Attenuation of<i>Mycobacterium tuberculosis</i>Functionally Disrupted in a Fatty Acyl–Coenzyme A Synthetase Gene<i>fadD5</i>

Dunphy, Kathleen Y.; Senaratne, Ryan H.; Masuzawa, Mamiko; Kendall, Lon V.; Riley, Lee W.

doi:10.1086/651452

Cited by 59 publications

(76 citation statements)

References 31 publications

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“…On the other hand, disruption of the other operons attenuates the mutants (Senaratne et al, 2008;Marjanovic et al, 2010). More recently, the mce1 operon was shown to be involved in fatty acid or mycolic acid importation (Dunphy et al, 2010), while mce4 was suggested to encode a cholesterol import system (Pandey and Sassetti, 2008). These observations support the idea that these operons are involved in bacterial and host lipid processing during infection.…”

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confidence: 64%

Sulfolipid accumulation in Mycobacterium tuberculosis disrupted in the mce2 operon

2011

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Mycobacterium tuberculosis, the causative agent of tuberculosis, has a lipid-rich cell wall that serves as an effective barrier against drugs and toxic host cell products, which may contribute to the organism's persistence in a host. M. tuberculosis contains four homologous operons called nice (mce1-4) that encode putative ABC transporters involved in lipid importation across the cell wall. Here, we analyzed the lipid composition of M. tuberculosis disrupted in the mce2 operon. High resolution mass spectrometric and thin layer chromatographic analyses of the mutant's cell wall lipid extracts showed accumulation of SL-1 and SL(1278) molecules. Radiographic quantitative analysis and densitometry revealed 2.9, 3.9 and 9.8-fold greater amount of [(35)S] SL-1 in the mce2 operon mutant compared to the wild type M. tuberculosis during the early/mid logarithmic, late logarithmic and stationary phase of growth in liquid broth, respectively. The amount of [(35)S] SL(1278) in the mutant also increased progressively over the same growth phases. The expression of the mce2 operon genes in the wild type strain progressively increased from the logarithmic to the stationary phase of bacterial growth in vitro, which inversely correlated with the proportion of radiolabel incorporation into SL-1 and SL(1278) at these phases. Since the mce2 operon is regulated in wild type M. tuberculosis, its cell wall may undergo changes in SL-1 and SL(1278) contents during a natural course of infection and this may serve as an important adaptive strategy for M. tuberculosis to maintain persistence in a host.

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confidence: 64%

Sulfolipid accumulation in Mycobacterium tuberculosis disrupted in the mce2 operon

2011

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“…During this nutrient-limited state, M. tuberculosis may down-regulate the propionyl-CoA/ methylmalonyl-CoA pathway involved in the synthesis of SL-1, DAT, and PAT, while increasing the synthesis of MA, which has even lower pro-infl ammatory activity 8,30 . Dunphy et al 93 proposed that the mce1 operon is involved in MA import. A prolonged starvation of the cells with thickened cell wall may serve as a signal to de-repress the mce1 operon to allow the importation of FM, a carbon source.…”

Section: Lipid Synthesis Control and A Bacterial Immunostatmentioning

confidence: 99%

Bacterial immunostat: Mycobacterium tuberculosis lipids and their role in the host immune response

Queiroz

Riley

2017

Rev. Soc. Bras. Med. Trop.

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The lipid-rich cell wall of Mycobacterium tuberculosis is a dynamic structure that is involved in the regulation of the transport of nutrients, toxic host-cell effector molecules, and anti-tuberculosis drugs. It is therefore postulated to contribute to the longterm bacterial survival in an infected human host. Accumulating evidence suggests that M. tuberculosis remodels the lipid composition of the cell wall as an adaptive mechanism against host-imposed stress. Some of these lipid species (trehalose dimycolate, diacylated sulphoglycolipid, and mannan-based lipoglycans) trigger an immunopathologic response, whereas others (phthiocerol dimycocerosate, mycolic acids, sulpholipid-1, and di-and polyacyltrehalose) appear to dampen the immune responses. These lipids appear to be coordinately expressed in the cell wall of M. tuberculosis during different phases of infection, ultimately determining the clinical fate of the infection. This review summarizes the current state of knowledge on the metabolism, transport, and homeostatic or immunostatic regulation of the cell wall lipids, and their orchestrated interaction with host immune responses that results in bacterial clearance, persistence, or tuberculosis.

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“…Originally thought to be simply involved in gaining entry to host cells, 3 more recent work 9 suggests that the Mce1 protein complex is also involved in the recycling of extracellular mycolic acids for use as a carbon source. Of particular interest, we show that the genes that were significantly upregulated by the macrophages in the period immediately after infection by M. tuberculosis H37Rv, but not D-mce1 H37Rv, were primarily involved in substrate trafficking.…”

Section: Discussionmentioning

confidence: 99%

“…6 However, more recent studies show that the mce operons encode for lipid uptake transporters 8 and that the mce1 operon is involved in fatty acid transport/metabolism; and more specifically, mycolic acid recycling. 9 In a previous study, we showed that a macrophage infection by a wild-type M. tuberculosis H37Rv strain resulted in the differential transcription of a large number of genes, by the macrophage, as early as 15 min post-infection, whereas the deletion of the Mce1 protein complex from the M. tuberculosis H37Rv strain, (M. tuberculosis D-mce1 H37Rv) delayed the uptake of the bacteria into the host macrophage, in addition to inducing an antiinflammatory response by 4 h post-infection. 10 For the current manuscript, the focus was shifted to genes showing sustained effects.…”

Section: Introductionmentioning

confidence: 99%

Mycobacterium tuberculosis Mce1 protein complex initiates rapid induction of transcription of genes involved in substrate trafficking

et al. 2012

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The mammalian cell entry (Mce)1 protein complex has an important role during the initial phase of a Mycobacterium tuberculosis (M. tuberculosis) infection. Murine macrophages were infected with M. tuberculosis H37Rv or D-mce1 H37Rv, and total RNA was isolated from the host cells at 15, 30 and 60 min, and 4 and 10 h post-infection. With the aim of studying the role for the Mce1 protein complex on host gene expression, the RNA was hybridized onto 44 K whole-genome microarrays. Selected genes were verified by reverse-transcriptase quantitative PCR (RT-QPCR). 'Transport' was the most overrepresented biological process during the first hour post H37Rv infection. Five genes (Abca1 (21.0-fold), Slc16a10 (3.1-fold), Slc6a12 (17.9-fold), Slc6a8 (2.3-fold) and Nr1h3, (5.5-fold)) involved in substrate trafficking were verified by RT-QPCR to be upregulated by 42-fold 1 h post H37Rv infection. By 1 h post D-mce1 H37Rv infection, only Abca1 and Slc6a12 were upregulated by 42-fold. A number of other genes, which may be directly involved in substrate trafficking or share the same transcription, were found to have expression profiles similar to the genes involved in substrate trafficking. The Mce1 protein complex has a significant role in the transcriptional activation of genes involved in substrate trafficking during the initial phase of an M. tuberculosis infection.

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Attenuation ofMycobacterium tuberculosisFunctionally Disrupted in a Fatty Acyl–Coenzyme A Synthetase GenefadD5

Cited by 59 publications

References 31 publications

Sulfolipid accumulation in Mycobacterium tuberculosis disrupted in the mce2 operon

Sulfolipid accumulation in Mycobacterium tuberculosis disrupted in the mce2 operon

Bacterial immunostat: Mycobacterium tuberculosis lipids and their role in the host immune response

Mycobacterium tuberculosis Mce1 protein complex initiates rapid induction of transcription of genes involved in substrate trafficking

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