RESUMEN
Respiratory syncytial virus (RSV) is an exceptional mucosal pathogen. It specializes in infection of the ciliated respiratory epithelium, causing disease of variable severity with little or no direct systemic effects. It infects virtually all children by the age of three years and then repeatedly infects throughout life; this it does despite relatively slight variations in antigenicity, apparently by inducing selective immunological amnesia. Inappropriate or dysregulated responses to RSV can be pathogenic, causing disease-enhancing inflammation that contributes to short- and long-term effects. In addition, RSV's importance as a largely unrecognized pathogen of debilitated older people is increasingly evident. Vaccines that induce nonpathogenic protective immunity may soon be available, and it is possible that different vaccines will be optimal for infants; older children; young to middle-age adults (including pregnant women); and elderly persons. At the dawn of RSV vaccination, it is timely to review what is known (and unknown) about immune responses to this fascinating virus.
Asunto(s)
Mucosa Respiratoria/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Virus Sincitiales Respiratorios/inmunología , Vacunas Virales/inmunología , Adulto , Anciano , Animales , Niño , Humanos , Evasión Inmune , Inmunomodulación , Mucosa Respiratoria/virologíaRESUMEN
Our understanding of the normal variation in the upper respiratory tract (URT) microbiota across the human lifespan and how these relate to host, environment, and health is limited. We studied the microbiota of 3,104 saliva (<10 year-olds)/oropharynx (≥10 year-olds) and 2,485 nasopharynx samples of 3,160 Dutch individuals 0-87 years of age, participating in a cross-sectional population-wide study (PIENTER-3) using 16S-rRNA sequencing. The microbiota composition was strongly related to age, especially in the nasopharynx, with maturation occurring throughout childhood and adolescence. Clear niche- and age-specific associations were found between the microbiota composition and host/environmental factors and health outcomes. Among others, social interaction, sex, and season were associated with the nasopharyngeal microbial community. By contrast, the oral microbiota was more related to antibiotics, tobacco, and alcohol use. We present an atlas of the URT microbiota across the lifespan in association with environment and health, establishing a baseline for future research.
Asunto(s)
Microbiota , Humanos , Anciano , Preescolar , Adulto , Niño , Persona de Mediana Edad , Adolescente , Anciano de 80 o más Años , Masculino , Femenino , Lactante , Adulto Joven , ARN Ribosómico 16S/genética , Estudios Transversales , Recién Nacido , Sistema Respiratorio/microbiología , Longevidad , Nasofaringe/microbiología , Saliva/microbiología , AmbienteRESUMEN
Dexamethasone is a life-saving treatment for severe COVID-19, yet its mechanism of action is unknown, and many patients deteriorate or die despite timely treatment initiation. Here, we identify dexamethasone treatment-induced cellular and molecular changes associated with improved survival in COVID-19 patients. We observed a reversal of transcriptional hallmark signatures in monocytes associated with severe COVID-19 and the induction of a monocyte substate characterized by the expression of glucocorticoid-response genes. These molecular responses to dexamethasone were detected in circulating and pulmonary monocytes, and they were directly linked to survival. Monocyte single-cell RNA sequencing (scRNA-seq)-derived signatures were enriched in whole blood transcriptomes of patients with fatal outcome in two independent cohorts, highlighting the potential for identifying non-responders refractory to dexamethasone. Our findings link the effects of dexamethasone to specific immunomodulation and reversal of monocyte dysregulation, and they highlight the potential of single-cell omics for monitoring in vivo target engagement of immunomodulatory drugs and for patient stratification for precision medicine approaches.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19 , Dexametasona , Monocitos , SARS-CoV-2 , Análisis de la Célula Individual , Humanos , Dexametasona/farmacología , Dexametasona/uso terapéutico , Monocitos/metabolismo , Monocitos/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Masculino , Femenino , Transcriptoma , Persona de Mediana Edad , Anciano , Glucocorticoides/uso terapéutico , Glucocorticoides/farmacología , Pulmón/patología , AdultoRESUMEN
Blood and lymphatic vessels form a versatile transport network and provide inductive signals to regulate tissue-specific functions. Blood vessels in bone regulate osteogenesis and hematopoiesis, but current dogma suggests that bone lacks lymphatic vessels. Here, by combining high-resolution light-sheet imaging and cell-specific mouse genetics, we demonstrate presence of lymphatic vessels in mouse and human bones. We find that lymphatic vessels in bone expand during genotoxic stress. VEGF-C/VEGFR-3 signaling and genotoxic stress-induced IL6 drive lymphangiogenesis in bones. During lymphangiogenesis, secretion of CXCL12 from proliferating lymphatic endothelial cells is critical for hematopoietic and bone regeneration. Moreover, lymphangiocrine CXCL12 triggers expansion of mature Myh11+ CXCR4+ pericytes, which differentiate into bone cells and contribute to bone and hematopoietic regeneration. In aged animals, such expansion of lymphatic vessels and Myh11-positive cells in response to genotoxic stress is impaired. These data suggest lymphangiogenesis as a therapeutic avenue to stimulate hematopoietic and bone regeneration.
