RESUMEN
The human pathogen Mycobacterium tuberculosis typically causes lung disease but can also disseminate to other tissues. We identified a M. tuberculosis (Mtb) outbreak presenting with unusually high rates of extrapulmonary dissemination and bone disease. We found that the causal strain carried an ancestral full-length version of the type VII-secreted effector EsxM rather than the truncated version present in other modern Mtb lineages. The ancestral EsxM variant exacerbated dissemination through enhancement of macrophage motility, increased egress of macrophages from established granulomas, and alterations in macrophage actin dynamics. Reconstitution of the ancestral version of EsxM in an attenuated modern strain of Mtb altered the migratory mode of infected macrophages, enhancing their motility. In a zebrafish model, full-length EsxM promoted bone disease. The presence of a derived nonsense variant in EsxM throughout the major Mtb lineages 2, 3, and 4 is consistent with a role for EsxM in regulating the extent of dissemination.
Asunto(s)
Enfermedades Óseas , Mycobacterium marinum , Mycobacterium tuberculosis , Tuberculosis , Animales , Humanos , Pez Cebra , Tuberculosis/microbiología , Macrófagos/microbiología , Proteínas Bacterianas/genéticaRESUMEN
Respiratory infections are common in infants and young children. However, the immune system develops and matures as the child grows, thus the effects of infection during this time of dynamic change may have long-term consequences. The infant immune system develops in conjunction with the seeding of the microbiome at the respiratory mucosal surface, at a time that the lungs themselves are maturing. We are now recognizing that any disturbance of this developmental trajectory can have implications for lifelong lung health. Here, we outline our current understanding of the molecular mechanisms underlying relationships between immune and structural cells in the lung with the local microorganisms. We highlight the importance of gaining greater clarity as to what constitutes a healthy respiratory ecosystem and how environmental exposures influencing this network will aid efforts to mitigate harmful effects and restore lung immune health.
Asunto(s)
Microbiota , Infecciones del Sistema Respiratorio , Lactante , Niño , Humanos , Preescolar , Pulmón , Sistema Inmunológico , Mucosa RespiratoriaRESUMEN
Oncogenic transformation is associated with profound changes in cellular metabolism, but whether tracking these can improve disease stratification or influence therapy decision-making is largely unknown. Using the iKnife to sample the aerosol of cauterized specimens, we demonstrate a new mode of real-time diagnosis, coupling metabolic phenotype to mutant PIK3CA genotype. Oncogenic PIK3CA results in an increase in arachidonic acid and a concomitant overproduction of eicosanoids, acting to promote cell proliferation beyond a cell-autonomous manner. Mechanistically, mutant PIK3CA drives a multimodal signaling network involving mTORC2-PKCζ-mediated activation of the calcium-dependent phospholipase A2 (cPLA2). Notably, inhibiting cPLA2 synergizes with fatty acid-free diet to restore immunogenicity and selectively reduce mutant PIK3CA-induced tumorigenicity. Besides highlighting the potential for metabolic phenotyping in stratified medicine, this study reveals an important role for activated PI3K signaling in regulating arachidonic acid metabolism, uncovering a targetable metabolic vulnerability that largely depends on dietary fat restriction. VIDEO ABSTRACT.
Asunto(s)
Ácido Araquidónico/análisis , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Eicosanoides/metabolismo , Animales , Ácido Araquidónico/metabolismo , Línea Celular Tumoral , Fosfatidilinositol 3-Quinasa Clase I/genética , Citosol/metabolismo , Eicosanoides/fisiología , Activación Enzimática , Femenino , Humanos , Metabolismo de los Lípidos/fisiología , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Redes y Vías Metabólicas/genética , Redes y Vías Metabólicas/fisiología , Ratones Endogámicos BALB C , Ratones Desnudos , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfolipasas A2/metabolismo , Fosforilación , Proteína Quinasa C/metabolismo , Transducción de Señal , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Neutrophils are critical to innate immunity, including host defense against bacterial and fungal infections. They achieve their host defense role by phagocytosing pathogens, secreting their granules full of cytotoxic enzymes, or expelling neutrophil extracellular traps (NETs) during the process of NETosis. NETs are weblike DNA structures decorated with histones and antimicrobial proteins released by activated neutrophils. Initially described as a means for neutrophils to neutralize pathogens, NET release also occurs in sterile inflammation, promotes thrombosis, and can mediate tissue damage. To effectively manipulate this double-edged sword to fight a particular disease, researchers must work toward understanding the mechanisms driving NETosis. Such understanding would allow the generation of new drugs to promote or prevent NETosis as needed. While knowledge regarding the (patho)physiological roles of NETosis is accumulating, little is known about the cellular and biophysical bases of this process. In this review, we describe and discuss our current knowledge of the molecular, cellular, and biophysical mechanisms mediating NET release as well as open questions in the field.
