolismo , Biotinilación , Encéfalo/metabolismo , Encéfalo/patología , Núcleo Celular/metabolismo , Progresión de la Enfermedad , Metabolismo Energético , Demencia Frontotemporal/genética , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Proteínas Mutantes/metabolismo , Mutación/genética , Degeneración Nerviosa/patología , Neuronas/metabolismo , Unión Proteica , Dominios Proteicos , Proteómica , Índice de Severidad de la Enfermedad , Fracciones Subcelulares/metabolismo , Tauopatías/genética , Proteínas tau/químicaRESUMEN
Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
Asunto(s)
COVID-19/complicaciones , COVID-19/diagnóstico , Convalecencia , Inmunidad Adaptativa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Autoanticuerpos/sangre , Biomarcadores/metabolismo , Proteínas Sanguíneas/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , COVID-19/inmunología , COVID-19/patología , COVID-19/virología , Progresión de la Enfermedad , Femenino , Humanos , Inmunidad Innata/genética , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Factores de Riesgo , SARS-CoV-2/aislamiento & purificación , Transcriptoma , Adulto Joven , Síndrome Post Agudo de COVID-19RESUMEN
Persistent symptoms following SARS-CoV-2 infection are increasingly reported, although the drivers of post-acute sequelae (PASC) of COVID-19 are unclear. Here we assessed 214 individuals infected with SARS-CoV-2, with varying disease severity, for one year from COVID-19 symptom onset to determine the early correlates of PASC. A multivariate signature detected beyond two weeks of disease, encompassing unresolving inflammation, anemia, low serum iron, altered iron-homeostasis gene expression and emerging stress erythropoiesis; differentiated those who reported PASC months later, irrespective of COVID-19 severity. A whole-blood heme-metabolism signature, enriched in hospitalized patients at month 1-3 post onset, coincided with pronounced iron-deficient reticulocytosis. Lymphopenia and low numbers of dendritic cells persisted in those with PASC, and single-cell analysis reported iron maldistribution, suggesting monocyte iron loading and increased iron demand in proliferating lymphocytes. Thus, defects in iron homeostasis, dysregulated erythropoiesis and immune dysfunction due to COVID-19 possibly contribute to inefficient oxygen transport, inflammatory disequilibrium and persisting symptomatology, and may be therapeutically tractable.
Asunto(s)
COVID-19 , Hierro , Humanos , Eritropoyesis , SARS-CoV-2 , Investigadores , Progresión de la EnfermedadRESUMEN
Eighty percent of individuals with multiple sclerosis (MS) initially develop a clinical pattern with periodic relapses followed by remissions, called relapsing-remitting MS (RRMS). This period of fluctuating disease may last for a decade or more. Clinical relapses reflect acute inflammation in the central nervous system (CNS), composed of the brain and spinal cord. Often, different anatomic areas in the CNS are involved each time a relapse occurs, resulting in varied clinical manifestations in each instance. Relapses are nearly always followed by some degree of remission, though recovery to baseline status before the flare is often incomplete. There are nine approved drugs for treatment of RRMS. The most potent drug for inhibiting relapses, the humanized anti-α4 integrin antibody known as Natalizumab, blocks homing of mononuclear cells to the CNS. The mechanisms of action of the approved drugs for RRMS provide a strong foundation for understanding the pathobiology of the relapse. Despite substantial progress in controlling relapses with the current armamentarium of medications, there is much to learn and ever more effective and safe therapies to develop.
Asunto(s)
Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple/inmunología , Animales , Progresión de la Enfermedad , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/genética , Esclerosis Múltiple Recurrente-Remitente/metabolismo , RecurrenciaRESUMEN
Although mutations leading to a compromised nuclear envelope cause diseases such as muscular dystrophies or accelerated aging, the consequences of mechanically induced nuclear envelope ruptures are less known. Here, we show that nuclear envelope ruptures induce DNA damage that promotes senescence in non-transformed cells and induces an invasive phenotype in human breast cancer cells. We find that the endoplasmic reticulum (ER)-associated exonuclease TREX1 translocates into the nucleus after nuclear envelope rupture and is required to induce DNA damage. Inside the mammary duct, cellular crowding leads to nuclear envelope ruptures that generate TREX1-dependent DNA damage, thereby driving the progression of in situ carcinoma to the invasive stage. DNA damage and nuclear envelope rupture markers were also enriched at the invasive edge of human tumors. We propose that DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells.
