RESUMEN
Pulmonary granulomas are widely considered the epicenters of the immune response to Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Recent animal studies have revealed factors that either promote or restrict TB immunity within granulomas. These models, however, typically ignore the impact of preexisting immunity on cellular organization and function, an important consideration because most TB probably occurs through reinfection of previously exposed individuals. Human postmortem research from the pre-antibiotic era showed that infections in Mtb-naïve individuals (primary TB) versus those with prior Mtb exposure (postprimary TB) have distinct pathologic features. We review recent animal findings in TB granuloma biology, which largely reflect primary TB. We also discuss our current understanding of postprimary TB lesions, about which much less is known. Many knowledge gaps remain, particularly regarding how preexisting immunity shapes granuloma structure and local immune responses at Mtb infection sites.
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis , Animales , Granuloma/etiología , Humanos , Pulmón/microbiología , Pulmón/patologíaRESUMEN
Fibrotic interstitial lung diseases (fILDs) have poor survival rates and lack effective therapies. Despite evidence for immune mechanisms in lung fibrosis, immunotherapies have been unsuccessful for major types of fILD. Here, we review immunological mechanisms in lung fibrosis that have the potential to impact clinical practice. We first examine innate immunity, which is broadly involved across fILD subtypes. We illustrate how innate immunity in fILD involves a complex interplay of multiple cell subpopulations and molecular pathways. We then review the growing evidence for adaptive immunity in lung fibrosis to provoke a re-examination of its role in clinical fILD. We close with future directions to address key knowledge gaps in fILD pathobiology: (1) longitudinal studies emphasizing early-stage clinical disease, (2) immune mechanisms of acute exacerbations, and (3) next-generation immunophenotyping integrating spatial, genetic, and single-cell approaches. Advances in these areas are essential for the future of precision medicine and immunotherapy in fILD.
Asunto(s)
Inmunidad Innata , Enfermedades Pulmonares Intersticiales , Humanos , Enfermedades Pulmonares Intersticiales/inmunología , Enfermedades Pulmonares Intersticiales/patología , Animales , Inmunidad Adaptativa , Inmunoterapia , Fibrosis Pulmonar/inmunología , Fibrosis Pulmonar/patología , Pulmón/patología , Pulmón/inmunologíaRESUMEN
Infections of the lung cause observable sickness thought to be secondary to inflammation. Signs of sickness are crucial to alert others via behavioral-immune responses to limit contact with contagious individuals. Gram-negative bacteria produce exopolysaccharide (EPS) that provides microbial protection; however, the impact of EPS on sickness remains uncertain. Using genome-engineered Pseudomonas aeruginosa (P. aeruginosa) strains, we compared EPS-producers versus non-producers and a virulent Escherichia coli (E. coli) lung infection model in male and female mice. EPS-negative P. aeruginosa and virulent E. coli infection caused severe sickness, behavioral alterations, inflammation, and hypothermia mediated by TLR4 detection of the exposed lipopolysaccharide (LPS) in lung TRPV1+ sensory neurons. However, inflammation did not account for sickness. Stimulation of lung nociceptors induced acute stress responses in the paraventricular hypothalamic nuclei by activating corticotropin-releasing hormone neurons responsible for sickness behavior and hypothermia. Thus, EPS-producing biofilm pathogens evade initiating a lung-brain sensory neuronal response that results in sickness.