Asunto(s)
Trampas Extracelulares/metabolismo , Animales , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Citoesqueleto/metabolismo , Citosol/metabolismo , ADN/metabolismo , HumanosRESUMEN
Communication between nerves and group 2 innate lymphoid cells (ILC2s) is thought to regulate allergic airway inflammation, but the molecular mechanisms are unclear. In this issue of Immunity, Cao et al. uncover an essential role for dopamine in inhibiting ILC2 function via metabolic restriction, thereby ameliorating key features of asthma pathogenesis.
Asunto(s)
Asma , Inmunidad Innata , Humanos , Dopamina , Linfocitos , Inflamación , Citocinas/metabolismoRESUMEN
Some patients hospitalized with acute COVID-19 suffer respiratory symptoms that persist for many months. We delineated the immune-proteomic landscape in the airways and peripheral blood of healthy controls and post-COVID-19 patients 3 to 6 months after hospital discharge. Post-COVID-19 patients showed abnormal airway (but not plasma) proteomes, with an elevated concentration of proteins associated with apoptosis, tissue repair, and epithelial injury versus healthy individuals. Increased numbers of cytotoxic lymphocytes were observed in individuals with greater airway dysfunction, while increased B cell numbers and altered monocyte subsets were associated with more widespread lung abnormalities. A one-year follow-up of some post-COVID-19 patients indicated that these abnormalities resolved over time. In summary, COVID-19 causes a prolonged change to the airway immune landscape in those with persistent lung disease, with evidence of cell death and tissue repair linked to the ongoing activation of cytotoxic T cells.
Asunto(s)
Linfocitos B/inmunología , COVID-19/inmunología , Monocitos/inmunología , Trastornos Respiratorios/inmunología , Sistema Respiratorio/inmunología , SARS-CoV-2/fisiología , Linfocitos T Citotóxicos/inmunología , Adulto , Anciano , COVID-19/complicaciones , Femenino , Estudios de Seguimiento , Humanos , Inmunidad Celular , Inmunoproteínas , Masculino , Persona de Mediana Edad , Proteoma , Trastornos Respiratorios/etiología , Sistema Respiratorio/patologíaRESUMEN
Cell migration in confined 3D tissue microenvironments is critical for both normal physiological functions and dissemination of tumor cells. We discovered a cytoskeletal structure that prevents damage to the nucleus during migration in confined microenvironments. The formin-family actin filament nucleator FMN2 associates with and generates a perinuclear actin/focal adhesion (FA) system that is distinct from previously characterized actin/FA structures. This system controls nuclear shape and positioning in cells migrating on 2D surfaces. In confined 3D microenvironments, FMN2 promotes cell survival by limiting nuclear envelope damage and DNA double-strand breaks. We found that FMN2 is upregulated in human melanomas and showed that disruption of FMN2 in mouse melanoma cells inhibits their extravasation and metastasis to the lung. Our results indicate a critical role for FMN2 in generating a perinuclear actin/FA system that protects the nucleus and DNA from damage to promote cell survival during confined migration and thus promote cancer metastasis.
Asunto(s)
Núcleo Celular/metabolismo , Adhesiones Focales , Neoplasias Pulmonares/secundario , Melanoma/patología , Proteínas de Microfilamentos/metabolismo , Metástasis de la Neoplasia , Proteínas Nucleares/metabolismo , Actinas/metabolismo , Animales , Roturas del ADN de Doble Cadena , Embrión de Mamíferos/citología , Matriz Extracelular/metabolismo , Femenino , Forminas , Humanos , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido NerviosoRESUMEN
Immunity in the human respiratory tract is provided by a diverse range of tissue-resident cells, including specialized epithelial and macrophage populations and a network of innate and innate-like lymphocytes, such as natural killer cells, innate lymphoid cells, and invariant T cells. Lung-resident memory T and B cells contribute to this network following initial exposure to antigenic stimuli. This review explores how advances in the study of human immunology have shaped our understanding of this resident immune network and its response to two of the most commonly encountered inflammatory stimuli in the airways: viruses and allergens. It discusses the many ways in which pathogenic infection and allergic inflammation mirror each other, highlighting the key checkpoints at which they diverge and how this can result in a lifetime of allergic exacerbation versus protective anti-viral immunity.
