natarajan palaniappan

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 ...

Monitoring tuberculosis (TB) treatment success is crucial for clinical decision-making. The only available tool in this regard is sputum microscopy, but it has demerits. Moreover, in case of smear negatives and extrapulmonary TB, an efficient tool is still sought for. Therefore, we evaluated T regulatory cell (Treg)-associated markers (CD25, CD39, and FoxP3) and cellular subsets in monitoring treatment success in treatment-completed groups. Expression profile of various markers and subsets were compared real time among treatment-naive pulmonary TB patients (TN-PTB), followed-up treatment-completed (TC-fu) cohort, and a not followed-up (TC-nfu) cohort. Peripheral blood mononuclear cells from various groups were incubated overnight and were stained with antibodies for specific markers and studied by flow cytometry. In both the treatment-completed groups, a decline in frequencies of CD25 marker and CD4CD25, CD4CD25FoxP3, CD4CD25CD39 Treg was observed with clearance of infection, indica...

Treatment monitoring is an essential aspect for tuberculosis (TB) disease management. Sputum smear microscopy is the only available tool for monitoring, but it suffers from demerits. Therefore, we sought to evaluate markers and cellular subsets of T regulatory (Treg) cells and T helper (Th) 17 cells in pulmonary TB patients (PTB) for TB treatment monitoring. Peripheral blood mononuclear cells (PBMCs) were stimulated(with purified protein derivative (PPD)) overnight which was followed by a polychromatic flow cytometry approach to study Treg and Th17 markers and cellular subsets in PTB ( = 12) undergoing antituberculous treatment (ATT). The baseline levels of these markers and cellular subsets were evaluated in normal healthy subjects (NHS). We observed a significant decrease in the expression of CD25 (<0.01) marker and percentage of T-cell subsets like CD4CD25(<0.001) and CD4CD25CD39(<0.05) at the end of intensive phase (IP) as well as in the continuation phase (CP) of ATT. ...

Emergence of drug-resistant tuberculosis (DR-TB) is a big challenge in TB control. The delay in diagnosis of DR-TB leads to its increased transmission, and therefore prevalence. Recent developments in genomics have enabled whole genome sequencing (WGS) of Mycobacterium tuberculosis (M. tuberculosis) from 3-day-old liquid culture and directly from uncultured sputa, while new bioinformatics tools facilitate to determine DR mutations rapidly from the resulting sequences. The present drug discovery and development pipeline is filled with candidate drugs which have shown efficacy against DR-TB. Furthermore, some of the FDA-approved drugs are being evaluated for repurposing, and this approach appears promising as several drugs are reported to enhance efficacy of the standard TB drugs, reduce drug tolerance, or modulate the host immune response to control the growth of intracellular M. tuberculosis. Recent developments in genomics and bioinformatics along with new drug discovery collectively have the potential to result in synergistic impact leading to the development of a rapid protocol to determine the drug resistance profile of the infecting strain so as to provide personalized medicine. Hence, in this review, we discuss recent developments in WGS, bioinformatics and drug discovery to perceive how they would transform the management of tuberculosis in a timely manner.

The benefit of daily over thrice-weekly antituberculosis therapy among HIV-positive patients with pulmonary tuberculosis (TB) who are receiving antiretroviral therapy remains unproven. To compare the efficacy and safety of daily, part-daily, and intermittent antituberculosis therapy regimens in the treatment of HIV-associated pulmonary TB. This open-label, randomized clinical trial was conducted by the National Institute for Research in Tuberculosis, south India. Adults infected with HIV with newly diagnosed, culture-positive, pulmonary TB were enrolled between September 14, 2009, and January 18, 2016. Patients were randomized to daily, part-daily, and intermittent antituberculosis therapy regimens, stratified by baseline CD4 lymphocyte count and sputum smear grade. Antiretroviral therapy was initiated as per national guidelines. Clinical and sputum microbiological examinations of patients were performed monthly until 18 months after randomization. Adverse events were recorded using...