RESUMEN
Respiratory viruses constitute a significant cause of illness and death worldwide. Respiratory virus-associated injuries include oxidative stress, ferroptosis, inflammation, pyroptosis, apoptosis, fibrosis, autoimmunity, and vascular injury. Several studies have demonstrated the involvement of the nuclear factor erythroid 2-related factor 2 (Nrf2) in the pathophysiology of viral infection and associated complications. It has thus emerged as a pivotal player in cellular defense mechanisms against such damage. Here, we discuss the impact of Nrf2 activation on airway injuries induced by respiratory viruses, including viruses, coronaviruses, rhinoviruses, and respiratory syncytial viruses. The inhibition or deregulation of Nrf2 pathway activation induces airway tissue damage in the presence of viral respiratory infections. In contrast, Nrf2 pathway activation demonstrates protection against tissue and organ injuries. Clinical trials involving Nrf2 agonists are needed to define the effect of Nrf2 therapeutics on airway tissues and organs damaged by viral respiratory infections.
Asunto(s)
Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , Infecciones del Sistema Respiratorio , Transducción de Señal , Factor 2 Relacionado con NF-E2/metabolismo , Humanos , Infecciones del Sistema Respiratorio/virología , Infecciones del Sistema Respiratorio/metabolismo , Infecciones del Sistema Respiratorio/patología , Animales , Virosis/metabolismo , Virosis/complicaciones , Virosis/patología , Virosis/virologíaRESUMEN
Humoral responses to respiratory viruses, such as influenza viruses, develop over time and are central to protection from repeated infection with the same or similar viruses. Epidemiological and experimental studies have linked exposures to environmental contaminants that bind the aryl hydrocarbon receptor (AHR) with modulated antibody responses to pathogenic microorganisms and common vaccinations. Other studies have prompted investigation into the potential therapeutic applications of compounds that activate AHR. Herein, using two different AHR ligands [2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester (ITE), to modulate the duration of AHR activity, we show that the humoral response to viral infection is dependent upon the duration and timing of AHR signaling, and that different cellular elements of the response have different sensitivities. When AHR activation was initiated prior to infection with influenza A virus, there was suppression of all measured elements of the humoral response (i.e., the frequency of T follicular helper cells, germinal center B cells, plasma cells, and circulating virus-specific antibody). However, when the timing of AHR activation was adjusted to either early (days -1 to +5 relative to infection) or later (days +5 onwards), then AHR activation affected different aspects of the overall humoral response. These findings highlight the importance of considering the timing of AHR activation in relation to triggering an immune response, particularly when targeting the AHR to manipulate disease processes.
Asunto(s)
Inmunidad Humoral , Dibenzodioxinas Policloradas , Receptores de Hidrocarburo de Aril , Receptores de Hidrocarburo de Aril/metabolismo , Animales , Inmunidad Humoral/efectos de los fármacos , Dibenzodioxinas Policloradas/toxicidad , Femenino , Factores de Tiempo , Ratones , Ratones Endogámicos C57BL , Indoles/farmacología , Transducción de Señal/efectos de los fármacos , Anticuerpos Antivirales , Infecciones por Orthomyxoviridae/inmunología , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/virología , Infecciones del Sistema Respiratorio/metabolismo , Ligandos , TiazolesRESUMEN
Severe viral lower respiratory tract infection (LRTI), resulting in both acute and long-term pulmonary disease, constitutes a substantial burden among young children. Viral LRTI triggers local oxidative stress pathways by infection and inflammation, and supportive care in the pediatric intensive care unit may further aggravate oxidative injury. The main goal of this exploratory study was to identify and monitor breath markers linked to oxidative stress in children over the disease course of severe viral LRTI. Exhaled breath was sampled during invasive ventilation, and volatile organic compounds (VOCs) were analyzed using gas chromatography and mass spectrometry. VOCs were selected in an untargeted principal component analysis and assessed for change over time. In addition, identified VOCs were correlated with clinical parameters. Seventy breath samples from 21 patients were analyzed. A total of 15 VOCs were identified that contributed the most to the explained variance of breath markers. Of these 15 VOCs, 10 were previously linked to pathways of oxidative stress. Eight VOCs, including seven alkanes and methyl alkanes, significantly decreased from the initial phase of ventilation to the day of extubation. No correlation was observed with the administered oxygen dose, whereas six VOCs showed a poor to strong positive correlation with driving pressure. In this prospective study of children with severe viral LRTI, the majority of VOCs that were most important for the explained variance mirrored clinical improvement. These breath markers could potentially help monitor the pulmonary oxidative status in these patients, but further research with other objective measures of pulmonary injury is required.