Asunto(s)
Infecciones por Escherichia coli , Escherichia coli , Pulmón , Polisacáridos Bacterianos , Infecciones por Pseudomonas , Pseudomonas aeruginosa , Animales , Femenino , Masculino , Ratones , Biopelículas , Escherichia coli/fisiología , Hipotermia/metabolismo , Hipotermia/patología , Inflamación/metabolismo , Inflamación/patología , Pulmón/microbiología , Pulmón/patología , Neumonía/microbiología , Neumonía/patología , Pseudomonas aeruginosa/fisiología , Células Receptoras Sensoriales , Polisacáridos Bacterianos/metabolismo , Infecciones por Escherichia coli/metabolismo , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/patología , Infecciones por Pseudomonas/metabolismo , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/patología , Nociceptores/metabolismoRESUMEN
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
Respiratory infections cause significant morbidity and mortality, yet it is unclear why some individuals succumb to severe disease. In patients hospitalized with avian A(H7N9) influenza, we investigated early drivers underpinning fatal disease. Transcriptomics strongly linked oleoyl-acyl-carrier-protein (ACP) hydrolase (OLAH), an enzyme mediating fatty acid production, with fatal A(H7N9) early after hospital admission, persisting until death. Recovered patients had low OLAH expression throughout hospitalization. High OLAH levels were also detected in patients hospitalized with life-threatening seasonal influenza, COVID-19, respiratory syncytial virus (RSV), and multisystem inflammatory syndrome in children (MIS-C) but not during mild disease. In olah-/- mice, lethal influenza infection led to survival and mild disease as well as reduced lung viral loads, tissue damage, infection-driven pulmonary cell infiltration, and inflammation. This was underpinned by differential lipid droplet dynamics as well as reduced viral replication and virus-induced inflammation in macrophages. Supplementation of oleic acid, the main product of OLAH, increased influenza replication in macrophages and their inflammatory potential. Our findings define how the expression of OLAH drives life-threatening viral disease.
Asunto(s)
COVID-19 , Gripe Humana , Animales , Humanos , Ratones , COVID-19/virología , COVID-19/genética , Gripe Humana/virología , Replicación Viral , Macrófagos/metabolismo , Macrófagos/virología , Femenino , Masculino , SARS-CoV-2 , Pulmón/virología , Pulmón/patología , Pulmón/metabolismo , Ratones Endogámicos C57BL , Ácido Oléico/metabolismo , Infecciones por Virus Sincitial Respiratorio/virología , Ratones Noqueados , Carga Viral , Hidrolasas de Éster Carboxílico/metabolismo , Hidrolasas de Éster Carboxílico/genética , Infecciones por Orthomyxoviridae/virología , Infecciones del Sistema Respiratorio/virología , NiñoRESUMEN
SARS-CoV-2 and other sarbecoviruses continue to threaten humanity, highlighting the need to characterize common mechanisms of viral immune evasion for pandemic preparedness. Cytotoxic lymphocytes are vital for antiviral immunity and express NKG2D, an activating receptor conserved among mammals that recognizes infection-induced stress ligands (e.g., MIC-A/B). We found that SARS-CoV-2 evades NKG2D recognition by surface downregulation of MIC-A/B via shedding, observed in human lung tissue and COVID-19 patient serum. Systematic testing of SARS-CoV-2 proteins revealed that ORF6, an accessory protein uniquely conserved among sarbecoviruses, was responsible for MIC-A/B downregulation via shedding. Further investigation demonstrated that natural killer (NK) cells efficiently killed SARS-CoV-2-infected cells and limited viral spread. However, inhibition of MIC-A/B shedding with a monoclonal antibody, 7C6, further enhanced NK-cell activity toward SARS-CoV-2-infected cells. Our findings unveil a strategy employed by SARS-CoV-2 to evade cytotoxic immunity, identify the culprit immunevasin shared among sarbecoviruses, and suggest a potential novel antiviral immunotherapy.
Asunto(s)
COVID-19 , Evasión Inmune , Células Asesinas Naturales , Subfamilia K de Receptores Similares a Lectina de Células NK , SARS-CoV-2 , Humanos , SARS-CoV-2/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , COVID-19/inmunología , COVID-19/virología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Animales , Citotoxicidad Inmunológica , Regulación hacia Abajo , Pulmón/inmunología , Pulmón/virología , Pulmón/patologíaRESUMEN
Mycobacterium tuberculosis (Mtb) cultured axenically without detergent forms biofilm-like cords, a clinical identifier of virulence. In lung-on-chip (LoC) and mouse models, cords in alveolar cells contribute to suppression of innate immune signaling via nuclear compression. Thereafter, extracellular cords cause contact-dependent phagocyte death but grow intercellularly between epithelial cells. The absence of these mechanopathological mechanisms explains the greater proportion of alveolar lesions with increased immune infiltration and dissemination defects in cording-deficient Mtb infections. Compression of Mtb lipid monolayers induces a phase transition that enables mechanical energy storage. Agent-based simulations demonstrate that the increased energy storage capacity is sufficient for the formation of cords that maintain structural integrity despite mechanical perturbation. Bacteria in cords remain translationally active despite antibiotic exposure and regrow rapidly upon cessation of treatment. This study provides a conceptual framework for the biophysics and function in tuberculosis infection and therapy of cord architectures independent of mechanisms ascribed to single bacteria.
