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Objective: Sri Lanka is a country where the molecular epidemiology of Mycobacterium tuberculosis (MTB) is poorly explored. Therefore, this study was performed to identify circulating lineages/sub-lineages of MTB and their transmission patterns. Methods: DNA was extracted from 89 isolates of MTB collected during 2012 and 2013 from new pulmonary tuberculosis patients in Kandy, Sri Lanka and analyzed by spoligotyping, large sequence polymorphism (LSP), mycobacterial interspersed repetitive unit–variable number tandem repeat (MIRU-VNTR) typing, and drug resistance-associated gene sequencing. Results: The predominant lineage was lineage 4 (Euro-American, 45.9%), followed by lineage 1 (Indo-Oceanic, 29.4%), lineage 2 (East-Asian, 23.5%), and lineage 3 (Central-Asian, 1.2%). Among 26 spoligotype patterns, eight were undesignated or new types and seven of these belonged to lineage 4. Undesignated lineage 4/SIT124 (n = 2/8) and SIT3234 (n = 8/8) clustered together based on 24-locus MIRU-VNTR typing. The dominant sub-lineage was Beijing/SIT1 (n = 19), with the isoniazid resistance katG G944C mutation (Ser315Thr) detected in two of them. Conclusions: The population structure of MTB in Kandy, Sri Lanka was different from that in the South Asian region. The clonal expansion of locally evolved lineage 4/SIT3234 and detection of the pre-multidrug resistant Beijing isolates from new tuberculosis patients is alarming and will require continuous monitoring. Keywords: Mycobacterium tuberculosis, Spoligotype, MIRU-VNTR, Lineage 4 (Euro-American lineage), Sri Lanka

Objectives: Myanmar is a World Health Organization high tuberculosis (TB) burden country with a high multidrug-resistant (MDR)-TB burden. Of significance, a high prevalence of the Beijing genotype of Mycobacterium tuberculosis (MTB) among MDR-MTB has been reported previously. A detailed genetic characterization of TB clinical isolates was performed in order to explore whether there is an association between the prevalence of the Beijing MTB genotype and MDR-TB in Myanmar. Methods: A total of 265 MDR-MTB clinical isolates collected in 2010 and 2012 were subjected to spoligotyping, mycobacterial interspersed repetitive unit–variable number tandem repeat (MIRU-VNTR) analysis, single nucleotide polymorphism (SNP) typing, and drug resistance-associated gene sequencing, including rpoC to detect potential compensatory evolution. Results: Of the total MDR-MTB isolates, 79.2% (210/265) were of the Beijing genotype, the majority of which were the ‘modern’ subtype. Beijing genotype isolates were differentiated by 15-locus MIRU-VNTR and a high clustering rate (53.0%) was observed in the modern subtype. These MIRU-VNTR patterns were similar to Beijing genotype clones spreading across Russia and Central Asia. A high prevalence of katG Ser315Thr, and genetic evidence of extensive drug resistance (XDR) and pre-XDR and compensatory mutations in rpoC were observed among clustered isolates. Conclusions: MDR-MTB strains of the Beijing genotype might be spreading in Myanmar and present a major challenge to TB control in this country. Keywords: Mycobacterium tuberculosis, Multidrug-resistant TB, Beijing genotype, MIRU-VNTR, Myanmar

Summary: Increased glycolytic metabolism recently emerged as an essential process driving host defense against Mycobacterium tuberculosis (Mtb), but little is known about how this process is regulated during infection. Here, we observe repression of host glycolysis in Mtb-infected macrophages, which is dependent on sustained upregulation of anti-inflammatory microRNA-21 (miR-21) by proliferating mycobacteria. The dampening of glycolysis by miR-21 is mediated through targeting of phosphofructokinase muscle (PFK-M) isoform at the committed step of glycolysis, which facilitates bacterial growth by limiting pro-inflammatory mediators, chiefly interleukin-1β (IL-1β). Unlike other glycolytic genes, PFK-M expression and activity is repressed during Mtb infection through miR-21-mediated regulation, while other less-active isoenzymes dominate. Notably, interferon-γ (IFN-γ), which drives Mtb host defense, inhibits miR-21 expression, forcing an isoenzyme switch in the PFK complex, augmenting PFK-M expression and macrophage glycolysis. These findings place the targeting of PFK-M by miR-21 as a key node controlling macrophage immunometabolic function. : Hackett et al. identify a role for the anti-inflammatory miR-21 in limiting host glycolysis during tuberculosis (TB) infection to favor bacterial replication. This occurs by targeting a pro-glycolytic isoform at the rate-limiting step in glycolysis, PFK-M, a process antagonized by the host Th1-cytokine IFN-γ, to promote full macrophage activation and antimicrobial function. Keywords: macrophage, metabolic reprogramming, tuberculosis, mycobacterium tuberculosis, glycolysis, microRNA, miR-21, interleukin-1b, phosphofructokinase, interferon gamma