Asunto(s)
Alérgenos/inmunología , Inmunidad Innata/inmunología , Inflamación/inmunología , Pulmón/inmunología , Infecciones del Sistema Respiratorio/inmunología , Virosis/inmunología , Animales , Humanos , Inflamación/virología , Pulmón/virología , Linfocitos/inmunología , Infecciones del Sistema Respiratorio/virologíaRESUMEN
Cell migration toward areas of higher extracellular matrix (ECM) rigidity via a process called "durotaxis" is thought to contribute to development, immune response, and cancer metastasis. To understand how cells sample ECM rigidity to guide durotaxis, we characterized cell-generated forces on the nanoscale within single mature integrin-based focal adhesions (FAs). We found that individual FAs act autonomously, exhibiting either stable or dynamically fluctuating ("tugging") traction. We show that a FAK/phosphopaxillin/vinculin pathway is essential for high FA traction and to enable tugging FA traction over a broad range of ECM rigidities. We show that tugging FA traction is dispensable for FA maturation, chemotaxis, and haptotaxis but is critical to direct cell migration toward rigid ECM. We conclude that individual FAs dynamically sample rigidity by applying fluctuating pulling forces to the ECM to act as sensors to guide durotaxis, and that FAK/phosphopaxillin/vinculin signaling defines the rigidity range over which this dynamic sensing process operates.
Asunto(s)
Movimiento Celular , Matriz Extracelular/química , Adhesiones Focales/química , Animales , Fenómenos Biomecánicos , Embrión de Mamíferos/citología , Matriz Extracelular/metabolismo , Quinasa 2 de Adhesión Focal/metabolismo , Ratones , Microscopía/métodos , Transducción de Señal , Imagen de Lapso de Tiempo , Quinasas Asociadas a rho/metabolismoRESUMEN
Pulmonary immune homeostasis is maintained by a network of tissue-resident cells that continually monitor the external environment, and in health, instruct tolerance to innocuous inhaled particles while ensuring that efficient and rapid immune responses can be mounted against invading pathogens. Here we review the multiple pathways that underlie effective lung immunity in health, and discuss how these may be affected by external environmental factors and contribute to chronic inflammation during disease. In this context, we examine the current understanding of the impact of the microbiota in immune development and function and in the setting of the threshold for immune responses that maintains the balance between tolerance and chronic inflammation in the lung. We propose that host interactions with microbes are critical for establishing the immune landscape of the lungs.
Asunto(s)
Envejecimiento/inmunología , Homeostasis/inmunología , Sistema Inmunológico/inmunología , Pulmón/inmunología , Microbiota/inmunología , Animales , Interacciones Huésped-Patógeno/inmunología , Humanos , Sistema Inmunológico/microbiología , Inflamación/inmunología , Inflamación/fisiopatología , Pulmón/microbiología , Microbiota/fisiología , Modelos InmunológicosRESUMEN
Judgement, as one of the core tenets of medicine, relies upon the integration of multilayered data with nuanced decision making. Cancer offers a unique context for medical decisions given not only its variegated forms with evolution of disease but also the need to take into account the individual condition of patients, their ability to receive treatment, and their responses to treatment. Challenges remain in the accurate detection, characterization, and monitoring of cancers despite improved technologies. Radiographic assessment of disease most commonly relies upon visual evaluations, the interpretations of which may be augmented by advanced computational analyses. In particular, artificial intelligence (AI) promises to make great strides in the qualitative interpretation of cancer imaging by expert clinicians, including volumetric delineation of tumors over time, extrapolation of the tumor genotype and biological course from its radiographic phenotype, prediction of clinical outcome, and assessment of the impact of disease and treatment on adjacent organs. AI may automate processes in the initial interpretation of images and shift the clinical workflow of radiographic detection, management decisions on whether or not to administer an intervention, and subsequent observation to a yet to be envisioned paradigm. Here, the authors review the current state of AI as applied to medical imaging of cancer and describe advances in 4 tumor types (lung, brain, breast, and prostate) to illustrate how common clinical problems are being addressed. Although most studies evaluating AI applications in oncology to date have not been vigorously validated for reproducibility and generalizability, the results do highlight increasingly concerted efforts in pushing AI technology to clinical use and to impact future directions in cancer care.
