Role of two‐component regulatory systems in intracellular survival of <i>Mycobacterium tuberculosis</i>

Li, Xue; Lv, Xi; Lin, Yingyan; Zhen, Junfeng; Ruan, Cao; Duan, Wei; Li, Yue; Xie, Jianping

doi:10.1002/jcb.28792

Cited by 13 publications

(6 citation statements)

References 99 publications

(173 reference statements)

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“…A total of 45 two-component system genes were obtained according to NCBI and literature search [ 2 , 7 , 41 ]. Python was utilized to detect mutations in genes associated with TCSs (Additional file 2: Table S3 ).…”

Section: Methodsmentioning

confidence: 99%

Association between two-component systems gene mutation and Mycobacterium tuberculosis transmission revealed by whole genome sequencing

Li,

Kong,

et al. 2023

BMC Genomics

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Background Two-component systems (TCSs) assume a pivotal function in Mycobacterium tuberculosis (M.tuberculosis) growth. However, the exact regulatory mechanism of this system needs to be elucidated, and only a few studies have investigated the effect of gene mutations within TCSs on M.tuberculosis transmission. This research explored the relationship between TCSs gene mutation and the global transmission of (M.tuberculosis). Results A total of 13531 M.tuberculosis strains were enrolled in the study. Most of the M.tuberculosis strains belonged to lineage4 (n=6497,48.0%), followed by lineage2 (n=5136,38.0%). Our results showed that a total of 36 single nucleotide polymorphisms (SNPs) were positively correlated with clustering of lineage2, such as Rv0758 (phoR, C820G), Rv1747(T1102C), and Rv1057(C1168T). A total of 30 SNPs showed positive correlation with clustering of lineage4, such as phoR(C182A, C1184G, C662T, T758G), Rv3764c (tcrY, G1151T), and Rv1747 C20T. A total of 19 SNPs were positively correlated with cross-country transmission of lineage2, such as phoR A575C, Rv1028c (kdpD, G383T, G1246C), and Rv1057 G817T. A total of 41 SNPs were positively correlated with cross-country transmission of lineage4, such as phoR(T758G, T327G, C284G), kdpD(G1755A, G625C), Rv1057 C980T, and Rv1747 T373G. Conclusions Our study identified that SNPs in genes of two-component systems were related to the transmission of M. tuberculosis. This finding adds another layer of complexity to M. tuberculosis virulence and provides insight into future research that will help to elucidate a novel mechanism of M. tuberculosis pathogenicity.

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Section: Methodsmentioning

confidence: 99%

Association between two-component systems gene mutation and Mycobacterium tuberculosis transmission revealed by whole genome sequencing

Li,

Kong,

et al. 2023

BMC Genomics

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“…Successful bacterial pathogens like Mtb and Mab employ extensive repertoires of transcription factors, including TCS, for coordinating gene expression to counteract host antimicrobial factors and immune pressure. The transcriptional regulatory networks and role of TCS of Mtb have been extensively characterized in multiple in vitro and in vivo models of infection ( Bacon and Marsh, 2007 ; Rohde et al., 2012 ; Li et al., 2019 ; Stupar et al., 2022 ; Vilcheze et al., 2022 ). In contrast, few transcriptomic studies defining Mab stress responses, or the role of specific transcription factors have been reported (Miranda-CasoLuengo et al., 2016 ; Dubois et al., 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium abscessus DosRS two-component system controls a species-specific regulon required for adaptation to hypoxia

Simcox

Tomlinson²,

Shaw³

et al. 2023

Front. Cell. Infect. Microbiol.

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Mycobacterium abscessus (Mab), an emerging opportunistic pathogen, predominantly infects individuals with underlying pulmonary diseases such as cystic fibrosis (CF). Current treatment outcomes for Mab infections are poor due to Mab’s inherent antibiotic resistance and unique host interactions that promote phenotypic tolerance and hinder drug access. The hypoxic, mucus-laden airways in the CF lung and antimicrobial phagosome within macrophages represent hostile niches Mab must overcome via alterations in gene expression for survival. Regulatory mechanisms important for the adaptation and long-term persistence of Mab within the host are poorly understood, warranting further genetic and transcriptomics study of this emerging pathogen. DosRSMab, a two-component signaling system (TCS), is one proposed mechanism utilized to subvert host defenses and counteract environmental stress such as hypoxia. The homologous TCS of Mycobacterium tuberculosis (Mtb), DosRSMtb, is known to induce a ~50 gene regulon in response to hypoxia, carbon monoxide (CO) and nitric oxide (NO) in vitro and in vivo. Previously, a small DosRMab regulon was predicted using bioinformatics based on DosRMtb motifs however, the role and regulon of DosRSMab in Mab pathogenesis have yet to be characterized in depth. To address this knowledge gap, our lab generated a Mab dosRS knockout strain (MabΔdosRS) to investigate differential gene expression, and phenotype in an in vitro hypoxia model of dormancy. qRT-PCR and lux reporter assays demonstrate Mab_dosR and 6 predicted downstream genes are induced in hypoxia. In addition, RNAseq revealed induction of a much larger hypoxia response comprised of >1000 genes, including 127 differentially expressed genes in a dosRS mutant strain. Deletion of DosRSMab led to attenuated growth under low oxygen conditions, a shift in morphotype from smooth to rough, and down-regulation of 216 genes. This study provides the first look at the global transcriptomic response of Mab to low oxygen conditions encountered in the airways of CF patients and within macrophage phagosomes. Our data also demonstrate the importance of DosRSMab for adaptation of Mab to hypoxia, highlighting a distinct regulon (compared to Mtb) that is significantly larger than previously described, including both genes conserved across mycobacteria as well as Mab-specific genes.

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“…regX3 and phoP belong to two-component regulatory systems (2CRS), whereas embR and Rv2488c are of the ompB and luxR families, respectively. Many of M. tb’ s 2CRS have been implicated in virulence and survival in host conditions ( Li et al, 2019 ) and this is true of regX3 , which with its partner senX3 is required for virulence in mice ( Li et al, 2019 ; Parish et al, 2003 ). Of note, regX3 regulates genes that are known to be involved in M. tb biofilm development ( Richards et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Rapid adaptation of a complex trait during experimental evolution of Mycobacterium tuberculosis

Smith

Youngblom

Kernien

et al. 2022

eLife

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tb), is a leading cause of death due to infectious disease. TB is not traditionally associated with biofilms, but M. tb biofilms are linked with drug and immune tolerance and there is increasing recognition of their contribution to the recalcitrance of TB infections. Here, we used M. tb experimental evolution to investigate this complex phenotype and identify candidate loci controlling biofilm formation. We identified novel candidate loci, adding to our understanding of the genetic architecture underlying M. tb biofilm development. Under selective pressure to grow as a biofilm, regulatory mutations rapidly swept to fixation and were associated with changes in multiple traits, including extracellular matrix production, cell size, and growth rate. Genetic and phenotypic paths to enhanced biofilm growth varied according to the genetic background of the parent strain, suggesting that epistatic interactions are important in M. tb adaptation to changing environments.

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Role of two‐component regulatory systems in intracellular survival of Mycobacterium tuberculosis

Cited by 13 publications

References 99 publications

Association between two-component systems gene mutation and Mycobacterium tuberculosis transmission revealed by whole genome sequencing

Association between two-component systems gene mutation and Mycobacterium tuberculosis transmission revealed by whole genome sequencing

Mycobacterium abscessus DosRS two-component system controls a species-specific regulon required for adaptation to hypoxia

Rapid adaptation of a complex trait during experimental evolution of Mycobacterium tuberculosis

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