The ESAT-6 gene cluster of Mycobacterium tuberculosis and other high G+C Gram-positive bacteria

Pittius, Nico C. Gey van; Gamieldien, Junaid; Hide, Winston; Brown, Gordon D.; Siezen, Roland J.; Beyers, Albertus D.

doi:10.1186/gb-2001-2-10-research0044

Cited by 303 publications

(137 citation statements)

References 37 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…tuberculosis contains many loci encoding homologues of esat-6 and cfp-10 as well as some of the surrounding genes in the ESX-1 region (8,23). It is certainly possible that EspA is required for the secretion of other ESAT-6-and CFP-10-like proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Of these, 53 were present in at least two of three samples. Seventy-five percent of the reproducibly identified proteins have predicted signal sequences, are ESX proteins (8), or have been shown to be secreted in a secA2-dependent fashion (21), indicating that our sampling enriched for secreted proteins. More proteins were identified in the H37Rv⌬RD1 culture filtrates (178 proteins were identified in three independently obtained samples).…”

Section: Lcq-ms͞ms Screen Identifies Esx-1 Secreted Proteinsmentioning

confidence: 99%

“…The BCG deletion, known as RD1, includes two genes that encode the abundantly secreted proteins, ESAT-6 and CFP-10. The RD1 deletion encompasses most but not all of a larger, 15-gene region known as ESX-1 (7), which is hypothesized to encode an alternative secretory system (8,9).…”

Section: Esat-6 Protein ͉ Mycobacterium Tuberculosis ͉ Virulence Factormentioning

confidence: 99%

See 2 more Smart Citations

Mutually dependent secretion of proteins required for mycobacterial virulence

Fortune

Jaeger²,

Sarracino³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

359

410

View full text Add to dashboard Cite

The ESX-1 locus is a region critical for full virulence in Mycobacterium tuberculosis, which encodes two secreted proteins as well as other genes involved in their secretion. The mechanism of secretion of the two proteins, ESAT-6 and CFP-10, and their function remain unknown. Using proteomic methods to search for additional proteins secreted by the ESX-1 locus, we discovered that a protein encoded by a chromosomally unlinked gene, espA, is also secreted by strains that contain the ESX-1 locus but not by strains with ESX-1 deletions. Mutations in individual ESX-1 genes, including those that encode ESAT-6 and CFP-10, were found to block EspA secretion. Surprisingly, mutants that lack espA reciprocally failed to secrete ESAT-6 and CFP-10 and were as attenuated as ESX-1 mutants in virulence assays. The results indicate that secretion of these proteins, which are each critical for virulence of pathogenic mycobacteria, is mutually dependent. The results further suggest that discerning the nature of the interaction and the structure of macromolecular complexes will provide insights into both an alternative mechanism of protein secretion and mycobacterial virulence.ESAT-6 protein ͉ Mycobacterium tuberculosis ͉ virulence factor I nteractions between bacterial pathogens and their hosts occur at the surface of cells. Many pathogenic bacteria secrete proteins involved in virulence (1). These proteins often interfere with normal host defenses and allow bacteria to survive and multiply. Strikingly, many of these virulence factors are secreted by nonclassical secretory systems that, in some cases, facilitate translocation of proteins across host cell membranes (2, 3).During the evolution of Mycobacterium bovis Bacille Calmette-Guérin (BCG), the attenuated bacillus widely used as vaccine against tuberculosis, a major deletion removed a set of nine ORFs (4). Similar deletions are found in Mycobacterium microti (5) and the Dassie bacillus (6), other relatively avirulent mycobacteria. The BCG deletion, known as RD1, includes two genes that encode the abundantly secreted proteins, ESAT-6 and CFP-10. The RD1 deletion encompasses most but not all of a larger, 15-gene region known as ESX-1 (7), which is hypothesized to encode an alternative secretory system (8, 9).The proteins encoded by the ESX-1 locus clearly play an important role in virulence. The secreted proteins encoded within the locus are potent T cell antigens (7, 10, 11). More significantly, Mycobacterium tuberculosis strains with RD1 deletions are far less virulent in mice than strains that are otherwise isogenic (12-14). They replicate poorly and cause less pathology in both immunocompetent and immunocompromised mice, although the latter ultimately succumb to infection. RD1-deleted strains of Mycobacterium marinum elicit only very modest macrophage aggregation and granuloma formation in zebrafish (15). Additional work suggests the RD1-encoded proteins may disrupt host cell membranes. In M. tuberculosis, these proteins may be required for lysis of infected cells (13) and c...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Lcq-ms͞ms Screen Identifies Esx-1 Secreted Proteinsmentioning

confidence: 99%

See 1 more Smart Citation

Mutually dependent secretion of proteins required for mycobacterial virulence

Fortune

Jaeger²,

Sarracino³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

359

410

View full text Add to dashboard Cite

show abstract

“…A survey of M. tuberculosis H37Rv genome sequence revealed at least 23 ESAT-6 homologues (9), 10 of which are encoded within five gene clusters that specify large soluble and membrane-bound ATPases with two or more FtsK͞SpoIIIE-like domains (FSDs) (16,17). Pallen (17) discovered ESAT-6 homologues in the sequenced genomes of other Gram-positive bacteria including B. subtilis, Bacillus anthracis, Clostridium acetobutylicum, Listeria monocytogenes, and S. aureus.…”

mentioning

confidence: 99%

EsxA and EsxB are secreted by an ESAT-6-like system that is required for the pathogenesis ofStaphylococcus aureusinfections