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis , Animales , Ratones , Biopelículas , Pulmón/microbiología , Pulmón/patología , Mycobacterium tuberculosis/fisiología , Tuberculosis/microbiología , Tuberculosis/patología , Virulencia , Fenómenos BiomecánicosRESUMEN
Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Antígenos Virales/inmunología , Candida albicans/química , Mananos/inmunología , Hidróxido de Aluminio/química , Animales , Anticuerpos Neutralizantes/inmunología , Especificidad de Anticuerpos/inmunología , Linfocitos B/inmunología , COVID-19/inmunología , COVID-19/prevención & control , COVID-19/virología , Chlorocebus aethiops , Epítopos/inmunología , Inmunidad Innata , Inmunización , Inflamación/patología , Interferones/metabolismo , Lectinas Tipo C/metabolismo , Ligandos , Pulmón/inmunología , Pulmón/patología , Pulmón/virología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Senos Paranasales/metabolismo , Subunidades de Proteína/metabolismo , Lectina 1 Similar a Ig de Unión al Ácido Siálico/metabolismo , Solubilidad , Glicoproteína de la Espiga del Coronavirus/metabolismo , Linfocitos T/inmunología , Factor de Transcripción ReIB/metabolismo , Células Vero , beta-Glucanos/metabolismoRESUMEN
Cytomegaloviruses (CMVs) have co-evolved with their mammalian hosts for millions of years, leading to remarkable host specificity and high infection prevalence. Macrophages, which already populate barrier tissues in the embryo, are the predominant immune cells at potential CMV entry sites. Here we show that, upon CMV infection, macrophages undergo a morphological, immunophenotypic, and metabolic transformation process with features of stemness, altered migration, enhanced invasiveness, and provision of the cell cycle machinery for viral proliferation. This complex process depends on Wnt signaling and the transcription factor ZEB1. In pulmonary infection, mouse CMV primarily targets and reprograms alveolar macrophages, which alters lung physiology and facilitates primary CMV and secondary bacterial infection by attenuating the inflammatory response. Thus, CMV profoundly perturbs macrophage identity beyond established limits of plasticity and rewires specific differentiation processes, allowing viral spread and impairing innate tissue immunity.
Asunto(s)
Citomegalovirus/fisiología , Macrófagos Alveolares/virología , Animales , Presentación de Antígeno , Efecto Espectador , Ciclo Celular , Línea Celular Transformada , Reprogramación Celular , Citomegalovirus/patogenicidad , Citomegalovirus/ultraestructura , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Proteínas Fluorescentes Verdes/metabolismo , Pulmón/patología , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/ultraestructura , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Fenotipo , Células Madre/patología , Replicación Viral/fisiología , Vía de Señalización WntRESUMEN
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.