Asunto(s)
Regeneración Ósea , Vasos Linfáticos , Anciano , Animales , Humanos , Ratones , Células Endoteliales , LinfangiogénesisRESUMEN
Respiratory syncytial virus (RSV) is the most common cause of serious respiratory infection in infants. Reinfections occur commonly, including in older adults. For six decades, effective vaccines remained elusive. Stabilization of the prefusion conformation of the RSV glycoprotein F was critical for development of effective vaccines to prevent RSV in older adults. To view this Bench to Bedside, open or download the PDF.
Asunto(s)
Infecciones por Virus Sincitial Respiratorio , Vacunas contra Virus Sincitial Respiratorio , Virus Sincitial Respiratorio Humano , Humanos , Anciano , Infecciones por Virus Sincitial Respiratorio/prevención & control , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Proteínas Virales de FusiónRESUMEN
Senescent cell accumulation has been implicated in the pathogenesis of aging-associated diseases, including cancer. The mechanism that prevents the accumulation of senescent cells in aging human organs is unclear. Here, we demonstrate that a virus-immune axis controls the senescent fibroblast accumulation in the human skin. Senescent fibroblasts increased in old skin compared with young skin. However, they did not increase with advancing age in the elderly. Increased CXCL9 and cytotoxic CD4+ T cells (CD4 CTLs) recruitment were significantly associated with reduced senescent fibroblasts in the old skin. Senescent fibroblasts expressed human leukocyte antigen class II (HLA-II) and human cytomegalovirus glycoprotein B (HCMV-gB), becoming direct CD4 CTL targets. Skin-resident CD4 CTLs eliminated HCMV-gB+ senescent fibroblasts in an HLA-II-dependent manner, and HCMV-gB activated CD4 CTLs from the human skin. Collectively, our findings demonstrate HCMV reactivation in senescent cells, which CD4 CTLs can directly eliminate through the recognition of the HCMV-gB antigen.
Asunto(s)
Antineoplásicos , Infecciones por Citomegalovirus , Humanos , Anciano , Citomegalovirus , Linfocitos T Citotóxicos , Antígenos HLA , Linfocitos T CD4-Positivos , Senescencia CelularRESUMEN
Whether and how certain transposable elements with viral origins, such as endogenous retroviruses (ERVs) dormant in our genomes, can become awakened and contribute to the aging process is largely unknown. In human senescent cells, we found that HERVK (HML-2), the most recently integrated human ERVs, are unlocked to transcribe viral genes and produce retrovirus-like particles (RVLPs). These HERVK RVLPs constitute a transmissible message to elicit senescence phenotypes in young cells, which can be blocked by neutralizing antibodies. The activation of ERVs was also observed in organs of aged primates and mice as well as in human tissues and serum from the elderly. Their repression alleviates cellular senescence and tissue degeneration and, to some extent, organismal aging. These findings indicate that the resurrection of ERVs is a hallmark and driving force of cellular senescence and tissue aging.
Asunto(s)
Envejecimiento , Retrovirus Endógenos , Anciano , Animales , Humanos , Ratones , Envejecimiento/genética , Envejecimiento/patología , Senescencia Celular , Retrovirus Endógenos/genética , PrimatesRESUMEN
Alzheimer's disease (AD) is the most common cause of dementia worldwide, but the molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas of the aged human prefrontal cortex covering 2.3 million cells from postmortem human brain samples of 427 individuals with varying degrees of AD pathology and cognitive impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed a coordinated increase of the cohesin complex and DNA damage response factors in excitatory neurons and in oligodendrocytes, and uncovered genes and pathways associated with high cognitive function, dementia, and resilience to AD pathology. Furthermore, we identified selectively vulnerable somatostatin inhibitory neuron subtypes depleted in AD, discovered two distinct groups of inhibitory neurons that were more abundant in individuals with preserved high cognitive function late in life, and uncovered a link between inhibitory neurons and resilience to AD pathology.
