Monocyte and Macrophage miRNA: Potent Biomarker and Target for Host-Directed Therapy for Tuberculosis

The end TB strategy reinforces the essentiality of readily accessible biomarkers for early tuberculosis diagnosis. Exploration of microRNA (miRNA) and pathway analysis opens an avenue for the discovery of possible therapeutic targets. miRNA is a small, non-coding oligonucleotide characterized by the mechanism of gene regulation, transcription, and immunomodulation. Studies on miRNA define their importance as an immune marker for active disease progression and as an immunomodulator for innate mechanisms, such as apoptosis and autophagy. Monocyte research is highly advancing toward TB pathogenesis and biomarker efficiency because of its innate and adaptive response connectivity. The combination of monocytes/macrophages and their relative miRNA expression furnish newer insight on the unresolved mechanism for Mycobacterium survival, exploitation of host defense, latent infection, and disease resistance. This review deals with miRNA from monocytes, their relative expression in different disease stages of TB, multiple gene regulating mechanisms in shaping immunity against tuberculosis, and their functionality as biomarker and host-mediated therapeutics. Future collaborative efforts involving multidisciplinary approach in various ethnic population with multiple factors (age, gender, mycobacterial strain, disease stage, other chronic lung infections, and inflammatory disease criteria) on these short miRNAs from body fluids and cells could predict the valuable miRNA biosignature network as a potent tool for biomarkers and host-directed therapy

“Vaai Ganam” - a screening program for early detection of oral potentially malignant disorders and oral cancer among truck drivers in Chennai – a cross-sectional survey

Introduction: Truck drivers, though forming an integral part of a vital trade link for the Indian population, lack basic life insurance and health care benefits offered by other organized sectors in Indian Industries. This paper aims to present the initial findings of the “VaaiGanam” program which proposes to identify tobacco use and the prevalence of Oral potentially malignant disorders (OPMDs) among truck drivers who are stationed or passing via Chennai and provide cessation services by behavioral therapy. Methods: This cross-sectional study was conducted by a dental screening team who were involved in data collection and screening of the 747 truck drivers who fulfilled the inclusion and exclusion criteria between Jan to Oct 2022. After data collection, oral examinations were done and suspicious lesions were sought for expert opinion. A standard punch biopsy was taken from those lesions requiring confirmation. Results: Among the 747 subjects who participated in this program, 704 (94.2%) were current users of various tobacco products, with 235 (31.4%) preferring smoking and the rest 469(62.8%) using smokeless tobacco products. Oral mucosal lesions were recorded in 49 (6.5%) of the study population, mostly among tobacco users. Punch/incisional biopsies were taken among 17 of the 49 subjects and oral dysplasia was histopathologically confirmed in 9 (mild epithelial dysplasia = 5; moderate epithelial dysplasia = 4) subjects.  Conclusion: Truck drivers with tobacco and substance abuse are at high risk of developing oral cancer and hence this study emphasizes the importance of periodic oral cancer screening programs for this vulnerable population to identify potentially malignant oral lesions at an early stage

Diverse Clinical Isolates of Mycobacterium tuberculosis Develop Macrophage-Induced Rifampin Tolerance.

The Mycobacterium tuberculosis lineage 4 strains CDC1551 and H37Rv develop tolerance to multiple antibiotics upon macrophage residence. To determine whether macrophage-induced tolerance is a general feature of clinical M. tuberculosis isolates, we assessed macrophage-induced drug tolerance in strains from lineages 1-3, representing the other predominant M. tuberculosis strains responsible for tuberculosis globally. All 3 lineages developed isoniazid tolerance. While lineage 1, 3, and 4 strains developed rifampin tolerance, lineage 2 Beijing strains did not. Their failure to develop tolerance may be explained by their harboring of a loss-of-function mutation in the Rv1258c efflux pump that is linked to macrophage-induced rifampicin tolerance

Genome Sequencing of Polydrug-, Multidrug-, and Extensively Drug-Resistant Mycobacterium tuberculosis Strains from South India.

The genomes of 16 clinical Mycobacterium tuberculosis isolates were subjected to whole-genome sequencing to identify mutations related to resistance to one or more anti-Mycobacterium drugs. The sequence data will help in understanding the genomic characteristics of M. tuberculosis isolates and their resistance mutations prevalent in South India.This publication presents research supported by the MRC-DBT-funded partnership between the National Institute for Research in Tuberculosis, Chennai, India (Indian Council of Medical Research, New Delhi 5/2-8/LDCE/2014 for S.K., Department of Biotechnology [BT/IN/DBT-MRC (UK)/12/SS/2015-2016] for D.N., M.N., S.P.T., S.S., and U.D.R.) and the University of Cambridge (UK Medical Research Council [MR/N501864/1] for N.K. and S.P.)

Downregulation of monocyte miRNAs: implications for immune dysfunction and disease severity in drug-resistant tuberculosis

Monocyte miRNAs govern both protective and pathological responses during tuberculosis (TB) through their differential expression and emerged as potent targets for biomarker discovery and host-directed therapeutics. Thus, this study examined the miRNA profile of sorted monocytes across the TB disease spectrum [drug-resistant TB (DR-TB), drug-sensitive TB (DS-TB), and latent TB] and in healthy individuals (HC) to understand the underlying pathophysiology and their regulatory mechanism

Identification and Characterization of Genetic Determinants of Isoniazid and Rifampicin Resistance in Mycobacterium tuberculosis in Southern India

Abstract: Drug-resistant tuberculosis (TB), one of the leading causes of death worldwide, arises mainly from spontaneous mutations in the genome of Mycobacterium tuberculosis. There is an urgent need to understand the mechanisms by which the mutations confer resistance in order to identify new drug targets and to design new drugs. Previous studies have reported numerous mutations that confer resistance to anti-TB drugs, but there has been little systematic analysis to understand their genetic background and the potential impacts on the drug target stability and/or interactions. Here, we report the analysis of whole-genome sequence data for 98 clinical M. tuberculosis isolates from a city in southern India. The collection was screened for phenotypic resistance and sequenced to mine the genetic mutations conferring resistance to isoniazid and rifampicin. The most frequent mutation among isoniazid and rifampicin isolates was S315T in katG and S450L in rpoB respectively. The impacts of mutations on protein stability, protein-protein interactions and protein-ligand interactions were analysed using both statistical and machine-learning approaches. Drug-resistant mutations were predicted not only to target active sites in an orthosteric manner, but also to act through allosteric mechanisms arising from distant sites, sometimes at the protein-protein interface