Burts

Williams

DeBord

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

304

439

View full text Add to dashboard Cite

Mycobacterium tuberculosis secretes ESAT-6, a virulence factor that triggers cell-mediated immune responses and IFN-␥ production during tuberculosis. ESAT-6 is transported across the bacterial envelope by a specialized secretion system with a FSD (FtsK-SpoIIIE domain) membrane protein. Although the presence of ESAT-6-like genes has been identified in the genomes of other microbes, the possibility that they may encode general virulence functions has hitherto not been addressed. Herein we show that the human pathogen Staphylococcus aureus secretes EsxA and EsxB, ESAT-6-like proteins, across the bacterial envelope. Staphylococcal esxA and esxB are clustered with six other genes and some of these are required for synthesis or secretion of EsxA and EsxB. Mutants that failed to secrete EsxA and EsxB displayed defects in the pathogenesis of S. aureus murine abscesses, suggesting that this specialized secretion system may be a general strategy of human bacterial pathogenesis.specialized secretion ͉ Gram-positive ͉ exoprotein ͉ ess

show abstract

“…3,4 The locus is essential for the growth of M. tuberculosis and the attenuated M. bovis strain used in BCG. 5 The team found that unlike M. tuberculosis and BCG, the more distant relative M. smegmatis could grow normally when esx-3 was deleted, and thus they selected the strain to study the locus' role.…”

mentioning

confidence: 99%

Smegmatis meets tuberculosis

Lou¹

2011

Science-Business eXchange

View full text Add to dashboard Cite

have created an attenuated strain of Mycobacterium smegmatis containing M. tuberculosis genes. The vector conferred better protection against tuberculosis than the standard bacillus Calmette-Guérin (BCG) vaccine in mice. 1 The not-for-profit Aeras has licensed the technology and is now working with the researchers to determine an optimal combination of genes to use in M. smegmatis.The only prophylactic for TB is the BCG vaccine, which is prepared from a live, attenuated bacterial strain closely related to M. tuberculosis called M. bovis. In BCG, deletion of the region of difference 1 locus is responsible for its attenuation and loss of virulence. 2 Although the vaccine protects infants from pulmonary TB, it is not effective at protecting adults, nor can it prevent transmission or clear latent infections.Albert Einstein College of Medicine's new vaccine originated from research on Mycobacterium secretion systems and their role in helping the bacteria evade the host immune system.M. tuberculosis employs multiple strategies to do this, including a specialized secretion system encoded by genes in the bacterium's esx-1 locus. The M. tuberculosis genome contains four additional esx loci-esx-2 through esx-5-that may encode secretion systems, but their functions are poorly understood.The researchers were exploring the role of the esx-3 locus in immune evasion because it is the only esx locus conserved across all strains of Mycobacterium. 3,4 The locus is essential for the growth of M. tuberculosis and the attenuated M. bovis strain used in BCG. 5 The team found that unlike M. tuberculosis and BCG, the more distant relative M. smegmatis could grow normally when esx-3 was deleted, and thus they selected the strain to study the locus' role.In mouse models of M. smegmatis infection, an esx-3-deleted strain was unable to evade the host innate immune system, whereas wildtype and esx-1-deleted strains did not elicit a strong innate immune response. Moreover, the esx-3-deleted strain had attenuated virulence.Next, the researchers inserted a set of 26 M. tuberculosis genes including all 11 esx-3 genes into the attenuated M. smegmatis strain. Despite the addition of esx-3 genes, the strain still was not virulent and could not evade the immune system.At this point, the researchers began to think they had the makings of a vaccine vector in hand.In proof-of-concept studies in mouse models of lethal M. tuberculosis infection, i.v. or subcutaneous immunization with the recombinant attenuated M. smegmatis strain increased survival and resulted in greater decreases in tissue bacterial load compared with immunization using the BCG vaccine. Several of the mice receiving the recombinant M. smegmatis vaccine had tissue bacterial load reductions that were over 1,000-fold greater than those for mice given BCG.Results were published in Nature Medicine. "This is the first time we have seen a vaccine that can produce over three-log reductions in tissue bacterial burdens over BCG and a bactericidal immune response that causes a sustained decline...

show abstract

The ESAT-6 gene cluster of Mycobacterium tuberculosis and other high G+C Gram-positive bacteria

Cited by 303 publications

References 37 publications

Mutually dependent secretion of proteins required for mycobacterial virulence

Mutually dependent secretion of proteins required for mycobacterial virulence

EsxA and EsxB are secreted by an ESAT-6-like system that is required for the pathogenesis ofStaphylococcus aureusinfections

Smegmatis meets tuberculosis

Contact Info

Product

Resources

About