RESUMEN
Although mouse infection models have been extensively used to study the host response to Mycobacterium tuberculosis, their validity in revealing determinants of human tuberculosis (TB) resistance and disease progression has been heavily debated. Here, we show that the modular transcriptional signature in the blood of susceptible mice infected with a clinical isolate of M. tuberculosis resembles that of active human TB disease, with dominance of a type I interferon response and neutrophil activation and recruitment, together with a loss in B lymphocyte, natural killer and T cell effector responses. In addition, resistant but not susceptible strains of mice show increased lung B cell, natural killer and T cell effector responses in the lung upon infection. Notably, the blood signature of active disease shared by mice and humans is also evident in latent TB progressors before diagnosis, suggesting that these responses both predict and contribute to the pathogenesis of progressive M. tuberculosis infection.
Asunto(s)
Transcriptoma/inmunología , Tuberculosis/inmunología , Animales , Linfocitos B/inmunología , Linfocitos B/microbiología , Humanos , Interferón Tipo I/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/microbiología , Pulmón/inmunología , Pulmón/microbiología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Mycobacterium tuberculosis/inmunología , Linfocitos T/inmunología , Linfocitos T/microbiología , Tuberculosis/microbiologíaRESUMEN
Tuberculosis (TB), caused by Mycobacterium tuberculosis infection, is a leading cause of mortality and morbidity, causing â¼1.5 million deaths annually. CD4+ T cells and several cytokines, such as the Th1 cytokine IFN-γ, are critical in the control of this infection. Conversely, the immunosuppressive cytokine IL-10 has been shown to dampen Th1 cell responses to M. tuberculosis infection impairing bacterial clearance. However, the critical cellular source of IL-10 during M. tuberculosis infection is still unknown. Using IL-10 reporter mice, we show in this article that during the first 14 d of M. tuberculosis infection, the predominant cells expressing IL-10 in the lung were Ly6C+ monocytes. However, after day 21 postinfection, IL-10-expressing T cells were also highly represented. Notably, mice deficient in T cell-derived IL-10, but not mice deficient in monocyte-derived IL-10, showed a significant reduction in lung bacterial loads during chronic M. tuberculosis infection compared with fully IL-10-competent mice, indicating a major role for T cell-derived IL-10 in TB susceptibility. IL-10-expressing cells were detected among both CD4+ and CD8+ T cells, expressed high levels of CD44 and Tbet, and were able to coproduce IFN-γ and IL-10 upon ex vivo stimulation. Furthermore, during M. tuberculosis infection, Il10 expression in CD4+ T cells was partially regulated by both IL-27 and type I IFN signaling. Together, our data reveal that, despite the multiple immune sources of IL-10 during M. tuberculosis infection, activated effector T cells are the major source accounting for IL-10-induced TB susceptibility.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Interleucina-10/inmunología , Tuberculosis/inmunología , Animales , Antígenos Ly/inmunología , Receptores de Hialuranos/genética , Receptores de Hialuranos/inmunología , Interferón Tipo I/inmunología , Interferón Tipo I/metabolismo , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Interleucina-10/biosíntesis , Interleucina-10/deficiencia , Interleucina-10/genética , Interleucinas/inmunología , Interleucinas/metabolismo , Ratones , Monocitos/inmunología , Mycobacterium tuberculosis/inmunología , Tuberculosis/microbiologíaRESUMEN
BACKGROUND AND OBJECTIVES: Anxiety and insomnia can be treated with internet-delivered Cognitive Behavioral Therapy (iCBT). iCBT may be well-suited to students who are known to be poor help-seekers and suffer these symptoms. iCBT can offer easy access to treatment and increase service availability. The aim of this study was to evaluate the efficacy of anxiety and insomnia iCBT programs in students. DESIGN: A randomized, controlled study. METHODS: Students were randomly allocated to intervention ("Anxiety Relief": n = 43; "Insomnia Relief": n = 48; control: n = 47). Interventions lasted six weeks. Outcome measures were the State-Trait Anxiety Inventory and the Pittsburgh Sleep Quality Index. RESULTS: Significant within-group reductions in anxiety (t(31) = 2.00, p = .03) with moderate between-groups (compared to control) effect size (d = .64) and increases in sleep quality (t(31) = 3.46, p = .002) with a moderate between-groups effect size (d = .55) were found for completers of the anxiety program from pre- to post-intervention. Significant within-group increases in sleep quality were found for completers of the insomnia program from pre- to post-intervention (t(35) = 4.28, p > .001) with a moderate between-groups effect size (d = .51). CONCLUSIONS: Findings support the use of iCBT for anxiety and insomnia in students, and indicate that further research is needed.