Asunto(s)
Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Daño del ADN , Exodesoxirribonucleasas/metabolismo , Membrana Nuclear/metabolismo , Fosfoproteínas/metabolismo , Animales , Línea Celular , Senescencia Celular , Colágeno/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Ratones , Invasividad Neoplásica , Membrana Nuclear/ultraestructura , Proteolisis , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Metastasis has been considered as the terminal step of tumor progression. However, recent genomic studies suggest that many metastases are initiated by further spread of other metastases. Nevertheless, the corresponding pre-clinical models are lacking, and underlying mechanisms are elusive. Using several approaches, including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. We uncovered that this metastasis-promoting effect is driven by epigenetic reprogramming that confers stem cell-like properties on cancer cells disseminated from bone lesions. Furthermore, we discovered that enhanced EZH2 activity mediates the increased stemness and metastasis capacity. The same findings also apply to single cell-derived populations, indicating mechanisms distinct from clonal selection. Taken together, our work revealed an unappreciated role of the bone microenvironment in metastasis evolution and elucidated an epigenomic reprogramming process driving terminal-stage, multi-organ metastases.
Asunto(s)
Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Metástasis de la Neoplasia , Neoplasias de la Próstata/patología , Microambiente Tumoral , Animales , Apoptosis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Proliferación Celular , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC.
Asunto(s)
Pólipos del Colon/patología , Neoplasias Colorrectales/patología , Microambiente Tumoral , Inmunidad Adaptativa , Adenoma/genética , Adenoma/patología , Adulto , Anciano , Animales , Carcinogénesis/genética , Carcinogénesis/patología , Muerte Celular , Diferenciación Celular , Pólipos del Colon/genética , Pólipos del Colon/inmunología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/inmunología , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Heterogeneidad Genética , Humanos , Masculino , Ratones , Persona de Mediana Edad , Mutación/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , RNA-Seq , Reproducibilidad de los Resultados , Análisis de la Célula Individual , Microambiente Tumoral/inmunologíaRESUMEN
Estrogen receptor α (ERα) is a hormone receptor and key driver for over 70% of breast cancers that has been studied for decades as a transcription factor. Unexpectedly, we discover that ERα is a potent non-canonical RNA-binding protein. We show that ERα RNA binding function is uncoupled from its activity to bind DNA and critical for breast cancer progression. Employing genome-wide cross-linking immunoprecipitation (CLIP) sequencing and a functional CRISPRi screen, we find that ERα-associated mRNAs sustain cancer cell fitness and elicit cellular responses to stress. Mechanistically, ERα controls different steps of RNA metabolism. In particular, we demonstrate that ERα RNA binding mediates alternative splicing of XBP1 and translation of the eIF4G2 and MCL1 mRNAs, which facilitates survival upon stress conditions and sustains tamoxifen resistance of cancer cells. ERα is therefore a multifaceted RNA-binding protein, and this activity transforms our knowledge of post-transcriptional regulation underlying cancer development and drug response.
Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Resistencia a Antineoplásicos , Receptor alfa de Estrógeno/metabolismo , Proteínas de Unión al ARN/metabolismo , Animales , Secuencia de Bases , Neoplasias de la Mama/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Receptor alfa de Estrógeno/química , Factor 4G Eucariótico de Iniciación/genética , Factor 4G Eucariótico de Iniciación/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Genómica , Humanos , Ratones Endogámicos NOD , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Oncogenes , Unión Proteica/efectos de los fármacos , Dominios Proteicos , Empalme del ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Estrés Fisiológico/efectos de los fármacos , Estrés Fisiológico/genética , Tamoxifeno/farmacología , Proteína 1 de Unión a la X-Box/metabolismoRESUMEN
Group 3 innate lymphoid cells (ILC3s) regulate immunity and inflammation, yet their role in cancer remains elusive. Here, we identify that colorectal cancer (CRC) manifests with altered ILC3s that are characterized by reduced frequencies, increased plasticity, and an imbalance with T cells. We evaluated the consequences of these changes in mice and determined that a dialog between ILC3s and T cells via major histocompatibility complex class II (MHCII) is necessary to support colonization with microbiota that subsequently induce type-1 immunity in the intestine and tumor microenvironment. As a result, mice lacking ILC3-specific MHCII develop invasive CRC and resistance to anti-PD-1 immunotherapy. Finally, humans with dysregulated intestinal ILC3s harbor microbiota that fail to induce type-1 immunity and immunotherapy responsiveness when transferred to mice. Collectively, these data define a protective role for ILC3s in cancer and indicate that their inherent disruption in CRC drives dysfunctional adaptive immunity, tumor progression, and immunotherapy resistance.
Asunto(s)
Neoplasias del Colon/inmunología , Neoplasias del Colon/terapia , Progresión de la Enfermedad , Inmunidad Innata , Inmunoterapia , Linfocitos/inmunología , Animales , Comunicación Celular/efectos de los fármacos , Plasticidad de la Célula/efectos de los fármacos , Neoplasias del Colon/microbiología , Heces/microbiología , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunidad Innata/efectos de los fármacos , Inflamación/inmunología , Inflamación/patología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/microbiología , Enfermedades Inflamatorias del Intestino/patología , Intestinos/patología , Linfocitos/efectos de los fármacos , Ratones Endogámicos C57BL , Microbiota/efectos de los fármacos , Invasividad Neoplásica , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Donantes de TejidosRESUMEN
Visualization of the cellular heterogeneity and spatial architecture of the tumor microenvironment (TME) is becoming increasingly important to understand mechanisms of disease progression and therapeutic response. This is particularly relevant in the era of cancer immunotherapy, in which the contexture of immune cell positioning within the tumor landscape has been proven to affect efficacy. Although single-cell technologies have mostly replaced conventional approaches to analyze specific cellular subsets within tumors, those that integrate a spatial dimension are now on the rise. In this Review, we assess the strengths and limitations of emerging spatial technologies with a focus on their applications in tumor immunology, as well as forthcoming opportunities for artificial intelligence (AI) and the value of integrating multiomics datasets to achieve a holistic picture of the TME.