Asunto(s)
Envejecimiento , Senescencia Celular , Enfermedades Pulmonares , Pulmón , Inmunidad Adaptativa , Anciano , Envejecimiento/inmunología , Envejecimiento/patología , COVID-19/inmunología , COVID-19/patología , Humanos , Pulmón/inmunología , Pulmón/patología , Enfermedades Pulmonares/inmunología , Enfermedades Pulmonares/patología , Estrés OxidativoRESUMEN
SARS-CoV-2-neutralizing antibodies (NAbs) protect against COVID-19. A concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated NAbs against the receptor-binding domain (RBD) or the N-terminal domain (NTD) of SARS-CoV-2 spike from individuals with acute or convalescent SARS-CoV-2 or a history of SARS-CoV infection. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific modes of binding. Select RBD NAbs also demonstrated Fc receptor-γ (FcγR)-mediated enhancement of virus infection in vitro, while five non-neutralizing NTD antibodies mediated FcγR-independent in vitro infection enhancement. However, both types of infection-enhancing antibodies protected from SARS-CoV-2 replication in monkeys and mice. Three of 46 monkeys infused with enhancing antibodies had higher lung inflammation scores compared to controls. One monkey had alveolar edema and elevated bronchoalveolar lavage inflammatory cytokines. Thus, while in vitro antibody-enhanced infection does not necessarily herald enhanced infection in vivo, increased lung inflammation can rarely occur in SARS-CoV-2 antibody-infused macaques.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , SARS-CoV-2/fisiología , Glicoproteína de la Espiga del Coronavirus/inmunología , Animales , Anticuerpos Antivirales/inmunología , Líquido del Lavado Bronquioalveolar/química , COVID-19/patología , COVID-19/virología , Citocinas/metabolismo , Femenino , Haplorrinos , Humanos , Pulmón/patología , Pulmón/virología , Masculino , Ratones , Ratones Endogámicos BALB C , Dominios Proteicos , ARN Guía de Kinetoplastida/metabolismo , Receptores de IgG/metabolismo , SARS-CoV-2/aislamiento & purificación , Glicoproteína de la Espiga del Coronavirus/química , Carga Viral , Replicación ViralRESUMEN
Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. Because rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment-induced emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of virus variants in SARS-COV-2 isolates found in COVID-19 patients treated with the two-antibody combination REGEN-COV, as well as in preclinical in vitro studies using single, dual, or triple antibody combinations, and in hamster in vivo studies using REGEN-COV or single monoclonal antibody treatments. Our study demonstrates that the combination of non-competing antibodies in REGEN-COV provides protection against all current SARS-CoV-2 variants of concern/interest and also protects against emergence of new variants and their potential seeding into the population in a clinical setting.
Asunto(s)
Anticuerpos Monoclonales/inmunología , COVID-19/inmunología , COVID-19/prevención & control , Mutación/genética , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Animales , COVID-19/virología , Chlorocebus aethiops , Cricetinae , Microscopía por Crioelectrón , Hospitalización , Humanos , Pulmón/patología , Pulmón/virología , Masculino , Pruebas de Neutralización , Células Vero , Carga ViralRESUMEN
Severe coronavirus disease 2019 (COVID-19) is characterized by overproduction of immune mediators, but the role of interferons (IFNs) of the type I (IFN-I) or type III (IFN-III) families remains debated. We scrutinized the production of IFNs along the respiratory tract of COVID-19 patients and found that high levels of IFN-III, and to a lesser extent IFN-I, characterize the upper airways of patients with high viral burden but reduced disease risk or severity. Production of specific IFN-III, but not IFN-I, members denotes patients with a mild pathology and efficiently drives the transcription of genes that protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In contrast, compared to subjects with other infectious or noninfectious lung pathologies, IFNs are overrepresented in the lower airways of patients with severe COVID-19 that exhibit gene pathways associated with increased apoptosis and decreased proliferation. Our data demonstrate a dynamic production of IFNs in SARS-CoV-2-infected patients and show IFNs play opposing roles at distinct anatomical sites.
Asunto(s)
COVID-19/patología , Interferones/metabolismo , Sistema Respiratorio/virología , Índice de Severidad de la Enfermedad , Factores de Edad , Envejecimiento/patología , COVID-19/genética , COVID-19/inmunología , Células Epiteliales/patología , Células Epiteliales/virología , Regulación de la Expresión Génica , Humanos , Interferones/genética , Leucocitos/patología , Leucocitos/virología , Pulmón/patología , Pulmón/virología , Síndrome de Dificultad Respiratoria/patología , Síndrome de Dificultad Respiratoria/virología , Carga ViralRESUMEN
SARS-CoV-2-induced hypercytokinemia and inflammation are critically associated with COVID-19 severity. Baricitinib, a clinically approved JAK1/JAK2 inhibitor, is currently being investigated in COVID-19 clinical trials. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages, and tissues was not reduced with baricitinib. Type I interferon (IFN) antiviral responses and SARS-CoV-2-specific T cell responses remained similar between the two groups. Animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib-treated animals had a rapid and remarkably potent suppression of lung macrophage production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for inflammation induced by SARS-CoV-2 infection.