Asunto(s)
Inteligencia Artificial , Diagnóstico por Imagen/métodos , Neoplasias/diagnóstico por imagen , HumanosRESUMEN
Neutrophil recruitment to sites of infection and inflammation is an essential process in the early innate immune response. Upon activation, a subset of neutrophils rapidly assembles the multiprotein complex known as the NLRP3 inflammasome. The NLRP3 inflammasome forms at the microtubule organizing center, which promotes the formation of interleukin (IL)-1ß and IL-18, essential cytokines in the immune response. We recently showed that mice deficient in NLRP3 (NLRP3-/-) have reduced neutrophil recruitment to the peritoneum in a model of thioglycolate-induced peritonitis. Here, we tested the hypothesis that this diminished recruitment could be, in part, the result of defects in neutrophil chemotaxis. We find that NLRP3-/- neutrophils show loss of cell polarization, as well as reduced directionality and velocity of migration toward increasing concentrations of leukotriene B4 (LTB4) in a chemotaxis assay in vitro, which was confirmed through intravital microscopy of neutrophil migration toward a laser-induced burn injury of the liver. Furthermore, pharmacologically blocking NLRP3 inflammasome assembly with MCC950 in vitro reduced directionality but preserved nondirectional movement, indicating that inflammasome assembly is specifically required for polarization and directional chemotaxis, but not cell motility per se. In support of this, pharmacological breakdown of the microtubule cytoskeleton via nocodazole treatment induced cell polarization and restored nondirectional cell migration in NLRP3-deficient neutrophils in the LTB4 gradient. Therefore, NLRP3 inflammasome assembly is required for establishment of cell polarity to guide the directional chemotactic migration of neutrophils.
Asunto(s)
Quimiotaxis , Leucotrieno B4 , Proteína con Dominio Pirina 3 de la Familia NLR , Animales , Ratones , Inflamasomas , Leucotrieno B4/metabolismo , Neutrófilos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismoRESUMEN
T cells are present in early stages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and play a major role in disease outcome and long-lasting immunity. Nasal administration of a fully human anti-CD3 monoclonal antibody (Foralumab) reduced lung inflammation as well as serum IL-6 and C-reactive protein in moderate cases of COVID-19. Using serum proteomics and RNA-sequencing, we investigated the immune changes in patients treated with nasal Foralumab. In a randomized trial, mild to moderate COVID-19 outpatients received nasal Foralumab (100 µg/d) given for 10 consecutive days and were compared to patients that did not receive Foralumab. We found that naïve-like T cells were increased in Foralumab-treated subjects and NGK7+ effector T cells were reduced. CCL5, IL32, CST7, GZMH, GZMB, GZMA, PRF1, and CCL4 gene expression were downregulated in T cells and CASP1 was downregulated in T cells, monocytes, and B cells in subjects treated with Foralumab. In addition to the downregulation of effector features, an increase in TGFB1 gene expression in cell types with known effector function was observed in Foralumab-treated subjects. We also found increased expression of GTP-binding gene GIMAP7 in subjects treated with Foralumab. Rho/ROCK1, a downstream pathway of GTPases signaling was downregulated in Foralumab-treated individuals. TGFB1, GIMAP7, and NKG7 transcriptomic changes observed in Foralumab-treated COVID-19 subjects were also observed in healthy volunteers, MS subjects, and mice treated with nasal anti-CD3. Our findings demonstrate that nasal Foralumab modulates the inflammatory response in COVID-19 and provides a novel avenue to treat the disease.
Asunto(s)
Anticuerpos Monoclonales , COVID-19 , Animales , Humanos , Ratones , Administración Intranasal , Anticuerpos Monoclonales/uso terapéutico , Proteínas de Unión al GTP , Proteínas de la Membrana , Quinasas Asociadas a rho , SARS-CoV-2 , Linfocitos T , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
[This corrects the article DOI: 10.1371/journal.ppat.1011461.].