Asunto(s)
Trastornos de Ansiedad/terapia , Terapia Cognitivo-Conductual/métodos , Internet , Autocuidado/métodos , Trastornos del Inicio y del Mantenimiento del Sueño/terapia , Estudiantes/psicología , Adolescente , Adulto , Trastornos de Ansiedad/psicología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Trastornos del Inicio y del Mantenimiento del Sueño/psicología , Estudiantes/estadística & datos numéricos , Resultado del Tratamiento , Reino Unido , Universidades , Adulto JovenRESUMEN
Influenza followed by severe acute bacterial pneumonia is a major cause of mortality worldwide. Several mechanisms account for this enhanced susceptibility, including increased production of type I interferon (IFN). In individuals infected with Mycobacterium tuberculosis, the influence of acute viral infections on tuberculosis progression is unclear. We show that prior exposure of mice to influenza A virus, followed by M. tuberculosis infection, leads to enhanced mycobacterial growth and decreased survival. Following M. tuberculosis/influenza virus coinfection, mycobacterial growth is enhanced by a type I IFN signaling pathway. Our findings highlight the detrimental influence influenza virus infection can have before or during M. tuberculosis infection.
Asunto(s)
Coinfección/inmunología , Virus de la Influenza A/inmunología , Mycobacterium tuberculosis/inmunología , Infecciones por Orthomyxoviridae/inmunología , Receptor de Interferón alfa y beta/inmunología , Tuberculosis/inmunología , Animales , Modelos Animales de Enfermedad , Femenino , Ratones , Ratones Endogámicos C57BL , Infecciones por Orthomyxoviridae/complicaciones , Transducción de Señal , Análisis de Supervivencia , Tuberculosis/complicacionesRESUMEN
RATIONALE: New approaches to define factors underlying the immunopathogenesis of pulmonary diseases including sarcoidosis and tuberculosis are needed to develop new treatments and biomarkers. Comparing the blood transcriptional response of tuberculosis to other similar pulmonary diseases will advance knowledge of disease pathways and help distinguish diseases with similar clinical presentations. OBJECTIVES: To determine the factors underlying the immunopathogenesis of the granulomatous diseases, sarcoidosis and tuberculosis, by comparing the blood transcriptional responses in these and other pulmonary diseases. METHODS: We compared whole blood genome-wide transcriptional profiles in pulmonary sarcoidosis, pulmonary tuberculosis, to community acquired pneumonia and primary lung cancer and healthy controls, before and after treatment, and in purified leucocyte populations. MEASUREMENTS AND MAIN RESULTS: An Interferon-inducible neutrophil-driven blood transcriptional signature was present in both sarcoidosis and tuberculosis, with a higher abundance and expression in tuberculosis. Heterogeneity of the sarcoidosis signature correlated significantly with disease activity. Transcriptional profiles in pneumonia and lung cancer revealed an over-abundance of inflammatory transcripts. After successful treatment the transcriptional activity in tuberculosis and pneumonia patients was significantly reduced. However the glucocorticoid-responsive sarcoidosis patients showed a significant increase in transcriptional activity. 144-blood transcripts were able to distinguish tuberculosis from other lung diseases and controls. CONCLUSIONS: Tuberculosis and sarcoidosis revealed similar blood transcriptional profiles, dominated by interferon-inducible transcripts, while pneumonia and lung cancer showed distinct signatures, dominated by inflammatory genes. There were also significant differences between tuberculosis and sarcoidosis in the degree of their transcriptional activity, the heterogeneity of their profiles and their transcriptional response to treatment.
Asunto(s)
Neoplasias Pulmonares/sangre , Neumonía/sangre , Sarcoidosis Pulmonar/sangre , Transcriptoma , Tuberculosis Pulmonar/sangre , Antituberculosos/uso terapéutico , Biomarcadores/sangre , Estudios de Casos y Controles , Glucocorticoides/uso terapéutico , Humanos , Mediadores de Inflamación/sangre , Interferones/fisiología , Neoplasias Pulmonares/diagnóstico , Neutrófilos/metabolismo , Neumonía/diagnóstico , Neumonía/tratamiento farmacológico , Receptores de Reconocimiento de Patrones/genética , Receptores de Reconocimiento de Patrones/metabolismo , Sarcoidosis Pulmonar/diagnóstico , Sarcoidosis Pulmonar/tratamiento farmacológico , Transcripción Genética , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/tratamiento farmacológicoRESUMEN
Tuberculosis, caused by Mycobacterium tuberculosis, remains a leading cause of mortality and morbidity worldwide, causing ≈ 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL-12, IL-1, and TNF-α, as well as IFN-γ and CD4(+) Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I IFN have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL-10 is known to inhibit the immune response to M. tuberculosis in murine models through the negative regulation of key proinflammatory cytokines and the subsequent Th1 response. We show in this study, using a combination of transcriptomic analysis, genetics, and pharmacological inhibitors, that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I IFN production. The TPL-2-ERK1/2 signaling pathway regulated production by macrophages of several cytokines important in the immune response to M. tuberculosis as well as regulating induction of a large number of additional genes, many in a type I IFN-dependent manner. In the absence of TPL-2 in vivo, excess type I IFN promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I IFN may promote susceptibility to this important disease.