Asunto(s)
Antiinflamatorios/administración & dosificación , Azetidinas/administración & dosificación , Tratamiento Farmacológico de COVID-19 , COVID-19/inmunología , Macaca mulatta , Infiltración Neutrófila/efectos de los fármacos , Purinas/administración & dosificación , Pirazoles/administración & dosificación , Sulfonamidas/administración & dosificación , Animales , COVID-19/fisiopatología , Muerte Celular/efectos de los fármacos , Degranulación de la Célula/efectos de los fármacos , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/inmunología , Quinasas Janus/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Activación de Linfocitos/efectos de los fármacos , Macrófagos Alveolares/inmunología , SARS-CoV-2/fisiología , Índice de Severidad de la Enfermedad , Linfocitos T/inmunología , Replicación Viral/efectos de los fármacosRESUMEN
Evidence has increasingly shown that the lungs are a major site of immune regulation. A robust and highly regulated immune response in the lung protects the host from pathogen infection, whereas an inefficient or deleterious response can lead to various pulmonary diseases. Many cell types, such as epithelial cells, dendritic cells, macrophages, neutrophils, eosinophils, and B and T lymphocytes, contribute to lung immunity. This review focuses on the recent advances in understanding how T lymphocytes mediate pulmonary host defenses against bacterial, viral, and fungal pathogens.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Pulmón/inmunología , Pulmón/patología , Tuberculosis Pulmonar/inmunología , Animales , Linfocitos T CD4-Positivos/metabolismo , Interacciones Huésped-Patógeno/inmunología , Humanos , Pulmón/microbiología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/microbiología , Ganglios Linfáticos/patología , Mycobacterium tuberculosis/inmunología , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/patologíaRESUMEN
A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis (Mtb). We have shown that systemic administration of Bacille Calmette-Guérin (BCG) or ß-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb. Here, we demonstrate that, unlike BCG or ß-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb. Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death specifically in myeloid progenitors. Additionally, activation of the IFN-I/iron axis in HSCs impairs trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the BM that controls the magnitude and intrinsic anti-microbial capacity of innate immunity to infection.
Asunto(s)
Células Madre Hematopoyéticas/microbiología , Inmunidad , Mycobacterium tuberculosis/fisiología , Mielopoyesis , Animales , Células de la Médula Ósea/metabolismo , Proliferación Celular , Susceptibilidad a Enfermedades , Homeostasis , Interferón Tipo I/metabolismo , Hierro/metabolismo , Cinética , Pulmón/microbiología , Pulmón/patología , Macrófagos/inmunología , Ratones Endogámicos C57BL , Células Mieloides/metabolismo , Necrosis , Transducción de Señal , Transcripción Genética , Tuberculosis/inmunología , Tuberculosis/microbiología , Tuberculosis/patologíaRESUMEN
Chronic obstructive pulmonary disease (COPD) is a progressive condition of chronic bronchitis, small airway obstruction, and emphysema that represents a leading cause of death worldwide. While inflammation, fibrosis, mucus hypersecretion, and metaplastic epithelial lesions are hallmarks of this disease, their origins and dependent relationships remain unclear. Here we apply single-cell cloning technologies to lung tissue of patients with and without COPD. Unlike control lungs, which were dominated by normal distal airway progenitor cells, COPD lungs were inundated by three variant progenitors epigenetically committed to distinct metaplastic lesions. When transplanted to immunodeficient mice, these variant clones induced pathology akin to the mucous and squamous metaplasia, neutrophilic inflammation, and fibrosis seen in COPD. Remarkably, similar variants pre-exist as minor constituents of control and fetal lung and conceivably act in normal processes of immune surveillance. However, these same variants likely catalyze the pathologic and progressive features of COPD when expanded to high numbers.