RESUMEN
In this study, we evaluated the impact of viral variant, in addition to other variables, on within-host viral burden, by analysing cycle threshold (Ct) values derived from nose and throat swabs, collected as part of the UK COVID-19 Infection Survey. Because viral burden distributions determined from community survey data can be biased due to the impact of variant epidemiology on the time-since-infection of samples, we developed a method to explicitly adjust observed Ct value distributions to account for the expected bias. By analysing the adjusted Ct values using partial least squares regression, we found that among unvaccinated individuals with no known prior exposure, viral burden was 44% lower among Alpha variant infections, compared to those with the predecessor strain, B.1.177. Vaccination reduced viral burden by 67%, and among vaccinated individuals, viral burden was 286% higher among Delta variant, compared to Alpha variant, infections. In addition, viral burden increased by 17% for every 10-year age increment of the infected individual. In summary, within-host viral burden increases with age, is reduced by vaccination, and is influenced by the interplay of vaccination status and viral variant.
Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Sesgo de Selección , SARS-CoV-2/genética , Carga Viral , COVID-19/epidemiología , COVID-19/prevención & control , VacunaciónRESUMEN
Upon bacterial infection, mounting the appropriate immune response is paramount to effective pathogen clearance. In a recent study, Agaronyan et al. show how Pseudomonas aeruginosa can divert host immunity to boost type 2 responses and drive mucus production, which can then act as a nutrient source for bacteria.
Asunto(s)
Infecciones por Pseudomonas , Pseudomonas aeruginosa , Humanos , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/fisiologíaRESUMEN
Understanding the localization of cells is important as local environmental cues influence both phenotype and effector function. In this issue of Immunity, Pepper and colleagues find that allergen-specific tissue-resident memory T cells are maintained by IL-2 and are key drivers of allergic pathology.
Asunto(s)
Asma/inmunología , Memoria Inmunológica/inmunología , Interleucina-2/inmunología , Pulmón/inmunología , Células Th2/inmunología , Animales , Femenino , MasculinoRESUMEN
BACKGROUND: Wheezing in childhood is prevalent, with over half of all children experiencing at least one episode by age six. The pathophysiology of wheeze, especially why some children develop asthma while others do not, remains unclear. OBJECTIVE: This study addresses the knowledge gap by investigating the transition from preschool wheeze to asthma using multi-omic profiling. METHODS: Unsupervised, group-agnostic integrative multi-omic factor analysis was performed using host/bacterial (meta-)transcriptomic and bacterial shotgun metagenomic datasets from bronchial brush samples paired with metabolomic/lipidomic data from bronchoalveolar lavage samples acquired from children 1-17 years old. RESULTS: Two multi-omic factors were identified: one characterising preschool-aged recurrent wheeze and another capturing an inferred trajectory from health to wheeze and school-aged asthma. Recurrent wheeze was driven by Type 1-immune signatures, coupled with upregulation of immune-related and neutrophil-associated lipids and metabolites. Comparatively, progression towards asthma from ages 1-18 was dominated by changes related to airway epithelial cell gene expression, Type 2-immune responses, and constituents of the airway microbiome, such as increased Haemophilus influenzae. CONCLUSION: These factors highlighted distinctions between an inflammation-related phenotype in preschool wheeze, and the predominance of airway epithelial-related changes linked with the inferred trajectory toward asthma. These findings provide insights into the differential mechanisms driving the progression from wheeze to asthma and may inform targeted therapeutic strategies.
RESUMEN
Novel systemic therapies for breast cancer are being rapidly implemented into clinical practice. These drugs often have different mechanisms of action and side-effect profiles compared with traditional chemotherapy. Underpinning practice-changing clinical trials focused on the systemic therapies under investigation, thus there are sparse data available on radiotherapy. Integration of these new systemic therapies with radiotherapy is therefore challenging. Given this rapid, transformative change in breast cancer multimodal management, the multidisciplinary community must unite to ensure optimal, safe, and equitable treatment for all patients. The aim of this collaborative group of radiation, clinical, and medical oncologists, basic and translational scientists, and patient advocates was to: scope, synthesise, and summarise the literature on integrating novel drugs with radiotherapy for breast cancer; produce consensus statements on drug-radiotherapy integration, where specific evidence is lacking; and make best-practice recommendations for recording of radiotherapy data and quality assurance for subsequent studies testing novel drugs.