Asunto(s)
Biomarcadores , Pruebas Respiratorias , Estrés Oxidativo , Infecciones del Sistema Respiratorio , Compuestos Orgánicos Volátiles , Humanos , Masculino , Pruebas Respiratorias/métodos , Femenino , Preescolar , Biomarcadores/metabolismo , Lactante , Compuestos Orgánicos Volátiles/metabolismo , Compuestos Orgánicos Volátiles/análisis , Infecciones del Sistema Respiratorio/virología , Infecciones del Sistema Respiratorio/metabolismo , Niño , Estudios ProspectivosRESUMEN
Chronic lung allograft dysfunction (CLAD) is a major complication after lung transplantation that results from a complex interplay of innate inflammatory and alloimmune factors, culminating in parenchymal and/or obliterative airway fibrosis. Excessive IL-17A signaling and chronic inflammation have been recognized as key factors in these pathological processes. Herein, we developed a model of repeated airway inflammation in mouse minor alloantigen-mismatched single-lung transplantation. Repeated intratracheal LPS instillations augmented pulmonary IL-17A expression. LPS also increased acute rejection, airway epithelial damage, and obliterative airway fibrosis, similar to human explanted lung allografts with antecedent episodes of airway infection. We then investigated the role of donor and recipient IL-17 receptor A (IL-17RA) in this context. Donor IL-17RA deficiency significantly attenuated acute rejection and CLAD features, whereas recipient IL-17RA deficiency only slightly reduced airway obliteration in LPS allografts. IL-17RA immunofluorescence positive staining was greater in human CLAD lungs compared with control human lung specimens, with localization to fibroblasts and myofibroblasts, which was also seen in mouse LPS allografts. Taken together, repeated airway inflammation after lung transplantation caused local airway epithelial damage, with persistent elevation of IL-17A and IL-17RA expression and particular involvement of IL-17RA on donor structural cells in development of fibrosis.
Asunto(s)
Fibrosis Pulmonar , Infecciones del Sistema Respiratorio , Ratones , Humanos , Animales , Interleucina-17/metabolismo , Receptores de Interleucina-17/metabolismo , Lipopolisacáridos/toxicidad , Lipopolisacáridos/metabolismo , Fibrosis Pulmonar/patología , Pulmón/patología , Inflamación/metabolismo , Fibrosis , Infecciones del Sistema Respiratorio/metabolismo , AloinjertosRESUMEN
Airway epithelium repair after infection consists of wound repair, re-synthesis of the extracellular matrix (ECM), and tight junction proteins. In humans, EPs® 7630 obtained from Pelargonium sidoides roots reduces the severity and duration of acute respiratory tract infections. The effect of EPs® 7630 on tissue repair of rhinovirus-16 (RV-16) infected and control human airway epithelial cells was assessed for: (i) epithelial cell proliferation by manual cell counts, (ii) epithelial wound repair by "scratch assay", (iii) ECM composition by Western-blotting and cell-based ELISA, and (iv) epithelial tight junction proteins by Western-blotting. EPs® 7630 stimulated cell proliferation through cAMP, CREB, and p38 MAPK. EPs® 7630 significantly improved wound repair. Pro-inflammatory collagen type-I expression was reduced by EPs® 7630, while fibronectin was increased. Virus-binding tight junction proteins desmoglein2, desmocollin2, ZO-1, claudin1, and claudin4 were downregulated by EPs® 7630. The RV16-induced shift of the ECM towards the pro-inflammatory type was prevented by EPs® 7630. Most of the effects of EPs® 7630 on tissue repair and regeneration were sensitive to inhibition of cAMP-induced signaling. The data suggest that EPs® 7630-dependent modification of epithelial cell metabolism and function might underlie the faster recovery time from viral infections, as reported by others in clinical studies.
