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The aim of this work was to screen miRNA signatures dysregulated in tuberculosis to improve our understanding of the biological role of miRNAs involved in the disease. Datasets deposited in publically available databases from microarray studies on infectious diseases and malignancies were retrieved, screened, and subjected to further analysis. Effect sizes were combined using the inverse-variance model and between-study heterogeneity was evaluated by the random effects model. 35 miRNAs were differentially expressed (12 up-regulated, 23 down-regulated; p

Tuberculosis (TB) is a communicable disease of major global importance and causes metabolic disorder of the patients. In a previous study, we found that the plasma metabolite profile of TB patients differs from that of healthy control subjects based on nuclear magnetic resonance (NMR) spectroscopy. In order to evaluate the TB specificity of the metabolite profile, a total of 110 patients, including 40 with diabetes, 40 with malignancy, and 30 with community-acquired pneumonia (CAP), assessed by NMR spectroscopy, and compared to those of patients with TB. Based on the orthogonal partial least-squares discriminant analysis (OPLS-DA), the metabolic profiles of these diseases were significant different, as compared to the healthy controls and TB patients, respectively. The score plots of the OPLS-DA model demonstrated that TB was easily distinguishable from diabetes, CAP and malignancy. Plasma levels of ketone bodies, lactate, and pyruvate were increased in TB patient compared to healthy control, but lower than CAP and malignancy. We conclude that the metabolic profiles were TB-specific and reflected MTB infection. Our results strongly support the NMR spectroscopy-based metabolomics could contribute to an improved understanding of disease mechanisms and may offer clues to new TB clinic diagnosis and therapies.

Summary The articles by De Knegt et al. and Singh et al. in a recent issue of this Journal address one of the current debates regarding the potential role of thioridazine in the treatment of tuberculosis. This commentary presents a summary of the available evidence, and, emphasizing the need for further research, asks the question: “How far can we go in repurposing thioridazine?”

New drugs that retain potency against multidrug/extensively drug-resistant strains of Mycobacterium tuberculosis, with the additional benefit of a shortened treatment duration and ease of administration, are urgently needed by tuberculosis (TB) control programs. Efforts to develop this new generation of treatment interventions have been plagued with numerous problems, the most significant being our insufficient understanding of mycobacterial metabolism during disease. This, combined with limited chemical diversity and poor entry of small molecules into the cell, has limited the number of new bioactive agents that result from drug screening efforts. The biochemical, target-driven approach to drug development has been largely abandoned in the TB field, to be replaced by whole-cell or target-based whole-cell screening approaches. In this context, the properties of a good drug target are unclear, since these are directly determined by the ability to find compounds, using current screening algorithms, which are able to kill M. tuberculosis. In this review, we discuss issues related to the identification and validation of drug targets and highlight some key properties for promising targets. Some of these include essentiality for growth, vulnerability, druggability, reduced propensity to evolve drug resistance and target location to facilitate ready access to drugs during chemotherapy. We present these in the context of recent drugs that have emerged through various approaches with the aim of consolidating the knowledge gained from these experiences to inform future efforts.

Clinical reports suggest an association of distinct Mycobacterium tuberculosis strains with CNS disease. We therefore examined CNS dissemination by different laboratory strains (two M. tuberculosis H37Rv, one CDC1551) in a guinea pig aerosol infection model. Although all strains grew exponentially in lungs, with similar bacterial burdens at the time of extrapulmonary dissemination, M. tuberculosis CDC1551 disseminated to the CNS significantly more than the H37Rv strains. No CNS lesions were observed throughout the study, with only a modest cytokine response. These data suggest that M. tuberculosis may have virulence factors that promote CNS dissemination, distinct from those required for pulmonary TB.

SummaryA major hurdle facing tuberculosis (TB) investigators who want to utilize a rapidly growing body of data from both systems biology approaches and omics technologies is the lack of a standard vocabulary for data annotation and reporting. Lacking a means to readily compare samples from different research groups, a significant quantity of potentially informative data is largely ignored by researchers. To facilitate standardizing data across studies, a simple ontology of TB terms was developed to provide a common vocabulary for annotating data sets. New terminology was developed to address animal models and experimental systems, and existing clinically focused terminology was modified and adapted. This ontology can be used to annotate host TB data in public databases and collaborations, thereby standardizing database searches and allowing researchers to more easily compare results. To demonstrate the utility of a standard TB ontology for host systems biology, a web application was developed to annotate and compare human and animal model gene expression data sets.