Asunto(s)
Neoplasias , Microambiente Tumoral , Humanos , Inteligencia Artificial , Progresión de la Enfermedad , Inmunoterapia , Neoplasias/terapiaRESUMEN
Millions of people are suffering from Long COVID or post-acute sequelae of COVID-19 (PASC). Several biological factors have emerged as potential drivers of PASC pathology. Some individuals with PASC may not fully clear the coronavirus SARS-CoV-2 after acute infection. Instead, replicating virus and/or viral RNA-potentially capable of being translated to produce viral proteins-persist in tissue as a 'reservoir'. This reservoir could modulate host immune responses or release viral proteins into the circulation. Here we review studies that have identified SARS-CoV-2 RNA/protein or immune responses indicative of a SARS-CoV-2 reservoir in PASC samples. Mechanisms by which a SARS-CoV-2 reservoir may contribute to PASC pathology, including coagulation, microbiome and neuroimmune abnormalities, are delineated. We identify research priorities to guide the further study of a SARS-CoV-2 reservoir in PASC, with the goal that clinical trials of antivirals or other therapeutics with potential to clear a SARS-CoV-2 reservoir are accelerated.
Asunto(s)
COVID-19 , Humanos , Síndrome Post Agudo de COVID-19 , ARN Viral/genética , SARS-CoV-2 , Antivirales , Progresión de la EnfermedadRESUMEN
There are 9 million cases of active tuberculosis reported annually; however, an estimated one-third of the world's population is infected with Mycobacterium tuberculosis and remains asymptomatic. Of these latent individuals, only 5-10% will develop active tuberculosis disease in their lifetime. CD4(+) T cells, as well as the cytokines IL-12, IFN-γ, and TNF, are critical in the control of Mycobacterium tuberculosis infection, but the host factors that determine why some individuals are protected from infection while others go on to develop disease are unclear. Genetic factors of the host and of the pathogen itself may be associated with an increased risk of patients developing active tuberculosis. This review aims to summarize what we know about the immune response in tuberculosis, in human disease, and in a range of experimental models, all of which are essential to advancing our mechanistic knowledge base of the host-pathogen interactions that influence disease outcome.
Asunto(s)
Tuberculosis Pulmonar/inmunología , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Mycobacterium tuberculosis/inmunología , Resultado del Tratamiento , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/epidemiologíaRESUMEN
The dichotomous model of "drivers" and "passengers" in cancer posits that only a few mutations in a tumor strongly affect its progression, with the remaining ones being inconsequential. Here, we leveraged the comprehensive variant dataset from the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) project to demonstrate that-in addition to the dichotomy of high- and low-impact variants-there is a third group of medium-impact putative passengers. Moreover, we also found that molecular impact correlates with subclonal architecture (i.e., early versus late mutations), and different signatures encode for mutations with divergent impact. Furthermore, we adapted an additive-effects model from complex-trait studies to show that the aggregated effect of putative passengers, including undetected weak drivers, provides significant additional power (â¼12% additive variance) for predicting cancerous phenotypes, beyond PCAWG-identified driver mutations. Finally, this framework allowed us to estimate the frequency of potential weak-driver mutations in PCAWG samples lacking any well-characterized driver alterations.
Asunto(s)
Genoma Humano/genética , Genómica/métodos , Mutación/genética , Neoplasias/genética , Análisis Mutacional de ADN/métodos , Progresión de la Enfermedad , Humanos , Neoplasias/patología , Secuenciación Completa del GenomaRESUMEN
To elucidate the role of Tau isoforms and post-translational modification (PTM) stoichiometry in Alzheimer's disease (AD), we generated a high-resolution quantitative proteomics map of 95 PTMs on multiple isoforms of Tau isolated from postmortem human tissue from 49 AD and 42 control subjects. Although Tau PTM maps reveal heterogeneity across subjects, a subset of PTMs display high occupancy and frequency for AD, suggesting importance in disease. Unsupervised analyses indicate that PTMs occur in an ordered manner, leading to Tau aggregation. The processive addition and minimal set of PTMs associated with seeding activity was further defined by analysis of size-fractionated Tau. To summarize, features in the Tau protein critical for disease intervention at different stages of disease are identified, including enrichment of 0N and 4R isoforms, underrepresentation of the C terminus, an increase in negative charge in the proline-rich region (PRR), and a decrease in positive charge in the microtubule binding domain (MBD).