Asunto(s)
Infecciones del Sistema Respiratorio , Virus , Humanos , Extractos Vegetales/farmacología , Proteínas de Uniones Estrechas/metabolismo , Infecciones del Sistema Respiratorio/metabolismo , Células Epiteliales/metabolismo , Uniones Estrechas/metabolismoRESUMEN
The respiratory tract is a gateway for viruses and bacteria from the external environment to invade the human body. Critical to the protection against these invaders are dendritic cells (DCs) - a group of highly specialized myeloid cells that monitors the lung microenvironment and relays contextual and antigenic information to T cells. Following the recognition of danger signals and/or pathogen molecular associated patterns in the lungs, DCs undergo activation. This process arms DCs with the unique ability to induce the proliferation and differentiation of T cells responding to matching antigen in complex with MHC molecules. Depending on how DCs interact with T cells, the ensuing T cell response can be tolerogenic or immunogenic and as such, the susceptibility and severity of respiratory infections is influenced by the signals DCs receive, integrate, and then convey to T cells. It is becoming increasingly clear that these facets of DC biology are heavily influenced by the cellular components and metabolites produced by the lung and gut microbiota. In this review, we discuss the roles of different DC subsets in respiratory infections and outline how microbial metabolites impact the development, propensity for activation and subsequent activation of DCs. In particular, we highlight these concepts in the context of respiratory immunity.
Asunto(s)
Células Dendríticas , Infecciones del Sistema Respiratorio , Diferenciación Celular , Humanos , Pulmón , Infecciones del Sistema Respiratorio/metabolismo , Linfocitos TRESUMEN
BACKGROUND: Postviral olfactory dysfunction (PVOD) following a viral upper respiratory tract infection (URI) is one of the most common causes of olfactory disorders, often lasting for over a year. To date, the molecular pathology of PVOD has not been elucidated. METHODS: A murine model of Toll-like receptor 3 (TLR3)-mediated upper respiratory tract inflammation was used to investigate the impact of URIs on the olfactory system. Inflammation was induced via the intranasal administration of polyinosinic-polycytidylic acid (poly(I:C), a TLR3 ligand) to the right nostril for 3 days. Peripheral olfactory sensory neurons (OSNs), immune cells in the olfactory mucosa, and glial cells in the olfactory bulb (OB) were analyzed histologically. Proinflammatory cytokines in the nasal tissue and OB were evaluated using the quantitative real-time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). RESULTS: In the treated mice, OSNs were markedly reduced in the olfactory mucosa, and T cell and neutrophil infiltration therein was observed 1 day after the end of poly(I:C) administration. Moreover, there was a considerable increase in microglial cells and slight increase in activated astrocytes in the OB. In addition, qPCR and ELISA revealed the elevated expression of interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma both in the OB and nasal tissue. CONCLUSIONS: Taken together, the decreased peripheral OSNs, OB microgliosis, and elevated proinflammatory cytokines suggest that immunological changes in the OB may be involved in the pathogenesis of PVOD.
Asunto(s)
Inflamación/metabolismo , Bulbo Olfatorio/metabolismo , Infecciones del Sistema Respiratorio/metabolismo , Receptor Toll-Like 3/metabolismo , Animales , Modelos Animales de Enfermedad , Inflamación/inducido químicamente , Ratones , Microglía/metabolismo , Mucosa Olfatoria/metabolismo , Poli I-C/farmacologíaRESUMEN
Pseudomonas aeruginosa and Staphylococcus aureus are both opportunistic pathogens that are frequently associated with chronic lung infections. While bacterial virulence determinants are critical in initiating infection, the metabolic flexibility of these bacteria promotes their persistence in the airway. Upon infection, these pathogens induce host immunometabolic reprogramming, resulting in an airway milieu replete with immune-signaling metabolites. These metabolites are often toxic to the bacteria and create a steep selection pressure for the emergence of bacterial isolates adapted for long-term survival in the inflamed lung. In this review, we discuss the main differences in the host immunometabolic response to P. aeruginosa and S. aureus, as well as how these pathogens alter their own metabolism to adapt to airway metabolites and cause persistent lung infections.
