Mycobacterial WhiB6 Differentially Regulates ESX-1 and the Dos Regulon to Modulate Granuloma Formation and Virulence in Zebrafish

Chen, Zhenkang; Hu, Yangbo; Cumming, Bridgette M.; Lu, Pei Jung; Feng, Lipeng; Deng, Jiao-Yu; Steyn, Adrie J. C.; Chen, Shiyun

doi:10.1016/j.celrep.2016.07.080

Cited by 77 publications

(109 citation statements)

References 65 publications

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“…We found several novel associations most strongly with the AG class of antituberculosis drugs. These include the transcriptional regulator whiB6 that is known to activate expression of the DosR regulon, and controls aerobic and anaerobic metabolism and virulence among other pathways 50 . Previous work has implicated another whiB-like transcriptional regulator, whiB7, in resistance to AGs 51 and whiB6 and the upstream intergenic region were previously associated with resistance in a prior GWAS albeit to non-AG agents.…”

Section: Aminoglycosides (Ag)mentioning

confidence: 99%

Genome wide association with quantitative resistance phenotypes in Mycobacterium tuberculosis reveals novel resistance genes and regulatory regions

Mustafa

Freschi

Calderón

et al. 2018

Preprint

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Drug resistance is threatening attempts at tuberculosis epidemic control. Molecular diagnostics for drug resistance that rely on the detection of resistance-related mutations could expedite patient care and accelerate progress in TB eradication. We performed minimum inhibitory concentration testing for 12 anti-TB drugs together with Illumina whole genome sequencing on 1452 clinical Mycobacterium tuberculosis (MTB) isolates. We then used a linear mixed model to evaluate genome wide associations between mutations in MTB genes or noncoding regions and drug resistance, followed by validation of our findings in an independent dataset of 792 patient isolates. Novel associations at 13 genomic loci were confirmed in the validation set, with 2 involving noncoding regions. We found promoter mutations to have smaller average effects on resistance levels than gene body mutations in genes where both can contribute to resistance. Enabled by a quantitative measure of resistance, we estimated the heritability of the resistance phenotype to 11 anti-TB drugs and identify a lower than expected contribution from known resistance genes. We also report the proportion of variation in resistance levels explained by the novel loci identified here. This study highlights the complexity of the genomic mechanisms associated with the MTB resistance phenotype, including the relatively large number of potentially causative or compensatory loci, and emphasizes the contribution of the noncoding portion of the genome.2 Introduction: Tuberculosis (TB) remains a major global public health threat. In 2016 there were an estimated 10.4 million TB cases globally and 1.7 million deaths due to the disease. One of the most challenging forms of disease is caused by multidrug resistant (MDR) Mycobacterium tuberculosis, with a global annual incidence of over half a million cases 1 . The World Health Organization (WHO) estimates that only two of every three patients with multidrug resistant TB are diagnosed, three in every four of the diagnosed are treated, and only one of every two of the treated patients are cured, resulting in the grim reality of about 75% of the incident cases persisting in the community or succumbing to their illness. Antibiotic resistance is also an increasing problem in other human pathogens, and transmission of antibiotic resistance from person to person is amplifying the public health threat 2 .Improved surveillance, diagnosis and treatment are designated priorities by the WHO and the US, European CDCs for addressing the antibiotic resistance challenge 1,3,4 . These measures will rely on an improved understanding of the mechanisms of resistance acquisition in bacteria. The knowledge of genetic mechanisms of antibiotic resistance has formed the basis of several commercial molecular diagnostics for TB that have had remarkable global uptake, despite the fact that they only reliably test for a subset of TB drugs and hence have not yet been able to replace the traditional more costly and slow process of mycobacterial culture and drug susce...

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Section: Aminoglycosides (Ag)mentioning

confidence: 99%

Genome wide association with quantitative resistance phenotypes in Mycobacterium tuberculosis reveals novel resistance genes and regulatory regions

Mustafa

Freschi

Calderón

et al. 2018

Preprint

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“…heat, diamide, NO, cumene peroxide) [155,180]. Recently, Steyn and colleagues showed that WhiB6 from M. marinum (closely related to M. tuberculosis) differentially regulates the DosR dormancy and the ESX-1 virulence factor regulons through its ability to sense NO and oxidative stress via its Fe-S cluster [39]. This led them to propose a model for the function of WhiB6 in which it is upregulated by NO when M. marinum is engulfed by activated macrophages.…”

Section: Wbl Proteins In Mycobacteriamentioning

confidence: 99%

13. Reactivity of iron-sulfur clusters with nitric oxide

Dodd¹,

Crack²,

Thomson³

et al. 2017

Characterization, Properties and Applications

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“…ESAT-6 is the virulence factor secreted by ESX-1 secretion system in M. tuberculosis (Solans et al 2014, Chen et al 2016). …”

mentioning

confidence: 99%

Complete plasmid sequence carrying type IV-like and type VII secretion systems from an atypical mycobacteria strain

Morgado

Abanto

Freitas

et al. 2017

Mem. Inst. Oswaldo Cruz

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The genus Mycobacterium is highly diverse and ubiquitous in nature, comprehending fast- and slow-growing species with distinct impact in public health. The plasmid-mediated horizontal gene transfer represents one of the major events in bacteria evolution. Here, we report the complete sequence of a 160,489 bp circular plasmid (pCBMA213_2) from an atypical and fast-growing environmental mycobacteria. This is a unique plasmid, in comparison with the characterised mycobacteria plasmids, harboring a type IV-like and ESX-P2 type VII secretion systems. pCBMA213_2 can be further explored for evolutionary and conjugation studies as well as a tool to manipulate DNA within this bacteria genus.

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Mycobacterial WhiB6 Differentially Regulates ESX-1 and the Dos Regulon to Modulate Granuloma Formation and Virulence in Zebrafish

Cited by 77 publications

References 65 publications

Genome wide association with quantitative resistance phenotypes in Mycobacterium tuberculosis reveals novel resistance genes and regulatory regions

Genome wide association with quantitative resistance phenotypes in Mycobacterium tuberculosis reveals novel resistance genes and regulatory regions

13. Reactivity of iron-sulfur clusters with nitric oxide

Complete plasmid sequence carrying type IV-like and type VII secretion systems from an atypical mycobacteria strain

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