Mce2 operon mutant strain of Mycobacterium tuberculosis is attenuated in C57BL/6 mice

Marjanovic, Olivera; Miyata, Takeo; Goodridge, Amador; Kendall, Lon V.; Riley, Lee W.

doi:10.1016/j.tube.2009.10.004

Cited by 45 publications

(50 citation statements)

References 18 publications

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“…The mce4 operon in M. tuberculosis has been identified as a cholesterol import system (46), while the functions of the other three mce operons are still unclear. However, several studies have shown that M. tuberculosis isolates deleted for mce2 are attenuated in mice (1,28,37). It remains to be seen if strains of the M. bovis Af2 clonal complex, with a naturally deleted mce2 operon, would also be attenuated in mice.…”

Section: Discussionmentioning

confidence: 99%

African 2, a Clonal Complex of Mycobacterium bovis Epidemiologically Important in East Africa

et al. 2011

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We have identified a clonal complex of Mycobacterium bovis isolated at high frequency from cattle in Uganda, Burundi, Tanzania, and Ethiopia. We have named this related group of M. bovis strains the African 2 (Af2) clonal complex of M. bovis. Af2 strains are defined by a specific chromosomal deletion (RDAf2) and can be identified by the absence of spacers 3 to 7 in their spoligotype patterns. Deletion analysis of M. bovis isolates from Algeria, Mali, Chad, Nigeria, Cameroon, South Africa, and Mozambique did not identify any strains of the Af2 clonal complex, suggesting that this clonal complex of M. bovis is localized in East Africa. The specific spoligotype pattern of the Af2 clonal complex was rarely identified among isolates from outside Africa, and the few isolates that were found and tested were intact at the RDAf2 locus. We conclude that the Af2 clonal complex is localized to cattle in East Africa. We found that strains of the Af2 clonal complex of M. bovis have, in general, four or more copies of the insertion sequence IS6110, in contrast to the majority of M. bovis strains isolated from cattle, which are thought to carry only one or a few copies.

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Section: Discussionmentioning

confidence: 99%

African 2, a Clonal Complex of Mycobacterium bovis Epidemiologically Important in East Africa

et al. 2011

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“…1B). It could be predicted that GltM protein directly acted on HBMEC as an invasion factor, like mycobacterial Mce proteins (8,24), if GltM was localized on the meningococcal surface. To examine the location of meningococcal GltM protein in N. meningitidis, the cellular proteins were fractionated and analyzed by Western blotting with an antiGltM rabbit antiserum (see Fig.…”

Section: Isolation Of Transposon Mutants Primarily Defective In Hbmecmentioning

confidence: 99%

“…MCE proteins have been characterized as mycobacterial invasion factors (8,24,38), and in this study three independent gltT and gltM mutants were isolated as invasiondefective mutants. Furthermore, it was identified in this study that the GltM protein was exposed to the meningococcal surface and that its level was reduced in gltT mutants.…”

Section: Vol 79 2011 L-glutamate Influx Enhances the Meningococcal mentioning

confidence: 99%

“…Among them, the deduced amino acid sequences with some similarity to mycobacterial mammalian cell entry (MCE) proteins are defined as belonging to the "MCE-related" or "MCE family" domain, which is widely found in bacterial genomes (EMBL-EBI database [http://ebi.ac.uk]). MCE proteins in Mycobacterium tuberculosis (the etiologic agent of tuberculosis) are identified as invasion factors while the biological functions of the MCE-related proteins remain unclear (24,35,38).…”

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confidence: 99%

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Meningococcal Internalization into Human Endothelial and Epithelial Cells Is Triggered by the Influx of Extracellular l -Glutamate via GltT l -Glutamate ABC Transporter in Neisseria meningitidis

2011

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Meningococcal internalization into human cells is likely to be a consequence of meningococcal adhesion to human epithelial and endothelial cells. Here, we identified three transposon mutants of Neisseria meningitidis that were primarily defective in the internalization of human brain microvascular endothelial cells (HBMEC), with insertions occurring in the gltT (a sodium-independent L-glutamate transporter) gene or its neighboring gene, NMB1964 (unknown function). NMB1964 was tentatively named gltM in this study because of the presence of a mammalian cell entry (MCE)-related domain in the deduced amino acid sequences. The null ⌬gltT-⌬gltM N. meningitidis mutant was also defective in the internalization into human umbilical vein endothelial cells and the human lung carcinoma epithelial cell line A549, and the defect was suppressed by transcomplementation of the mutants with gltT ؉ -gltM ؉ genes. The intracellular survival of the ⌬gltT-⌬gltM mutant in HBMEC was not largely different from that of the wild-type strain under our experimental conditions. Introduction of a1-bp deletion and amber or ochre mutations in gltT-gltM genes resulted in the loss of efficient internalization into HBMEC. The defect in meningococcal internalization into HBMEC and L-glutamate uptake in the ⌬gltT-⌬gltM mutant were suppressed only in strains expressing both GltT and GltM proteins. The efficiency of meningococcal invasion to HBMEC decreased under L-glutamate-depleted conditions. Furthermore, ezrin, a key membrane-cytoskeleton linker, accumulated beneath colonies of the gltT ؉ -gltM ؉ N. meningitidis strain but not of the ⌬gltT-⌬gltM mutant. These findings suggest that L-glutamate influx via the GltT-GltM L-glutamate ABC transporter serves as a cue for N. meningitidis internalization into host cells.

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“…At 4 h (day 0) andTraSH analysis of M. tuberculosis (40). Furthermore, an mce2 mutant of H37Rv was recently reported to grow normally in the RAW cell line, although the mutant was attenuated in mice (31).…”

Section: Resultsmentioning

confidence: 99%

Genome-Wide Identification of Mycobacterium tuberculosis Exported Proteins with Roles in Intracellular Growth

et al. 2011

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The exported proteins of Mycobacterium tuberculosis that are localized at the bacterial cell surface or secreted into the environment are ideally situated to interact with host factors and to function in virulence. In this study, we constructed a novel ␤-lactamase reporter transposon and used it directly in M. tuberculosis for genome-wide identification of exported proteins. From 177 ␤-lactam-resistant transposon mutants, we identified 111 different exported proteins. The majority of these proteins have no known function, and for nearly half of the proteins, our demonstration that they are exported when fused to a ␤-lactamase reporter is the first experimental proof of their extracytoplasmic localization. The transposon mutants in our banked library were of further value as a collection of mutants lacking individual exported proteins. By individually testing each of 111 mutants for growth in macrophages, six attenuated mutants with insertions in mce1A, mce1B, mce2F, rv0199, ctaC, and lppX were identified. Given that much of the M. tuberculosis genome encodes proteins of unknown function, our library of mapped transposon mutants is a valuable resource for efforts in functional genomics. This work also demonstrates the power of a ␤-lactamase reporter transposon that could be applied similarly to other bacterial pathogens.

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Mce2 operon mutant strain of Mycobacterium tuberculosis is attenuated in C57BL/6 mice

Cited by 45 publications

References 18 publications

African 2, a Clonal Complex of Mycobacterium bovis Epidemiologically Important in East Africa

African 2, a Clonal Complex of Mycobacterium bovis Epidemiologically Important in East Africa

Meningococcal Internalization into Human Endothelial and Epithelial Cells Is Triggered by the Influx of Extracellular l -Glutamate via GltT l -Glutamate ABC Transporter in Neisseria meningitidis

Genome-Wide Identification of Mycobacterium tuberculosis Exported Proteins with Roles in Intracellular Growth

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