Asunto(s)
Metabolismo Energético , Pulmón/metabolismo , Infecciones por Pseudomonas/metabolismo , Pseudomonas aeruginosa/metabolismo , Infecciones del Sistema Respiratorio/metabolismo , Infecciones Estafilocócicas/metabolismo , Staphylococcus aureus/metabolismo , Adaptación Fisiológica , Animales , Interacciones Huésped-Patógeno , Humanos , Pulmón/inmunología , Pulmón/microbiología , Infecciones por Pseudomonas/inmunología , Infecciones por Pseudomonas/microbiología , Pseudomonas aeruginosa/inmunología , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/microbiología , Infecciones Estafilocócicas/inmunología , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/inmunología , Succinatos/metabolismoRESUMEN
OBJECTIVES: Compare three host response strategies to distinguish bacterial and viral etiologies of acute respiratory illness (ARI). METHODS: In this observational cohort study, procalcitonin, a 3-protein panel (CRP, IP-10, TRAIL), and a host gene expression mRNA panel were measured in 286 subjects with ARI from four emergency departments. Multinomial logistic regression and leave-one-out cross validation were used to evaluate the protein and mRNA tests. RESULTS: The mRNA panel performed better than alternative strategies to identify bacterial infection: AUC 0.93 vs. 0.83 for the protein panel and 0.84 for procalcitonin (P<0.02 for each comparison). This corresponded to a sensitivity and specificity of 92% and 83% for the mRNA panel, 81% and 73% for the protein panel, and 68% and 87% for procalcitonin, respectively. A model utilizing all three strategies was the same as mRNA alone. For the diagnosis of viral infection, the AUC was 0.93 for mRNA and 0.84 for the protein panel (p<0.05). This corresponded to a sensitivity and specificity of 89% and 82% for the mRNA panel, and 85% and 62% for the protein panel, respectively. CONCLUSIONS: A gene expression signature was the most accurate host response strategy for classifying subjects with bacterial, viral, or non-infectious ARI.
Asunto(s)
Bacterias/aislamiento & purificación , Infecciones Bacterianas/diagnóstico , Infecciones del Sistema Respiratorio/epidemiología , Virosis/diagnóstico , Virus/aislamiento & purificación , Adulto , Infecciones Bacterianas/complicaciones , Infecciones Bacterianas/metabolismo , Infecciones Bacterianas/microbiología , Biomarcadores/metabolismo , Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Diagnóstico Diferencial , Servicio de Urgencia en Hospital , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Polipéptido alfa Relacionado con Calcitonina/genética , Polipéptido alfa Relacionado con Calcitonina/metabolismo , Pronóstico , Curva ROC , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Infecciones del Sistema Respiratorio/etiología , Infecciones del Sistema Respiratorio/metabolismo , Infecciones del Sistema Respiratorio/patología , Estudios Retrospectivos , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Estados Unidos/epidemiología , Virosis/complicaciones , Virosis/virologíaRESUMEN
BACKGROUND: Human metapneumovirus (hMPV) is one of the important pathogens in infant respiratory tract infection. However, the molecular epidemiology of hMPV among children < 14 years of age hospitalized with severe acute respiratory infection (SARI) is unclear. We investigated the hMPV infection status and genotypes of children hospitalized with SARI from January 2016 to December 2020 in Huzhou, China. METHODS: A nasopharyngeal flocked swab, nasal wash, or nasopharyngeal swab/or opharyngeal swab combination sample was collected from children with SARI in Huzhou from January 2016 to December 2020. Quantitative reverse transcription-polymerase chain reaction was performed to detect hMPV RNA. The hMPV F gene was amplified and sequenced, followed by analysis using MEGA software (ver. 7.0). Epidemiological data were analyzed using Microsoft Excel 2010 and SPSS (ver. 22.0) software. RESULTS: A total of 1133 children with SARI were recruited from 2016 to 2020. Among them, 56 (4.94%) were positive for hMPV-RNA. Children < 5 years of age accounted for 85.71% of the positive cases. The hMPV incidence was high in spring and winter, especially in December and January to March. Phylogenetic analysis of the F-gene sequences of 28 hMPV strains showed that the A1, B1, and B2 genotypes were prevalent in Huzhou, and the dominant hMPV genotype varied according to surveillance year. CONCLUSIONS: HMPV is an important respiratory pathogen in children in Huzhou, with a high incidence in winter and spring in children < 5 years of age. In this study, genotypes A1, B1, and B2 were the most prevalent.