Asunto(s)
Enfermedad de Alzheimer , Encéfalo , Anciano , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Encéfalo/patología , Cognición , Disfunción Cognitiva/metabolismo , Neuronas/metabolismoRESUMEN
Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 T cells. Clonal CD8 T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific T cell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedades Neurodegenerativas , Humanos , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Ligandos , Encéfalo , Envejecimiento , Lípidos , BiomarcadoresRESUMEN
Fingerprints are of long-standing practical and cultural interest, but little is known about the mechanisms that underlie their variation. Using genome-wide scans in Han Chinese cohorts, we identified 18 loci associated with fingerprint type across the digits, including a genetic basis for the long-recognized "pattern-block" correlations among the middle three digits. In particular, we identified a variant near EVI1 that alters regulatory activity and established a role for EVI1 in dermatoglyph patterning in mice. Dynamic EVI1 expression during human development supports its role in shaping the limbs and digits, rather than influencing skin patterning directly. Trans-ethnic meta-analysis identified 43 fingerprint-associated loci, with nearby genes being strongly enriched for general limb development pathways. We also found that fingerprint patterns were genetically correlated with hand proportions. Taken together, these findings support the key role of limb development genes in influencing the outcome of fingerprint patterning.
Asunto(s)
Dermatoglifia , Dedos/crecimiento & desarrollo , Organogénesis/genética , Polimorfismo de Nucleótido Simple , Dedos del Pie/crecimiento & desarrollo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Pueblo Asiatico/genética , Tipificación del Cuerpo/genética , Niño , Estudios de Cohortes , Femenino , Miembro Anterior/crecimiento & desarrollo , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Proteína del Locus del Complejo MDS1 y EV11/genética , Masculino , Ratones , Persona de Mediana Edad , Adulto JovenRESUMEN
Severe COVID-19 is linked to both dysfunctional immune response and unrestrained immunopathology, and it remains unclear whether T cells contribute to disease pathology. Here, we combined single-cell transcriptomics and single-cell proteomics with mechanistic studies to assess pathogenic T cell functions and inducing signals. We identified highly activated CD16+ T cells with increased cytotoxic functions in severe COVID-19. CD16 expression enabled immune-complex-mediated, T cell receptor-independent degranulation and cytotoxicity not found in other diseases. CD16+ T cells from COVID-19 patients promoted microvascular endothelial cell injury and release of neutrophil and monocyte chemoattractants. CD16+ T cell clones persisted beyond acute disease maintaining their cytotoxic phenotype. Increased generation of C3a in severe COVID-19 induced activated CD16+ cytotoxic T cells. Proportions of activated CD16+ T cells and plasma levels of complement proteins upstream of C3a were associated with fatal outcome of COVID-19, supporting a pathological role of exacerbated cytotoxicity and complement activation in COVID-19.
Asunto(s)
COVID-19/inmunología , COVID-19/patología , Activación de Complemento , Proteoma , SARS-CoV-2/inmunología , Linfocitos T Citotóxicos/inmunología , Transcriptoma , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/virología , Factores Quimiotácticos/metabolismo , Citotoxicidad Inmunológica , Células Endoteliales/virología , Femenino , Humanos , Activación de Linfocitos , Masculino , Microvasos/virología , Persona de Mediana Edad , Monocitos/metabolismo , Neutrófilos/metabolismo , Receptores de IgG/metabolismo , Análisis de la Célula Individual , Adulto JovenRESUMEN
HIV-1-infected cells that persist despite antiretroviral therapy (ART) are frequently considered "transcriptionally silent," but active viral gene expression may occur in some cells, challenging the concept of viral latency. Applying an assay for profiling the transcriptional activity and the chromosomal locations of individual proviruses, we describe a global genomic and epigenetic map of transcriptionally active and silent proviral species and evaluate their longitudinal evolution in persons receiving suppressive ART. Using genome-wide epigenetic reference data, we show that proviral transcriptional activity is associated with activating epigenetic chromatin features in linear proximity of integration sites and in their inter- and intrachromosomal contact regions. Transcriptionally active proviruses were actively selected against during prolonged ART; however, this pattern was violated by large clones of virally infected cells that may outcompete negative selection forces through elevated intrinsic proliferative activity. Our results suggest that transcriptionally active proviruses are dynamically evolving under selection pressure by host factors.