Asunto(s)
Regulación de la Expresión Génica/inmunología , Interferón Tipo I/biosíntesis , Quinasas Quinasa Quinasa PAM/inmunología , Sistema de Señalización de MAP Quinasas , Proteínas Proto-Oncogénicas/inmunología , Tuberculosis/inmunología , Animales , Carga Bacteriana , Citocinas/biosíntesis , Citocinas/genética , Resistencia a la Enfermedad , Regulación hacia Abajo/inmunología , Femenino , Perfilación de la Expresión Génica , Interferón Tipo I/genética , Interleucina-10/inmunología , Listeria monocytogenes/inmunología , Listeria monocytogenes/aislamiento & purificación , Listeriosis/inmunología , Quinasas Quinasa Quinasa PAM/deficiencia , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Monocitos/inmunología , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/aislamiento & purificación , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas/deficiencia , Transcripción GenéticaRESUMEN
There are 9 million cases of active tuberculosis reported annually; however, an estimated one-third of the world's population is infected with Mycobacterium tuberculosis and remains asymptomatic. Of these latent individuals, only 5-10% will develop active tuberculosis disease in their lifetime. CD4(+) T cells, as well as the cytokines IL-12, IFN-γ, and TNF, are critical in the control of Mycobacterium tuberculosis infection, but the host factors that determine why some individuals are protected from infection while others go on to develop disease are unclear. Genetic factors of the host and of the pathogen itself may be associated with an increased risk of patients developing active tuberculosis. This review aims to summarize what we know about the immune response in tuberculosis, in human disease, and in a range of experimental models, all of which are essential to advancing our mechanistic knowledge base of the host-pathogen interactions that influence disease outcome.
Asunto(s)
Tuberculosis Pulmonar/inmunología , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Predisposición Genética a la Enfermedad , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Mycobacterium tuberculosis/inmunología , Resultado del Tratamiento , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/epidemiologíaRESUMEN
Vaccination with Mycobacterium bovis bacillus Calmette-Guérin (BCG) remains the only prophylactic vaccine against tuberculosis, caused by Mycobacterium tuberculosis, but gives variable protection against pulmonary disease. The generation of host Th1 responses following BCG vaccination is accepted as the major mechanism of protection against M. tuberculosis infection. Early production of IL-17 in the lungs following M. tuberculosis challenge of mice previously vaccinated with M. tuberculosis peptides in adjuvant has been shown to be required for efficient Th1 cell recruitment. IL-10 regulates various processes involved in generation of Th1 and Th17 responses. Previous studies have shown IL-10 as a negative regulator of the immune response to primary M. tuberculosis infection, with Il10(-/-) mice having reduced lung bacterial loads. In this study we show that inhibition of IL-10 signaling during BCG vaccination enhances host-generated Ag-specific IFN-γ and IL-17A responses, and that this regimen gives significantly greater protection against aerogenic M. tuberculosis challenge in both susceptible and relatively resistant strains of mice. In M. tuberculosis-susceptible CBA/J mice, Ab blockade of IL-10R specifically during BCG vaccination resulted in additional protection against M. tuberculosis challenge of >1-log(10) compared with equivalent isotype-treated controls. The protection observed following BCG vaccination concurrent with anti-IL-10R mAb treatment was sustained through chronic M. tuberculosis infection and correlated with enhanced lung Th1 and Th17 responses and increased IFN-γ and IL-17A production by γδ T cells and an innate-like Thy1.2(+)CD3(-) lymphoid population. We show that IL-10 inhibits optimal BCG-elicited protection, therefore suggesting that antagonists of IL-10 may be of great benefit as adjuvants in preventive vaccination against tuberculosis.
