Systematic Genetic Nomenclature for Type VII Secretion Systems

Bitter, Wilbert; Houben, Edith N.G.; Bottai, Darria; Brodin, Priscille; Brown, Eric J.; Cox, Jeffery S.; Derbyshire, Keith M.; Fortune, Sarah M.; Gao, Lian-Yong; Liu, Jun; Pittius, Nicolaas C. Gey van; Pym, Alexander S.; Rubín, Eric J.; Sherman, David R.; Cole, Stewart T.; Brosch, Roland

doi:10.1371/journal.ppat.1000507

Cited by 236 publications

(241 citation statements)

References 60 publications

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“…1). Of particular note, members of the ESX-1 type VII secretion system that are critical for full virulence of M. tuberculosis (36)(37)(38)(39) were significantly overexpressed in both of these isolates compared to H37Rv, including the esxA (esat-6), esxB (cfp-10), and espI genes. It should be noted that for the HN878 arrays, the relative expression level of esxA (ϩ1.9) fell just below the Z-score threshold of Ͼ2.0.…”

Section: Resultsmentioning

confidence: 99%

Unique Regulation of the DosR Regulon in the Beijing Lineage of Mycobacterium tuberculosis

et al. 2017

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The DosR regulon, a set of 48 genes normally expressed in Mycobacterium tuberculosis under conditions that inhibit aerobic respiration, is controlled via the DosR-DosS/DosT two-component system. While the regulon requires induction in most M. tuberculosis isolates, for members of the Beijing lineage, its expression is uncoupled from the need for signaling. In our attempts to understand the mechanistic basis for this uncoupling in the Beijing background, we previously reported the identification of two synonymous single-nucleotide polymorphisms (SNPs) within the adjacent Rv3134c gene. In the present study, we have interrogated the impact of these SNPs on dosR expression in wild-type strains, as well as a range of dosRdosS-dosT mutants, for both Beijing and non-Beijing M. tuberculosis backgrounds. In this manner, we have unequivocally determined that the C601T dosR promoter SNP is the sole requirement for the dramatic shift in the pattern of DosR regulon expression seen in this globally important lineage. Interestingly, we also show that DosT is completely nonfunctional within these strains. Thus, a complex series of evolutionary steps has led to the present-day Beijing DosR phenotype that, in turn, potentially confers a fitness advantage in the face of some form of host-associated selective pressure.IMPORTANCE Mycobacterium tuberculosis strains of the Beijing lineage have been described as being of enhanced virulence compared to other lineages, and in certain regions, they are associated with the dramatic spread of multidrug-resistant tuberculosis (TB). In terms of trying to understand the functional basis for these broad epidemiological phenomena, it is interesting that, in contrast to the other major lineages, the Beijing strains all constitutively overexpress members of the DosR regulon. Here, we identify the mutational events that led to the evolution of this unique phenotype. In addition, our work highlights the fact that important phenotypic differences exist between distinct M. tuberculosis lineages, with the potential to impact the efficacy of diagnosis, vaccination, and treatment programs.KEYWORDS Tuberculosis, DosR regulon, strain variation, evolution, Mycobacterium tuberculosis D espite being an ancient disease, human tuberculosis (TB) resulting from infection with Mycobacterium tuberculosis still remains a leading cause of death worldwide as a consequence of multiple contributing factors, including drug resistance, HIV coinfection, and inadequate access to high-quality health care (1). Furthermore, recent evidence suggests that the level of genetic diversity that exists among distinct M. tuberculosis isolates was previously underestimated and has the potential to impact pathogenicity, as well as to limit the effectiveness of current diagnostic and therapeutic interventions (2-4).

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Section: Resultsmentioning

confidence: 99%

Unique Regulation of the DosR Regulon in the Beijing Lineage of Mycobacterium tuberculosis

et al. 2017

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“…In the inserted region, ESAT-6 like (esx) proteins, such as InsB (MTBK_24790) and InsC (MTBK_24800) (18,19), and PPE proteins, including InsD (MTBK_24810; partial form of PPE38) and MTBK_24820 (N-terminally added PPE39 protein), are inserted in a row. Unlike other PE-PPE proteins located in a row in the ESX region (20), MTBK_24820 exists independently, without PE proteins in the insertion region. MTBK_24820 is a PPE-MTPR subfamily with repeats of NxGxGNxG in the C terminus (17,21) and is orthologous to the M. tuberculosis H37Rv PPE39 protein (annotated Rv2353c) (22).…”