Asunto(s)
Metapneumovirus/genética , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/genética , Secuencia de Bases/genética , Niño , Preescolar , China/epidemiología , Femenino , Genotipo , Hospitalización/tendencias , Humanos , Lactante , Masculino , Metapneumovirus/clasificación , Metapneumovirus/patogenicidad , Epidemiología Molecular/métodos , Tipificación Molecular/métodos , Infecciones por Paramyxoviridae/epidemiología , Infecciones por Paramyxoviridae/genética , Infecciones por Paramyxoviridae/virología , Filogenia , Infecciones del Sistema Respiratorio/metabolismo , Análisis de Secuencia de ADN/métodosRESUMEN
Combustion related particulate matter air pollution (PM) is associated with an increased risk of respiratory infections in adults. The exact mechanism underlying this association has not been determined. We hypothesized that increased concentrations of combustion related PM would result in dysregulation of the innate immune system. This epidemiological study includes 111 adult patients hospitalized with respiratory infections who underwent transcriptional analysis of their peripheral blood. We examined the association between gene expression at the time of hospitalization and ambient measurements of particulate air pollutants in the 28 days prior to hospitalization. For each pollutant and time lag, gene-specific linear models adjusting for infection type were fit using LIMMA (Linear Models For Microarray Data), and pathway/gene set analyses were performed using the CAMERA (Correlation Adjusted Mean Rank) program. Comparing patients with viral and/or bacterial infection, the expression patterns associated with air pollution exposure differed. Adjusting for the type of infection, increased concentrations of Delta-C (a marker of biomass smoke) and other PM were associated with upregulation of iron homeostasis and protein folding. Increased concentrations of black carbon (BC) were associated with upregulation of viral related gene pathways and downregulation of pathways related to antigen presentation. The pollutant/pathway associations differed by lag time and by type of infection. This study suggests that the effect of air pollution on the pathogenesis of respiratory infection may be pollutant, timing, and infection specific.
Asunto(s)
Material Particulado/efectos adversos , Infecciones del Sistema Respiratorio/inmunología , Humo/efectos adversos , Transcriptoma , Adulto , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Humanos , Inmunidad/genética , Masculino , New York/epidemiología , Infecciones del Sistema Respiratorio/etiología , Infecciones del Sistema Respiratorio/genética , Infecciones del Sistema Respiratorio/metabolismo , Hollín/efectos adversosRESUMEN
Respiratory tract infections (RTI) are a major cause of morbidity and mortality in humans. A large number of RTIs is caused by viruses, often resulting in more severe disease in infants, elderly and the immunocompromised. Upon viral infection, most individuals experience common cold-like symptoms associated with an upper RTI. However, in some cases a severe and sometimes life-threatening lower RTI may develop. Reproducible and scalable in vitro culture models that accurately reflect the human respiratory tract are needed to study interactions between respiratory viruses and the host, and to test novel therapeutic interventions. Multiple in vitro respiratory cell culture systems have been described, but the majority of these are based on immortalized cell lines. Although useful for studying certain aspects of viral infections, such monomorphic, unicellular systems fall short in creating an understanding of the processes that occur at an integrated tissue level. Novel in vitro models involving primary human airway epithelial cells and, more recently, human airway organoids, are now in use. In this review, we describe the evolution of in vitro cell culture systems and their characteristics in the context of viral RTIs, starting from advances after immortalized cell cultures to more recently developed organoid systems. Furthermore, we describe how these models are used in studying virus-host interactions, e.g. tropism and receptor studies as well as interactions with the innate immune system. Finally, we provide an outlook for future developments in this field, including co-factors that mimic the microenvironment in the respiratory tract.
Asunto(s)
Susceptibilidad a Enfermedades , Células Epiteliales/virología , Interacciones Huésped-Patógeno , Técnicas In Vitro , Mucosa Respiratoria/virología , Infecciones del Sistema Respiratorio/metabolismo , Infecciones del Sistema Respiratorio/virología , Técnicas de Cultivo de Célula , Línea Celular , Células Cultivadas , Técnicas de Cocultivo , Susceptibilidad a Enfermedades/inmunología , Células Epiteliales/metabolismo , Humanos , Especificidad de Órganos , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Infecciones del Sistema Respiratorio/patologíaRESUMEN
Primary ciliary dyskinesia (PCD) is a rare genetic ciliopathy in which mucociliary clearance is disturbed by the abnormal motion of cilia or there is a severe reduction in the generation of multiple motile cilia. Lung damage ensues due to recurrent airway infections, sometimes even resulting in respiratory failure. So far, no causative treatment is available and treatment efforts are primarily aimed at improving mucociliary clearance and early treatment of bacterial airway infections. Treatment guidelines are largely based on cystic fibrosis (CF) guidelines, as few studies have been performed on PCD. In this review, we give a detailed overview of the clinical studies performed investigating PCD to date, including three trials and several case reports. In addition, we explore precision medicine approaches in PCD, including gene therapy, mRNA transcript and read-through therapy.