Asunto(s)
Vacuna BCG/inmunología , Interferón gamma/biosíntesis , Interleucina-10/antagonistas & inhibidores , Interleucina-17/biosíntesis , Transducción de Señal/inmunología , Células TH1/inmunología , Células Th17/inmunología , Tuberculosis Pulmonar/inmunología , Animales , Anticuerpos Bloqueadores/administración & dosificación , Vacuna BCG/administración & dosificación , Benzamidas , Células Cultivadas , Femenino , Mesilato de Imatinib , Inmunidad Innata , Interleucina-10/metabolismo , Interleucina-10/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Noqueados , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Receptores de Interleucina-10/antagonistas & inhibidores , Receptores de Interleucina-10/inmunología , Receptores de Interleucina-10/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/microbiología , Células TH1/microbiología , Células Th17/metabolismo , Células Th17/microbiología , Tuberculosis Pulmonar/prevención & controlRESUMEN
Neutrophils are rapidly recruited to sites of mycobacterial infection, where they phagocytose bacilli. Whether neutrophils can kill mycobacteria in vivo probably depends on the tissue microenvironment, stage of infection, individual host, and infecting organism. The interaction of neutrophils with macrophages, as well as the downstream effects on T cell activity, could result in a range of outcomes from early clearance of infection to dissemination of viable bacteria together with an attenuated acquired immune response. In established disease, neutrophils accumulate in situations of high pathogen load or immunological dysfunction, and are likely to contribute to pathology. These activities may have clinical importance in terms of new treatments, targeted interventions and vaccine strategies.
Asunto(s)
Neutrófilos/inmunología , Tuberculosis/inmunología , Animales , Humanos , Macrófagos/inmunología , Mycobacterium/inmunología , Tuberculosis/microbiologíaRESUMEN
IL-10 regulates the balance of an immune response between pathogen clearance and immunopathology. We show here that Mycobacterium tuberculosis (Mtb) infection in the absence of IL-10 (IL-10(-/-) mice) results in reduced bacterial loads in the lung. This reduction was preceded by an accelerated and enhanced IFN-γ response in the lung, an increased influx of CD4(+) T cells into the lung, and enhanced production of chemokines and cytokines, including CXCL10 and IL-17, in both the lung and the serum. Neutralization of IL-17 affected neither the enhanced production of CXCL10 nor the accumulation of IFN-γ-producing T cells in the lungs, but led to reduced numbers of granulocytes in the lung and reduced bacterial loads in the spleens of Mtb-infected mice. This suggests that IL-17 may contribute to dissemination of Mtb.
Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Interferón gamma/biosíntesis , Interleucina-17/biosíntesis , Pulmón/metabolismo , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Animales , Anticuerpos Bloqueadores/farmacología , Carga Bacteriana/efectos de los fármacos , Carga Bacteriana/genética , Carga Bacteriana/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/microbiología , Linfocitos T CD4-Positivos/patología , Movimiento Celular , Células Cultivadas , Quimiocina CXCL10/biosíntesis , Quimiocina CXCL10/genética , Femenino , Interferón gamma/genética , Interleucina-10/genética , Interleucina-17/genética , Interleucina-17/inmunología , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Mycobacterium tuberculosis/patogenicidad , Balance Th1 - Th2/efectos de los fármacos , Tuberculosis/genéticaRESUMEN
BACKGROUND: The strategies students adopt in their study are influenced by a number of social-cognitive factors and impact upon their academic performance. AIMS: The present study examined the interrelationships between motivation orientation (intrinsic and extrinsic), self-efficacy (in reading academic texts and essay writing), and approaches to studying (deep, strategic, and surface). The study also examined changes in approaches to studying over time. SAMPLE: A total of 163 first-year undergraduate students in psychology at a UK university took part in the study. METHODS: Participants completed the Work Preference Inventory motivation questionnaire, self-efficacy in reading and writing questionnaires and the short version of the Revised Approaches to Study Inventory. RESULTS: The results showed that both intrinsic and extrinsic motivation orientations were correlated with approaches to studying. The results also showed that students classified as high in self-efficacy (reading and writing) were more likely to adopt a deep or strategic approach to studying, while students classified as low in self-efficacy (reading and writing) were more likely to adopt a surface approach. More importantly, changes in students' approaches to studying over time were related to their self-efficacy beliefs, where students with low levels of self-efficacy decreased in their deep approach and increased their surface approach across time. Students with high levels of self-efficacy (both reading and writing) demonstrated no such change in approaches to studying. CONCLUSIONS: Our results demonstrate the important role of self-efficacy in understanding both motivation and learning approaches in undergraduate students. Furthermore, given that reading academic text and writing essays are essential aspects of many undergraduate degrees, our results provide some indication that focusing on self-efficacy beliefs amongst students may be beneficial to improving their approaches to study.