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Close related Drug-Resistance Beijing isolates of Mycobacterium tuberculosis reveal a different transcriptomic signature in a murine disease progression model.

ABSTRACT: Mycobacterium tuberculosis (MTB) Beijing genotype is associated with high virulence and drug resistance worldwide. In Colombia, the Beijing genotype circulates since 1997 predominantly on the pacific coast, being the Beijing-Like SIT-190 more prevalent. This genotype conforms to a drug-resistant cluster and shows a fatal outcome in patients. To better understand virulence determinants, we performed a transcriptomic analysis with a Beijing-Like SIT-190 isolate (BL-323), and Beijing-Classic SIT-1 isolate (BC-391) in progressive tuberculosis (TB) murine model. RNA was extracted from mice lungs on days 3, 14, 28, and 60. On average, 0.6% of the total reads mapped against MTB genomes and of those, 90% against coding genes. The strains were independently associated as determined by hierarchical cluster and multidimensional scaling analysis. Gene ontology showed that in strain BL-323 enriched functions were related to host immune response and hypoxia, while proteolysis and protein folding were enriched in the BC-391 strain. Altogether, our results suggested a differential transcriptional program when evaluating these two closely related strains. The data presented here could potentially impact the control of this emerging, highly virulent and drug resistance genotype.

ORGANISM(S): Mycobacterium tuberculosis

PROVIDER: GSE198877 | GEO | 2022/03/24

REPOSITORIES: GEO

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Project description:The identification of multidrug resistant (MDR), extensively and totally drug resistant Mycobacterium tuberculosis (Mtb), in vulnerable sites such as Mumbai, is a grave threat to the control of tuberculosis. The current study aimed at explaining the rapid expression of MDR in Directly Observed Treatment Short Course (DOTS) compliant patients, represents the first study comparing global transcriptional profiles of 3 pairs of clinical Mtb isolates, collected longitudinally at initiation and completion of DOTS. While the isolates were drug susceptible (DS) at onset and MDR at completion of DOTS, they exhibited identical DNA fingerprints at both points of collection. The whole genome transcriptional analysis was performed using total RNA from H37Rv and 3 locally predominant spoligotypes viz. MANU1, CAS and Beijing, hybridized on MTBv3 (BuG@S) microarray, and yielded 36, 98 and 45 differentially expressed genes respectively. Genes encoding transcription factors (sig, rpoB), cell wall biosynthesis (emb genes), protein synthesis (rpl) and additional central metabolic pathways (ppdK, pknH, pfkB) were found to be down regulated in the MDR isolates as compared to the DS isolate of the same genotype. Up regulation of drug efflux pumps, ABC transporters, trans-membrane proteins and stress response transcriptional factors (whiB) in the MDR isolates was observed. The data indicated that Mtb, without specific mutations in drug target genes may persist in the host due to additional mechanisms like drug efflux pumps and lowered rate of metabolism. Furthermore this population of Mtb, which also showed reduced DNA repair activity, would result in selection and stabilization of spontaneous mutations in drug target genes, causing selection of a MDR strain in the presence of drug pressures. Efflux pump such as drrA may play a significant role in increasing fitness of low level drug resistant cells and assist in survival of Mtb till acquisition of drug resistant mutations with least fitness cost. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-134]

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Close related Drug-Resistance Beijing isolates of Mycobacterium tuberculosis reveal a different transcriptomic signature in a murine disease progression model.

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