Asunto(s)
VIH-1/genética , Provirus/genética , Transcripción Genética , Anciano , Secuencia de Bases , Evolución Biológica , Cromatina/metabolismo , Células Clonales , ADN Viral/genética , Epigénesis Genética/efectos de los fármacos , Femenino , Humanos , Ionomicina/farmacología , Masculino , Persona de Mediana Edad , Filogenia , Provirus/efectos de los fármacos , ARN Viral/genética , Acetato de Tetradecanoilforbol/farmacología , Transcripción Genética/efectos de los fármacos , Integración Viral/genética , Latencia del Virus/efectos de los fármacos , Latencia del Virus/genéticaRESUMEN
Brain metastasis (BrM) is the most common form of brain cancer, characterized by neurologic disability and an abysmal prognosis. Unfortunately, our understanding of the biology underlying human BrMs remains rudimentary. Here, we present an integrative analysis of >100,000 malignant and non-malignant cells from 15 human parenchymal BrMs, generated by single-cell transcriptomics, mass cytometry, and complemented with mouse model- and in silico approaches. We interrogated the composition of BrM niches, molecularly defined the blood-tumor interface, and revealed stromal immunosuppressive states enriched with infiltrated T cells and macrophages. Specific single-cell interrogation of metastatic tumor cells provides a framework of 8 functional cell programs that coexist or anticorrelate. Collectively, these programs delineate two functional BrM archetypes, one proliferative and the other inflammatory, that are evidently shaped through tumor-immune interactions. Our resource provides a foundation to understand the molecular basis of BrM in patients with tumor cell-intrinsic and host environmental traits.
Asunto(s)
Neoplasias Encefálicas/patología , Neoplasias Encefálicas/secundario , Adulto , Anciano , Animales , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/sangre , Neoplasias Encefálicas/inmunología , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Femenino , Variación Genética , Humanos , Evasión Inmune , Activación de Linfocitos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Modelos Biológicos , Células Mieloides/patología , Análisis de Componente Principal , RNA-Seq , Análisis de la Célula Individual , Linfocitos T/inmunologíaRESUMEN
An outbreak of over 1,000 COVID-19 cases in Provincetown, Massachusetts (MA), in July 2021-the first large outbreak mostly in vaccinated individuals in the US-prompted a comprehensive public health response, motivating changes to national masking recommendations and raising questions about infection and transmission among vaccinated individuals. To address these questions, we combined viral genomic and epidemiological data from 467 individuals, including 40% of outbreak-associated cases. The Delta variant accounted for 99% of cases in this dataset; it was introduced from at least 40 sources, but 83% of cases derived from a single source, likely through transmission across multiple settings over a short time rather than a single event. Genomic and epidemiological data supported multiple transmissions of Delta from and between fully vaccinated individuals. However, despite its magnitude, the outbreak had limited onward impact in MA and the US overall, likely due to high vaccination rates and a robust public health response.
Asunto(s)
COVID-19/epidemiología , COVID-19/inmunología , COVID-19/transmisión , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/virología , Niño , Preescolar , Trazado de Contacto/métodos , Brotes de Enfermedades , Femenino , Genoma Viral , Humanos , Lactante , Recién Nacido , Masculino , Massachusetts/epidemiología , Persona de Mediana Edad , Epidemiología Molecular , Filogenia , SARS-CoV-2/clasificación , Vacunación , Secuenciación Completa del Genoma , Adulto JovenRESUMEN
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
Pneumococcal infections cause serious illness and death among older adults. The capsular polysaccharide vaccine PPSV23 and conjugated alternative PCV13 can prevent these infections; yet, underlying immunological responses and baseline predictors remain unknown. We vaccinated 39 older adults (>60 years) with PPSV23 or PCV13 and observed comparable antibody responses (day 28) and plasmablast transcriptional responses (day 10); however, the baseline predictors were distinct. Analyses of baseline flow cytometry and bulk and single-cell RNA-sequencing data revealed a baseline phenotype specifically associated with weaker PCV13 responses, which was characterized by increased expression of cytotoxicity-associated genes, increased frequencies of CD16+ natural killer cells and interleukin-17-producing helper T cells and a decreased frequency of type 1 helper T cells. Men displayed this phenotype more robustly and mounted weaker PCV13 responses than women. Baseline expression levels of a distinct gene set predicted PPSV23 responses. This pneumococcal precision vaccinology study in older adults uncovered distinct baseline predictors that might transform vaccination strategies and initiate novel interventions.