Asunto(s)
Trastornos de la Motilidad Ciliar , Infecciones Bacterianas/genética , Infecciones Bacterianas/metabolismo , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/terapia , Trastornos de la Motilidad Ciliar/genética , Trastornos de la Motilidad Ciliar/metabolismo , Trastornos de la Motilidad Ciliar/microbiología , Trastornos de la Motilidad Ciliar/terapia , Ensayos Clínicos como Asunto , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Fibrosis Quística/microbiología , Fibrosis Quística/terapia , Humanos , Pulmón/metabolismo , Pulmón/microbiología , Infecciones del Sistema Respiratorio/genética , Infecciones del Sistema Respiratorio/metabolismo , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/terapiaRESUMEN
Chlamydia pneumoniae is a type of pathogenic gram-negative bacteria that causes various respiratory tract infections including asthma. Chlamydia species infect humans and cause respiratory infection by rupturing the lining of the respiratory which includes the throat, lungs and windpipe. Meanwhile, the function of interleukin-4 (IL-4) in Ch. pneumoniae respiratory infection and its association with the development of airway hyperresponsiveness (AHR) in adulthood and causing allergic airway disease (AAD) are not understood properly. We therefore investigated the role of IL-4 in respiratory infection and allergy caused by early life Chlamydia infection. In this study, Ch. pneumonia strain was propagated and cultured in HEp-2 cells according to standard protocol and infant C57BL/6 mice around 3-4 weeks old were infected to study the role of IL-4 in respiratory infection and allergy caused by early life Chlamydia infection. We observed that IL-4 is linked with Chlamydia respiratory infection and its absence lowers respiratory infection. IL-4R α2 is also responsible for controlling the IL-4 signaling pathway and averts the progression of infection and inflammation. Furthermore, the IL-4 signaling pathway also influences infection-induced AHR and aids in increasing AAD severity. STAT6 also promotes respiratory infection caused by Ch. pneumoniae and further enhanced its downstream process. Our study concluded that IL-4 is a potential target for preventing infection-induced AHR and severe asthma.
Asunto(s)
Infecciones por Chlamydia/metabolismo , Interleucina-4/metabolismo , Hipersensibilidad Respiratoria/metabolismo , Infecciones del Sistema Respiratorio/metabolismo , Animales , Infecciones por Chlamydia/complicaciones , Infecciones por Chlamydia/microbiología , Chlamydophila pneumoniae/patogenicidad , Pulmón/metabolismo , Pulmón/patología , Activación de Macrófagos/genética , Ratones , Ratones Endogámicos C57BL , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Hipersensibilidad Respiratoria/etiología , Hipersensibilidad Respiratoria/patología , Infecciones del Sistema Respiratorio/etiología , Infecciones del Sistema Respiratorio/microbiología , Transducción de SeñalRESUMEN
B and T lymphocyte attenuator (BTLA), an immunomodulatory molecule widely expressed on the surface of immune cells, can influence various signaling pathways and negatively regulate the activation and proliferation of immune cells by binding to its ligand herpes virus entry mediator (HVEM). BTLA plays an important role in immunoregulation and is involved in the pathogenesis of various respiratory diseases, including airway inflammation, asthma, infection, pneumonia, acute respiratory distress syndrome and lung cancer. In recent years, some studies have found that BTLA also has played a positive regulatory effect on immunity system in the occurrence and development of respiratory diseases. Since severe pulmonary infection is a risk factor for sepsis, this review also summarized the new findings on the role of BTLA in sepsis.
Asunto(s)
Enfermedades Pulmonares/metabolismo , Pulmón/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Asma/inmunología , Asma/metabolismo , Humanos , Pulmón/inmunología , Enfermedades Pulmonares/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neumonía/inmunología , Neumonía/metabolismo , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/metabolismo , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/metabolismo , Sepsis/inmunología , Sepsis/metabolismo , Transducción de SeñalRESUMEN
The H9N2 avian influenza viruses infect poultry worldwide, and can potentially cause a human pandemic without adaptation. Vitamin D3 (D3) is increasingly being recognized for its extra-skeletal roles, such as the inflammatory and immune responses to infection. The aim of this study was to analyze the changes in vitamin D metabolizing enzymes and vitamin D receptor (VDR) in the lung tissues of mice infected with H9N2. The mice were intranasally inoculated with the appropriate dose of the virus, and various clinical indices were measured on days 3, 7, 14 and 21 post-infection. H9N2 infection significantly increased the expression levels of 1α-hydroxylase mRNA and protein, which is the activating enzyme of 25-hydroxyvitamin D (25(OH)D3), but had no significant effect on the 25(OH)D3 inactivating enzyme 24-hydroxylase, indicating that inactive D3 might be converted to its active form in the H9N2-infected lungs. Furthermore, a significant increase was also observed in the VDR mRNA and protein levels, suggesting enhanced responsiveness of the lung tissues to 1, 25(OH)2D3 post H9N2 infection. In addition, daily 25(OH)D3 injection from day 2-14 post-infection did not affect the clinical signs, virus replication and cytokine (IL-1ß and TNF-α) production in the lungs of the infected mice. Given that the biological effects of D3 rely on its activation, and the binding of 1, 25(OH)2D3 to VDR in specific tissues, our findings provide novel insights into the possible role of vitamin D in the development and progression of influenza.
