Genetic Diversity in Mycobacterium tuberculosis Clinical Isolates and Resulting Outcomes of Tuberculosis Infection and Disease

Tuberculosis claims more human lives than any other bacterial infectious disease and represents a clear and present danger to global health as new tools for vaccination, treatment, and interruption of transmission have been slow to emerge. Additionally, tuberculosis presents with notable clinical heterogeneity, which complicates diagnosis, treatment, and the establishment of nonrelapsing cure. How this heterogeneity is driven by the diversity ofclinical isolates of the causative agent, Mycobacterium tuberculosis, has recently garnered attention. Herein, we review advances in the understanding of how naturally occurring variation in clinical isolates affects transmissibility, pathogenesis, immune modulation, and drug resistance. We also summarize how specific changes in transcriptional responses can modulate infection or disease outcome, together with strain-specific effects on gene essentiality. Further understanding of how this diversity of M. tuberculosis isolates affects disease and treatment outcomes will enable the development of more effective therapeutic options and vaccines for this dreaded disease.

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RNA expression analysis of efflux pump genes in clinical isolates of multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis

10.26226/morressier.56d5ba2cd462b80296c94d42 ◽

2016 ◽

Author(s):

Hee Joo Lee

Keyword(s):

Mycobacterium Tuberculosis ◽

Expression Analysis ◽

Efflux Pump ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Rna Expression ◽

Drug Resistant ◽

Extensively Drug Resistant

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Faculty Opinions recommendation of Rifampin and isoniazid resistance associated mutations in Mycobacterium tuberculosis clinical isolates in Seville, Spain.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1005343.52604 ◽

2002 ◽

Author(s):

Gaby Pfyffer

Keyword(s):

Mycobacterium Tuberculosis ◽

Clinical Isolates ◽

Isoniazid Resistance

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Faculty Opinions recommendation of First linezolid-resistant clinical isolates of Mycobacterium tuberculosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1061849.513793 ◽

2007 ◽

Author(s):

Gaby Pfyffer

Keyword(s):

Mycobacterium Tuberculosis ◽

Clinical Isolates

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Relationship between rifampin MICs for and rpoB mutations of Mycobacterium tuberculosis strains isolated in Japan.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.4.1053 ◽

1996 ◽

Vol 40 (4) ◽

pp. 1053-1056 ◽

Cited By ~ 80

Author(s):

H Ohno ◽

H Koga ◽

S Kohno ◽

T Tashiro ◽

K Hara

Keyword(s):

Mycobacterium Tuberculosis ◽

Point Mutation ◽

Rpob Gene ◽

The Other ◽

Clinical Isolates ◽

Sequencing Analysis ◽

The Relationship

We analyzed the relationship between rifampin MICs and rpoB mutations of 40 clinical isolates of Mycobacterium tuberculosis. A point mutation in either codon 516, 526, or 531 was found in 13 strains requiring MICs of > or = 64 micrograms/ml, while 21 strains requiring MICs of < or = 1 microgram/ml showed no alteration in these codons. However, 3 of these 21 strains contained a point mutation in either codon 515 or 533. Of the other six strains requiring MICs between 2 and 32 micrograms/ml, three contained a point mutation in codon 516 or 526, while no alteration was detected in the other three. Our results indicate that the sequencing analysis of a 69-bp fragment in the rpoB gene is useful in predicting rifampin-resistant phenotypes.

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Analysis of genetic polymorphisms affecting the four phospholipase C (plc) genes in Mycobacterium tuberculosis complex clinical isolates

Microbiology ◽

10.1099/mic.0.26778-0 ◽

2004 ◽

Vol 150 (4) ◽

pp. 967-978 ◽

Cited By ~ 25

Author(s):

C. Viana-Niero ◽

P. E. de Haas ◽

D. van Soolingen ◽

S. C. Leão

Keyword(s):

Mycobacterium Tuberculosis ◽

Phospholipase C ◽

Genetic Polymorphisms ◽

Blot Hybridization ◽

Southern Blot Hybridization ◽

Clinical Isolates ◽

Significant Similarity ◽

Genomic Deletions ◽

Genes Encoding ◽

Mycobacterium Africanum

The Mycobacterium tuberculosis genome contains four highly related genes which present significant similarity to Pseudomonas aeruginosa genes encoding phospholipase C enzymes. Three of these genes, plcA, plcB and plcC, are organized in tandem (locus plcABC). The fourth gene, plcD, is located in a different region. This study investigates variations in plcABC and plcD genes in clinical isolates of M. tuberculosis, Mycobacterium africanum and ‘Mycobacterium canettii’. Genetic polymorphisms were examined by PCR, Southern blot hybridization, sequence analysis and RT-PCR. Seven M. tuberculosis isolates contain insertions of IS6110 elements within plcA, plcC or plcD. In 19 of 25 M. tuberculosis isolates examined, genomic deletions were identified, resulting in loss of parts of genes or complete genes from the plcABC and/or plcD loci. Partial plcD deletion was observed in one M. africanum isolate. In each case, deletions were associated with the presence of a copy of the IS6110 element and in all occurrences IS6110 was transposed in the same orientation. A mechanism of deletion resulting from homologous recombination of two copies of IS6110 was recognized in a group of genetically related M. tuberculosis isolates. Five M. tuberculosis isolates presented major polymorphisms in the plcABC and plcD regions, along with loss of expression competence that affected all four plc genes. Phospholipase C is a well-known bacterial virulence factor. The precise role of phospholipase C in the pathogenicity of M. tuberculosis is unknown, but considering the potential importance that the plc genes may have in the virulence of the tubercle bacillus, the study of isolates cultured from patients with active tuberculosis bearing genetic variations affecting these genes may provide insights into the significance of phospholipase C enzymes for tuberculosis pathogenicity.

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Mutations of folC cause increased susceptibility to sulfamethoxazole in Mycobacterium tuberculosis

Scientific Reports ◽

10.1038/s41598-020-80213-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ruiqi Wang ◽

Kun Li ◽

Jifang Yu ◽

Jiaoyu Deng ◽

Yaokai Chen

Keyword(s):

Mycobacterium Tuberculosis ◽

Type Strain ◽

Wild Type Strain ◽

Clinical Isolates ◽

Aminobenzoic Acid ◽

Wild Type ◽

Dihydropteroate Synthase ◽

Expression Levels ◽

Encoding Gene ◽

Increased Susceptibility

AbstractPrevious studies showed that mutation of folC caused decreased expression of the dihydropteroate synthase encoding gene folP2 in Mycobacterium tuberculosis (M. tuberculosis). We speculated that mutation of folC in M. tuberculosis might affect the susceptibility to sulfamethoxazole (SMX). To prove this, 53 clinical isolates with folC mutations were selected and two folC mutants (I43A, I43T) were constructed based on M. tuberculosis H37Ra. The results showed that 42 of the 53 clinical isolates (79.2%) and the two lab-constructed folC mutants were more sensitive to SMX. To probe the mechanism by which folC mutations make M. tuberculosis more sensitive to SMX, folP2 was deleted in H37Ra, and expression levels of folP2 were compared between H37Ra and the two folC mutants. Although deletion of folP2 resulted in increased susceptibility to SMX, no difference in folP2 expression was observed. Furthermore, production levels of para-aminobenzoic acid (pABA) were compared between the folC mutants and the wild-type strain, and results showed that folC mutation resulted in decreased production of pABA. Taken together, we show that folC mutation leads to decreased production of pABA in M. tuberculosis and thus affects its susceptibility to SMX, which broadens our understanding of mechanisms of susceptibilities to antifolates in this bacterium.

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