Asunto(s)
Anticuerpos Antibacterianos , Streptococcus pneumoniae , Masculino , Humanos , Femenino , Anciano , Vacunas Conjugadas , Método Doble Ciego , Vacunación , Vacunas Neumococicas , PolisacáridosRESUMEN
Sepsis induces immune alterations, which last for months after the resolution of illness. The effect of this immunological reprogramming on the risk of developing cancer is unclear. Here we use a national claims database to show that sepsis survivors had a lower cumulative incidence of cancers than matched nonsevere infection survivors. We identify a chemokine network released from sepsis-trained resident macrophages that triggers tissue residency of T cells via CCR2 and CXCR6 stimulations as the immune mechanism responsible for this decreased risk of de novo tumor development after sepsis cure. While nonseptic inflammation does not provoke this network, laminarin injection could therapeutically reproduce the protective sepsis effect. This chemokine network and CXCR6 tissue-resident T cell accumulation were detected in humans with sepsis and were associated with prolonged survival in humans with cancer. These findings identify a therapeutically relevant antitumor consequence of sepsis-induced trained immunity.
Asunto(s)
Macrófagos , Neoplasias , Sepsis , Humanos , Sepsis/inmunología , Macrófagos/inmunología , Femenino , Neoplasias/inmunología , Neoplasias/terapia , Masculino , Receptores CXCR6/metabolismo , Animales , Linfocitos T/inmunología , Receptores CCR2/metabolismo , Persona de Mediana Edad , Ratones , Anciano , Quimiocinas/metabolismo , AdultoRESUMEN
The evolution of T cell molecular signatures in the distal lung of patients with severe pneumonia is understudied. Here, we analyzed T cell subsets in longitudinal bronchoalveolar lavage fluid samples from 273 patients with severe pneumonia, including unvaccinated patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or with respiratory failure not linked to pneumonia. In patients with SARS-CoV-2 pneumonia, activation of interferon signaling pathways, low activation of the NF-κB pathway and preferential targeting of spike and nucleocapsid proteins early after intubation were associated with favorable outcomes, whereas loss of interferon signaling, activation of NF-κB-driven programs and specificity for the ORF1ab complex late in disease were associated with mortality. These results suggest that in patients with severe SARS-CoV-2 pneumonia, alveolar T cell interferon responses targeting structural SARS-CoV-2 proteins characterize individuals who recover, whereas responses against nonstructural proteins and activation of NF-κB are associated with poor outcomes.
Asunto(s)
COVID-19 , FN-kappa B , SARS-CoV-2 , Humanos , COVID-19/inmunología , SARS-CoV-2/inmunología , Masculino , Femenino , Persona de Mediana Edad , FN-kappa B/metabolismo , Anciano , Líquido del Lavado Bronquioalveolar/inmunología , Adulto , Transducción de Señal/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Interferones/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T/inmunología , Alveolos Pulmonares/inmunología , Alveolos Pulmonares/patologíaRESUMEN
Prognostically relevant RNA expression states exist in pancreatic ductal adenocarcinoma (PDAC), but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. In vivo, we identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments (TMEs). Benchmarking models against this reference map, we reveal strong culture-specific biases in cancer cell transcriptional state representation driven by altered TME signals. We restore expression state heterogeneity by adding back in vivo-relevant factors and show plasticity in culture models. Further, we prove that non-genetic modulation of cell state can strongly influence drug responses, uncovering state-specific vulnerabilities. This work provides a broadly applicable framework for aligning cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity and manipulating cell state to target associated vulnerabilities.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/metabolismo , Microambiente Tumoral , Adulto , Anciano , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Análisis de la Célula IndividualRESUMEN
The population is aging at a rate never seen before in human history. As the number of elderly adults grows, it is imperative we expand our understanding of the underpinnings of aging biology. Human lungs are composed of a unique panoply of cell types that face ongoing chemical, mechanical, biological, immunological, and xenobiotic stress over a lifetime. Yet, we do not fully appreciate the mechanistic drivers of lung aging and why age increases the risk of parenchymal lung disease, fatal respiratory infection, and primary lung cancer. Here, we review the molecular and cellular aspects of lung aging, local stress response pathways, and how the aging process predisposes to the pathogenesis of pulmonary disease. We place these insights into context of the COVID-19 pandemic and discuss how innate and adaptive immunity within the lung is altered with age.