Host blood RNA transcript and protein signatures for sputum-independent diagnostics of tuberculosis in adults

To achieve the ambitious targets for tuberculosis (TB) prevention, care, and control stated by the End TB Strategy, new health care strategies, diagnostic tools are warranted. Host-derived biosignatures are explored for their TB diagnostic potential in accordance with the WHO target product profiles (TPPs) for point-of-care (POC) testing. We aimed to identify sputum-independent TB diagnostic signatures in newly diagnosed adult pulmonary-TB (PTB) patients recruited in the context of a prospective household contact cohort study conducted in Andhra Pradesh, India. Whole-blood mRNA samples from 158 subjects (PTB, n = 109; age-matched household controls, n = 49) were examined by dual-color Reverse-Transcriptase Multiplex Ligation-dependent Probe-Amplification (dcRT-MLPA) for the expression of 198 pre-defined genes and a Mesoscale discovery assay for the concentration of 18 cytokines/chemokines in TB-antigen stimulated QuantiFERON supernatants. To identify signatures, we applied a two-step approach; in the first step, univariate filtering was used to identify and shortlist potentially predictive biomarkers; this step may be seen as removing redundant biomarkers. In the second step, a logistic regression approach was used such that group membership (PTB vs. household controls) became the binary response in a Lasso regression model. We identified an 11-gene signature that distinguished PTB from household controls with AUCs of ≥0.98 (95% CIs: 0.94–1.00), and a 4-protein signature (IFNγ, GMCSF, IL7 and IL15) that differentiated PTB from household controls with AUCs of ≥0.87 (95% CIs: 0.75–1.00), in our discovery cohort. Subsequently, we evaluated the performance of the 11-gene signature in two external validation data sets viz, an independent cohort at the Glenfield Hospital, University Hospitals of Leicester NHS Trust, Leicester, UK (GSE107994 data set), and the Catalysis treatment response cohort (GSE89403 data set) from South Africa. The 11-gene signature validated and distinguished PTB from healthy and asymptomatic M. tuberculosis infected household controls in the GSE107994 data set, with an AUC of 0.95 (95% CI: 0.91–0.98) and 0.94 (95% CI: 0.89–0.98). More interestingly in the GSE89403 data set, the 11-gene signature distinguished PTB from household controls and patients with other lung diseases with an AUC of 0.93 (95% CI: 0.87–0.99) and 0.73 (95% CI: 0.56–0.89). These criteria meet the WHO TTP benchmarks for a non–sputum-based triage test for TB diagnosis. We suggest that further validation is required before clinical implementation of the 11-gene signature we have identified markers will be possible.publishedVersio

Residual Type 1 Immunity in Patients Genetically Deficient for Interleukin 12 Receptor β1 (IL-12Rβ1): Evidence for an IL-12Rβ1–Independent Pathway of IL-12 Responsiveness in Human T Cells

Genetic lack of interleukin 12 receptor β1 (IL-12Rβ1) surface expression predisposes to severe infections by poorly pathogenic mycobacteria or Salmonella and causes strongly decreased, but not completely abrogated, interferon (IFN)-γ production. To study IL-12Rβ1–independent residual IFN-γ production, we have generated mycobacterium–specific T cell clones (TCCs) from IL-12Rβ1–deficient individuals. All TCCs displayed a T helper type 1 phenotype and the majority responded to IL-12 by increased IFN-γ production and proliferative responses upon activation. This response to IL-12 could be further augmented by exogenous IL-18. IL-12Rβ2 was found to be normally expressed in the absence of IL-12Rβ1, and could be upregulated by IFN-α. Expression of IL-12Rβ2 alone, however, was insufficient to induce signal transducer and activator of transcription (Stat)4 activation in response to IL-12, whereas IFN-α/IFN-αR ligation resulted in Stat4 activation in both control and IL-12Rβ1–deficient cells. IL-12 failed to upregulate cell surface expression of IL-18R, integrin α6, and IL-12Rβ2 on IL-12Rβ1–deficient cells, whereas this was normal on control cells. IL-12–induced IFN-γ production in IL-12Rβ1–deficient T cells could be inhibited by the p38 mitogen-activated protein kinase (MAP) kinase inhibitor SB203580 and the MAP kinase kinase (MEK) 1/2 inhibitor U0126, suggesting involvement of MAP kinases in this alternative, Stat4-independent, IL-12 signaling pathway

