Search

Incomplete understanding of mechanisms involved in the host-pathogen interactions constrains our efforts to eliminate tuberculosis. In many individuals, resulting from immune response to mycobacterial infection organised structures called granulomas are formed. To identify host responses that may control at least the early stages of infection, we employed an in vitro granuloma model. Here, human PBMCs were infected with live Mycobacterium tuberculosis in culture, and the appearance of granuloma-like structures was monitored over the next several days. Production of cytokines and chemokines in culture supernatants was monitored at various times, and the resulting temporal profiles were examined for possible correlations with either granuloma formation, or bacterial growth. While a positive association of TNF-α and IFN-γ secretion levels with extent of granuloma formation could clearly be identified, we were, however, unable to detect any statistically significant relationship between any cytokine/chemokine and bacterial growth. Examination of specific host cellular biochemical pathways revealed that either modulation of neutral lipid homeostasis through inhibition of the Gi-protein coupled receptor GPR109A, or regulation of host metabolic pathways through addition of vitamin D, provided a more effective means of controlling infection. A subsequent genotypic analysis for a select subset of genes belonging to pathways known to be significant for TB pathology revealed associations of polymorphisms with cytokine secretions and bacterial growth independently. Collectively therefore, the present study supports that key metabolic pathways of the host cell, rather than levels of relevant cytokines/chemokines might be more critical for regulating the intracellular mycobacterial load, in the context of granuloma formation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Tuberculosis (TB) is a significant cause of morbidity worldwide, especially in the low and middle-income countries like India and is found to be more common in the rural areas. Delays in diagnosis and initiation of treatment along with lower treatment adherence and completion rates have increased the morbidity and mortality of TB in the rural areas. The collation of information accumulated through the assessment of people's Knowledge, Attitude, and Practices (KAP) towards TB, helps in charting new health programs for the public, identifying lacunae, and devising interventions based on these lacunae which in turn will help us to achieve the vision of a "TB free India” by 2025. Aim: To find out KAP and any association amongst them regarding TB among the study subjects. Materials and Methods: This was a cross-sectional study conducted on patients attending Outpatient Department (OPD) at the Rural Health Training Centre (RHTC) attached to NCR Institute of Medical Sciences, Meerut, Uttar Pradesh, India, during January 2021 to April 2021. From a sample of 106 patients data of KAP regarding TB was collected via a structured questionnaire which was predesigned and pretested. Pearson’s Chi-square test was used to ascertain the association between subjects' KAP about TB. A p-value <0.05 was taken as the predictor of statistical significance. Results: Out of 106 patients, 72 (67.92%), 80 (75.47%) and 52 (49.06%) had adequate KAP respectively. Participants having adequate knowledge showed positive attitude and good practices and this association was found to be statistically significant. Conclusion: The study results reflect that having adequate knowledge of the disease transforms into good practices and a positive attitude towards a person suffering from the said disease as well as helps the people to have a positive frame of mind in case they themselves contract the disease. Health education and behaviour change communication hence needs to be scaled up in rural communities to prevent, detect and treat tuberculosis in order to achieve a TB free India. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) has tremendous public health relevance. It most frequently affects the lung and is characterized by the development of unique tissue lesions, termed granulomas. These lesions encompass various immune populations, with macrophages being most extensively investigated. Myeloid derived suppressor cells (MDSCs) have been recently identified in TB patients, both in the circulation and at the site of infection, however their interactions with Mycobacterium tuberculosis (Mtb) and their impact on granulomas remain undefined. We generated human monocytic MDSCs and observed that their suppressive capacities are retained upon Mtb infection. We employed an in vitro granuloma model, which mimics human TB lesions to some extent, with the aim of analyzing the roles of MDSCs within granulomas. MDSCs altered the structure of and affected bacterial containment within granuloma-like structures. These effects were partly controlled through highly abundant secreted IL-10. Compared to macrophages, MDSCs activated primarily the NF-κB and MAPK pathways and the latter largely contributed to the release of IL-10 and replication of bacteria within in vitro generated granulomas. Moreover, MDSCs upregulated PD-L1 and suppressed proliferation of lymphocytes, albeit with negligible effects on Mtb replication. Further comprehensive characterization of MDSCs in TB will contribute to a better understanding of disease pathogenesis and facilitate the design of novel immune-based interventions for this deadly infection. [ABSTRACT FROM AUTHOR]

With rising incidence of acquired drug resistance among life-threatening pathogens, alternative approaches to improve therapy and vaccination have taken center stage. To this end, genome-wide and pathway-specific siRNA libraries are being employed increasingly to identify genes that regulate immune responses against a number of pathogens. In this study using calcium and cysteine protease pathway-specific siRNA libraries, we identified genes that play critical roles in modulating diverse functions of dendritic cells (DCs) during Mycobacterium tuberculosis infection. Knockdown of many of these genes in the two pathways resulted in reduced bacterial burden within DCs. These included genes that regulated activation of transcription factors, ubiquitin-specific peptidases, and genes that are involved in autophagy and neddylation. Knockdown of certain genes increased the expression of IL-12p40 and surface densities of costimulatory molecules in an antigen- and receptor-specific manner. Increased IL-12p40 and costimulatory molecules on DCs also promoted the development of Th1 responses from a Th2 inducing antigen. Furthermore, modulation of autophagy and oxidative burst appeared to be one of the mechanisms by which these genes regulated survival of M. tuberculosis within DCs. Although some genes regulated specific responses, others regulated multiple responses that included IL-12 production, T cell priming, as well as intracellular survival of M. tuberculosis. Further dissection of the mechanisms such as neddylation, by which these genes regulate immune responses, would improve our understanding of host parameters that are modulated during M. tuberculosis infection. [ABSTRACT FROM AUTHOR]