Asunto(s)
25-Hidroxivitamina D3 1-alfa-Hidroxilasa/metabolismo , Subtipo H9N2 del Virus de la Influenza A/aislamiento & purificación , Pulmón/virología , Infecciones por Orthomyxoviridae/complicaciones , Receptores de Calcitriol/metabolismo , Infecciones del Sistema Respiratorio/virología , 25-Hidroxivitamina D3 1-alfa-Hidroxilasa/genética , Animales , Pulmón/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae/metabolismo , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/virología , Receptores de Calcitriol/genética , Infecciones del Sistema Respiratorio/metabolismo , Infecciones del Sistema Respiratorio/patologíaRESUMEN
BACKGROUND: Lung transplant (LTx) recipients are at increased risk for airway infections, but the cause of infection is often difficult to establish with traditional culture-based techniques. The objectives of the study was to compare the airway microbiome in LTx patients with and without ongoing airway infection and identify differences in their microbiome composition. METHODS: LTx recipients were prospectively followed with bronchoalveolar lavage (BAL) during the first year after transplantation. The likelihood of airway infection at the time of sampling was graded based on clinical criteria and BAL cultures, and BAL fluid levels of the inflammatory markers heparin-binding protein (HBP), IL-1ß and IL-8 were determined with ELISA. The bacterial microbiome of the samples were analysed with 16S rDNA sequencing and characterized based on richness and evenness. The distance in microbiome composition between samples were determined using Bray-Curtis and weighted and unweighted UniFrac. RESULTS: A total of 46 samples from 22 patients were included in the study. Samples collected during infection and samples with high levels of inflammation were characterized by loss of bacterial diversity and a significantly different species composition. Burkholderia, Corynebacterium and Staphylococcus were enriched during infection and inflammation, whereas anaerobes and normal oropharyngeal flora were less abundant. The most common findings in BAL cultures, including Pseudomonas aeruginosa, were not enriched during infection. CONCLUSION: This study gives important insights into the dynamics of the airway microbiome of LTx recipients, and suggests that lung infections are associated with a disruption in the homeostasis of the microbiome.
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Bacterias/crecimiento & desarrollo , Trasplante de Pulmón , Pulmón/microbiología , Microbiota , Infecciones del Sistema Respiratorio/microbiología , Adulto , Anciano , Bacterias/aislamiento & purificación , Líquido del Lavado Bronquioalveolar/microbiología , Disbiosis , Femenino , Humanos , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Pulmón/metabolismo , Pulmón/cirugía , Trasplante de Pulmón/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Respiratory syncytial virus (RSV) bronchiolitis is a leading cause of infant hospitalization and mortality. We previously identified that prostaglandin D2 (PGD2), released following RSV infection of primary human airway epithelial cells or pneumonia virus of mice (PVM) infection of neonatal mice, elicits pro- or antiviral innate immune responses as a consequence of D-type prostanoid receptor 2 (DP2) or DP1 activation, respectively. Here, we sought to determine whether treatment with the DP1 agonist BW245c decreases the severity of bronchiolitis in PVM-infected neonatal mice. Consistent with previous findings, BW245c treatment increased IFN-λ production and decreased viral load in week 1 of the infection. However, unexpectedly, BW245c treatment increased mortality in week 2 of the infection. This increased morbidity was associated with viral spread to the parenchyma, an increased cellular infiltrate of TNF-α-producing cells (neutrophils, monocytes, and CD4+ T cells), and the heightened production of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß. These phenotypes, as well as the increased mortality, were significantly attenuated following the administration of anti-TNF-α to PVM-infected, BW245c-treated mice. In summary, pharmacological activation of the DP1 receptor in PVM-infected neonatal mice boosts antiviral innate and adaptive immunity, however, this is ultimately detrimental, as a consequence of increased TNF-α-induced morbidity and mortality.