Asunto(s)
Pulmón/patología , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Adulto , Anciano , Animales , Femenino , Fibrosis/fisiopatología , Humanos , Inflamación/patología , Pulmón/metabolismo , Masculino , Metaplasia/fisiopatología , Ratones , Persona de Mediana Edad , Neutrófilos/inmunología , Neumonía/patología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Análisis de la Célula Individual/métodos , Células Madre/metabolismoRESUMEN
SARS-CoV-2 infection is mild in the majority of individuals but progresses into severe pneumonia in a small proportion of patients. The increased susceptibility to severe disease in the elderly and individuals with co-morbidities argues for an initial defect in anti-viral host defense mechanisms. Long-term boosting of innate immune responses, also termed "trained immunity," by certain live vaccines (BCG, oral polio vaccine, measles) induces heterologous protection against infections through epigenetic, transcriptional, and functional reprogramming of innate immune cells. We propose that induction of trained immunity by whole-microorganism vaccines may represent an important tool for reducing susceptibility to and severity of SARS-CoV-2.
Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/inmunología , Inmunidad Innata , Inmunomodulación , Neumonía Viral/inmunología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/fisiología , Animales , Vacuna BCG/inmunología , COVID-19 , Ensayos Clínicos como Asunto , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/fisiopatología , Infecciones por Coronavirus/transmisión , Humanos , Inmunidad Innata/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Linfopenia/patología , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Pandemias , Neumonía Viral/patología , Neumonía Viral/fisiopatología , Neumonía Viral/transmisión , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/inmunología , Síndrome Respiratorio Agudo Grave/patología , Replicación ViralRESUMEN
Fibrosis can develop in most organs and causes organ failure. The most common type of lung fibrosis is known as idiopathic pulmonary fibrosis, in which fibrosis starts at the lung periphery and then progresses toward the lung center, eventually causing respiratory failure. Little is known about the mechanisms underlying the pathogenesis and periphery-to-center progression of the disease. Here we discovered that loss of Cdc42 function in alveolar stem cells (AT2 cells) causes periphery-to-center progressive lung fibrosis. We further show that Cdc42-null AT2 cells in both post-pneumonectomy and untreated aged mice cannot regenerate new alveoli, resulting in sustained exposure of AT2 cells to elevated mechanical tension. We demonstrate that elevated mechanical tension activates a TGF-ß signaling loop in AT2 cells, which drives the periphery-to-center progression of lung fibrosis. Our study establishes a direct mechanistic link between impaired alveolar regeneration, mechanical tension, and progressive lung fibrosis.
Asunto(s)
Células Madre Adultas/metabolismo , Fibrosis Pulmonar Idiopática/etiología , Alveolos Pulmonares/metabolismo , Células Madre Adultas/patología , Anciano , Células Epiteliales Alveolares/patología , Animales , Fenómenos Biomecánicos/fisiología , Femenino , Fibrosis/patología , Humanos , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Pulmón/patología , Masculino , Ratones , Persona de Mediana Edad , Alveolos Pulmonares/patología , Regeneración , Transducción de Señal , Células Madre/patología , Estrés Mecánico , Estrés Fisiológico/fisiología , Factor de Crecimiento Transformador beta/metabolismo , Proteína de Unión al GTP cdc42/genética , Proteína de Unión al GTP cdc42/metabolismoRESUMEN
Understanding how potent neutralizing antibodies (NAbs) inhibit SARS-CoV-2 is critical for effective therapeutic development. We previously described BD-368-2, a SARS-CoV-2 NAb with high potency; however, its neutralization mechanism is largely unknown. Here, we report the 3.5-Å cryo-EM structure of BD-368-2/trimeric-spike complex, revealing that BD-368-2 fully blocks ACE2 recognition by occupying all three receptor-binding domains (RBDs) simultaneously, regardless of their "up" or "down" conformations. Also, BD-368-2 treats infected adult hamsters at low dosages and at various administering windows, in contrast to placebo hamsters that manifested severe interstitial pneumonia. Moreover, BD-368-2's epitope completely avoids the common binding site of VH3-53/VH3-66 recurrent NAbs, evidenced by tripartite co-crystal structures with RBDs. Pairing BD-368-2 with a potent recurrent NAb neutralizes SARS-CoV-2 pseudovirus at pM level and rescues mutation-induced neutralization escapes. Together, our results rationalized a new RBD epitope that leads to high neutralization potency and demonstrated BD-368-2's therapeutic potential in treating COVID-19.