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confidence: 95%

Protective Vaccine Efficacy of the Complete Form of PPE39 Protein from Mycobacterium tuberculosis Beijing/K Strain in Mice

Kim

Hur

et al. 2017

Clin Vaccine Immunol

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The aim of this study was to evaluate the protective efficacy of MTBK_ 24820, a complete form of PPE39 protein derived from a predominant Beijing/K strain of Mycobacterium tuberculosis in South Korea. Mice were immunized with MTKB_24820, M. bovis Bacilli Calmette-Guérin (BCG), or adjuvant prior to a high-dosed Beijing/K strain aerosol infection. After 4 and 9 weeks, bacterial loads were determined and histopathologic and immunologic features in the lungs and spleens of the M. tuberculosis-infected mice were analyzed. Putative immunogenic T-cell epitopes were examined using synthetic overlapping peptides. Successful immunization of MTBK_24820 in mice was confirmed by increased IgG responses (P Ͻ 0.05) and recalled gamma interferon (IFN-␥), interleukin-2 (IL-2), IL-6, and IL-17 responses (P Ͻ 0.05 or P Ͻ 0.01) to MTBK_24820. After challenge with the Beijing/K strain, an approximately 0.5 to 1.0 log 10 reduction in CFU in lungs and fewer lung inflammation lesions were observed in MTBK_24820-immunized mice compared to those for control mice. Moreover, MTBK_24820 immunization elicited significantly higher numbers of CD4 ϩ T cells producing protective cytokines, such as IFN-␥ and IL-17, in lungs and spleens (P Ͻ 0.01) and CD4 ϩ multifunctional T cells producing IFN-␥, tumor necrosis factor alpha (TNF-␣), and/or IL-17 (P Ͻ 0.01) than in control mice, suggesting protection comparable to that of BCG against the hypervirulent Beijing/K strain. The dominant immunogenic T-cell epitopes that induced IFN-␥ production were at the N terminus (amino acids 85 to 102 and 217 to 234). Its vaccine potential, along with protective immune responses in vivo, may be informative for vaccine development, particularly in regions where the M. tuberculosis Beijing/K-strain is frequently isolated from TB patients.

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“…In M. tuberculosis, the products of orthologous genes are thought to fuel protein transport by the type VII secretion system and contribute to substrate recognition (8,27). The chromosome of M. tuberculosis harbors multiple ESX gene clusters, as well as genomic islands that encode non-WXG100 secretion substrates and regulatory factors for these secretion pathways (1,5,14). In S. aureus, ess was initially identified as a single locus flanked by two genes for WXG100 proteins, esxA esaA essA essB esaB essC esaC esxB.…”

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confidence: 99%

EsaD, a Secretion Factor for the Ess Pathway inStaphylococcus aureus

et al. 2011

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Staphylococcus aureus encodes the Sec-independent Ess secretion pathway, an ortholog of mycobacterial T7 secretion systems which is required for the virulence of this Gram-positive microbe. The Ess (ESX secretion) pathway was previously defined as a genomic cluster of eight genes, esxA, esaA, essA, essB, esaB, essC, esaC, and esxB. essABC encode membrane proteins involved in the stable expression of esxA, esxB, and esaC, genes specifying three secreted polypeptide substrates. esaB, which encodes a small cytoplasmic protein, represses the synthesis of EsaC but not that of EsxA and EsxB. Here we investigated a hitherto uncharacterized gene, esaD, located downstream of esxB. Expression of esaD is activated by mutations in esaB and essB. EsaD, the 617-amino-acid product of esaD, is positioned in the membrane and is also accessible to EsaD-specific antibodies on the bacterial surface. S. aureus mutants lacking esaD are defective in the secretion of EsxA. Following intravenous inoculation of mice, S. aureus esaD mutants generate fewer abscesses with a reduced bacterial load compared to wild-type parent strain Newman. The chromosomes of Listeria and Bacillus species with Ess pathways also harbor esaD homologues downstream of esxB, suggesting that the contributory role of EsaD in Ess secretion may be shared among Gram-positive pathogens.

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Systematic Genetic Nomenclature for Type VII Secretion Systems

Cited by 236 publications

References 60 publications

Unique Regulation of the DosR Regulon in the Beijing Lineage of Mycobacterium tuberculosis

Unique Regulation of the DosR Regulon in the Beijing Lineage of Mycobacterium tuberculosis

Protective Vaccine Efficacy of the Complete Form of PPE39 Protein from Mycobacterium tuberculosis Beijing/K Strain in Mice

EsaD, a Secretion Factor for the Ess Pathway inStaphylococcus aureus

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