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Susceptibilidad a Enfermedades , Receptores de Prostaglandina/agonistas , Infecciones del Sistema Respiratorio/etiología , Infecciones del Sistema Respiratorio/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Virosis/etiología , Virosis/metabolismo , Enfermedad Aguda , Animales , Biomarcadores , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/inmunología , Ratones , Monocitos/inmunología , Monocitos/metabolismo , Neutrófilos/inmunología , Neutrófilos/metabolismo , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/mortalidad , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Virosis/diagnósticoRESUMEN
Genetic variants may predispose children to recurrent respiratory infections (RRIs) but studies on genotype-environment interaction are rare. We hypothesized that the risk for RRIs is elevated in children with innate immune gene variants, and that prenatal exposure to maternal psychological distress further increases the risk. In a birth cohort, children with RRIs (n = 96) were identified by the age of 24 months and compared with the remaining cohort children (n = 894). The risk for RRIs in children with preselected genetic variants and the interaction between maternal distress during pregnancy and child genotype were assessed with logistic regression. The IL6 minor allele G was associated with elevated risk for RRIs (OR 1.55; 95% CI 1.14-2.12). Overall, there was no interaction between maternal psychological distress and child genotype. Exploratory analyses showed that, the association between the variant type of IL6 and the risk for RRIs was dependent on prenatal exposure to maternal psychological distress in males (OR 1.96; 95% CI 1.04-3.67). Our study didn't find genotype-environment interaction between prenatal maternal distress and child genotype. Exploratory analyses suggest sex differences in gene-environment interaction related to susceptibility to RRIs.
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Infecciones del Sistema Respiratorio/genética , Estrés Fisiológico/fisiología , Adulto , Preescolar , Estudios de Cohortes , Femenino , Frecuencia de los Genes/genética , Interacción Gen-Ambiente , Variación Genética/genética , Genotipo , Humanos , Lactante , Interleucina-6/genética , Masculino , Madres/psicología , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Distrés Psicológico , Infecciones del Sistema Respiratorio/metabolismo , Infecciones del Sistema Respiratorio/fisiopatología , Factores de Riesgo , Estrés Psicológico/psicologíaRESUMEN
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease. Several risk factors such as smoking, air pollution, inhaled toxins, high body mass index and infectious agents are involved in the pathogenesis of IPF. In the present study, this meta-analysis study investigates the prevalence of viral and bacterial infections in the IPF patients and any possible association between these infections with pathogenesis of IPF. METHODS: The authors carried out this systematic literature review from different reliable databases such as PubMed, ISI Web of Science, Scopus and Google Scholar to December 2020.Keywords used were the following "Idiopathic pulmonary fibrosis", "Infection", "Bacterial Infection" and "Viral Infection", alone or combined together with the Boolean operators "OR", "AND" and "NOT" in the Title/Abstract/Keywords field. Pooled proportion and its 95% CI were used to assess the prevalence of viral and bacterial infections in the IPF patients. RESULTS: In this systematic review and meta-analyses, 32 studies were selected based on the exclusion/inclusion criteria. Geographical distribution of included studies was: eight studies in American people, 8; in European people, 15 in Asians, and one in Africans. The pooled prevalence for viral and bacterial infections w ere 53.72% (95% CI 38.1-69.1%) and 31.21% (95% CI 19.9-43.7%), respectively. The highest and lowest prevalence of viral infections was HSV (77.7% 95% CI 38.48-99.32%), EBV (72.02%, 95% CI 44.65-90.79%) and Influenza A (7.3%, 95% CI 2.66-42.45%), respectively. Whereas the highest and lowest prevalence in bacterial infections were related to Streptococcus sp. (99.49%, 95% CI 96.44-99.9%) and Raoultella (1.2%, 95% CI 0.2-3.08%), respectively. CONCLUSIONS: The results of this review were confirmed that the presence of viral and bacterial infections are the risk factors in the pathogenesis of IPF. In further analyses, which have never been shown in the previous studies, we revealed the geographic variations in the association strengths and emphasized other methodological parameters (e.g., detection method). Also, our study supports the hypothesis that respiratory infection could play a key role in the pathogenesis of IP.