Diagnosis of childhood tuberculosis and host RNA expression in Africa

Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV

Autorregulación y trabajo autónomo del estudiante en una actividad de aprendizaje basada en TIC

Este estudio analiza las estrategias de autorregulación en una práctica basada en las TIC con trabajo autónomo del estudiante (TAE). Participaron 53 estudiantes del primer curso de psicología de la Universidad Autónoma de Barcelona que realizaron prácticas de atención y percepción. Los objetivos, contenidos, materiales y evaluación de la práctica se diseñaron y desarrollaron en un entorno en línea. Posteriormente, se aplicaron varios cuestionarios con la finalidad de identificar las autovaloraciones que sobre la actividad autorregulatoria y el nivel de participación manifestaron los estudiantes. Los resultados muestran que los componentes de la dimensión cognitiva de la autorregulación (concepciones de aprendizaje y estrategias metacognitivas) se relacionan significativamente entre sí; sin embargo, no explican las diferencias encontradas en la valoración que los estudiantes realizan de su participación activa. Los factores del componente motivacional (orientación y autoeficacia) se encuentran, igualmente, relacionados entre sí, pero sólo la autoeficacia explica las diferencias observadas en la valoración de la participación activaThis work analyses a self-regulation strategies in autonomous task in an ICT-based learning activity. Participants were 53 psychology undergraduates at the Universidad Autónoma de Barcelona who made a practice in Attention and Perception Psychology. The aims, contents, materials and assessment of the practice were implemented in a virtual environment. We applied several questionnaires in order to identify the students' self-assessments about their self-regulatory activity and participation level. The results showed that cognitive dimension components in the self-regulation construct (conception of learning and metacognitive strategies) are significantly interrelated. However, this dimension does not account for the differences found in self-assessments students' active participation. With regard to motivational dimension factors (goal orientation and self-efficacy), a significant relation between them is observed, but only self-efficacy explains the differences found in self-assessments' active participatio

Significance of antigen and epitope specificity in tuberculosis

Immunogenetics and cellular immunology of bacterial infectious disease

Significance of antigen and epitope specificity in tuberculosis

Dissection of the specificity of host immune responses following infection with Mycobacterium tuberculosis is essential for designing effective vaccination and diagnostic biomarkers as well as for better understanding of immunopathogenesis of active tuberculosis. The articles in this volume of the Topics in Microbial Immunology review the significance of this area of research from both experimental models and clinical surveys. This includes T cell recognition of MHC permissive epitopes, use of algorithms for genome-based prediction of immunodominant epitopes, evaluation of candidate antigens/epitopes and adjuvants for vaccination and immunodiagnosis. Future research strategies indicate the need for better understanding of the relationship between epitope specificity and the phenotype of responding T cells and search for biomarkers with a capacity to discriminate and predict the change from latent infection to active disease. These research avenues have important potentials for improving the prevention and control of tuberculosis

Tuberculosis biomarkers: from diagnosis to protection

New approaches to control tuberculosis (TB) worldwide are needed. In particular, new tools for diagnosis and new biomarkers are required to evaluate both pathogen and host key elements of the response to infection. Non-sputum based diagnostic tests, biomarkers predictive of adequate responsiveness to treatment, and biomarkers of risk of developing active TB disease are major goals. Here, we review the current state of the field. Although reports on new candidate biomarkers are numerous, validation and independent confirmation are rare. Efforts are needed to reduce the gap between the exploratory <em>up-stream</em> identification of candidate biomarkers, and the validation of biomarkers against clear clinical endpoints in different populations. This will need a major commitment from both scientists and funding bodies