Expression of adipose differentiation-related protein (ADRP) and perilipin in macrophages infected with<i>Mycobacterium leprae</i>

Tanigawa, Kazunari; Suzuki, Koichi; Nakamura, Kazuaki; Akama, Takeshi; Kawashima, Akira; Wu, Huhehasi; Hayashi, Masanori; Takahashi, Shin‐Ichiro; Ikuyama, Shoichiro; Ito, Tetsuhide; Ishii, Norihisa

doi:10.1111/j.1574-6968.2008.01369.x

Cited by 59 publications

(78 citation statements)

References 36 publications

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“…A similar situation can be found in the regulation of adipophilin/adipose differentiation-related protein (ADRP) expression in M. leprae-infected macrophages [24]. Although PGN suppresses ADRP expression, infection by M. leprae inhibits the suppression.…”

Section: Discussionmentioning

confidence: 53%

“…Although PGN suppresses ADRP expression, infection by M. leprae inhibits the suppression. Therefore, it was speculated that live M. leprae actively induces and supports ADRP expression to facilitate the accumulation of lipids within the phagosome and to maintain a suitable environment for intracellular survival within macrophages [24]. Unlike other mycobacteria, M. leprae is not capable of activating dendritic cell-mediated T cell responses [25,26].…”

Section: Discussionmentioning

confidence: 99%

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Tryptophan aspartate-containing coat protein (CORO1A) suppresses Toll-like receptor signalling in Mycobacterium leprae infection

Tanigawa

Suzuki

Kimura³

et al. 2009

Clinical and Experimental Immunology

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SummaryMycobacterium leprae is an intracellular pathogen that survives within the phagosome of host macrophages. Several host factors are involved in producing tolerance, while others are responsible for killing the mycobacterium. Tryptophan aspartate-containing coat protein (TACO; also known as CORO1A or coronin-1) inhibits the phagosome maturation that allows intracellular parasitization. In addition, the Toll-like receptor (TLR) activates the innate immune response. Both CORO1A and TLR-2 co-localize on the phagosomal membrane in the dermal lesions of patients with lepromatous leprosy. Therefore, we hypothesized that CORO1A and TLR-2 might interact functionally. This hypothesis was tested by investigating the effect of CORO1A in TLR-2-mediated signalling and, inversely, the effect of TLR-2-mediated signalling on CORO1A expression. We found that CORO1A suppresses TLR-mediated signal activation in human macrophages, and that TLR2-mediated activation of the innate immune response resulted in suppression of CORO1A expression. However, M. leprae infection inhibited the TLR-2-mediated CORO1A suppression and nuclear factor-kB activation. These results suggest that the balance between TLR-2-mediated signalling and CORO1A expression will be key in determining the fate of M. leprae following infection.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Tryptophan aspartate-containing coat protein (CORO1A) suppresses Toll-like receptor signalling in Mycobacterium leprae infection

Tanigawa

Suzuki

Kimura³

et al. 2009

Clinical and Experimental Immunology

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“…If some pseudogenes function to regulate gene expression, it may explain why M. leprae is able to survive with only a limited number of protein-coding genes. Comprehensive analysis of small RNA revealed that small interfering RNAs are expressed from pseudogenes and regulate gene expression (37). In this study, we found that pseudogenes in the functional categories of "degradation" and "energy metabolism" in the "small-molecule metabolism" class were strongly transcribed on a frequent basis.…”

Section: Discussionmentioning

confidence: 68%

Whole-Genome Tiling Array Analysis of Mycobacterium leprae RNA Reveals High Expression of Pseudogenes and Noncoding Regions

et al. 2009

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Whole-genome sequence analysis of Mycobacterium leprae has revealed a limited number of protein-coding genes, with half of the genome composed of pseudogenes and noncoding regions. We previously showed that some M. leprae pseudogenes are transcribed at high levels and that their expression levels change following infection. In order to clarify the RNA expression profile of the M. leprae genome, a tiling array in which overlapping 60-mer probes cover the entire 3.3-Mbp genome was designed. The array was hybridized with M. leprae RNA from the SHR/NCrj-rnu nude rat, and the results were compared to results from an open reading frame array and confirmed by reverse transcription-PCR. RNA expression was detected from genes, pseudogenes, and noncoding regions. The signal intensities obtained from noncoding regions were higher than those from pseudogenes. Expressed noncoding regions include the M. leprae unique repetitive sequence RLEP and other sequences without any homology to known functional noncoding RNAs. Although the biological functions of RNA transcribed from M. leprae pseudogenes and noncoding regions are not known, RNA expression analysis will provide insights into the bacteriological significance of the species. In addition, our study suggests that M. leprae will be a useful model organism for the study of the molecular mechanism underlying the creation of pseudogenes and the role of microRNAs derived from noncoding regions.Mycobacterium leprae, the causative agent of leprosy, cannot be cultivated in vitro. Therefore, bacteriological and pathological information, such as the mechanisms of infection, parasitization, and replication, are still largely unknown. However, whole-genome sequencing has provided insight into many biological characteristics of M. leprae (5). The M. leprae genome consists of 3.3 Mbp, which is much smaller than the 4.4 Mbp of the Mycobacterium tuberculosis genome. M. leprae has 1,605 genes and 1,115 pseudogenes, while M. tuberculosis has 3,959 genes and only 6 pseudogenes. The number and ratio of pseudogenes in M. leprae are exceptionally large by comparison with the pseudogene numbers and ratios for other pathogenic and nonpathogenic bacteria and archaea (21). A feature of M. leprae pseudogenes is the massive fragmentation caused by many insertions of stop codons (26). The functional roles, if any, of these unique pseudogenes and noncoding regions are unknown. However, we have shown that some M. leprae pseudogenes are highly expressed as RNA and that their expression levels change following macrophage infection (36). In that study, a membrane-based DNA array was created utilizing a cosmid DNA library that covered Ͼ98% of the M. leprae genome. mRNAs purified from M. leprae-infected macrophages and control bacilli were enriched by cDNA subtraction and hybridized to these arrays. Southern blot analysis of the positive cosmid clones identified 12 genes that might be important for the survival and infection of M. leprae.

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“…We showed recently that M. leprae induces LD biogenesis and accumulation in bacterial-containing phagosomes in SCs and is responsible, at least in part, for originating foamy degeneration of M. lepraeinfected SCs in LL nerves (22). Accordingly, as was proposed for macrophages in the context of dermal lesions (9,23), it is reasonable to speculate that the lipid-storage phenomenon observed in M. leprae-infected SCs is an important contributor to the immunoinflammatory function of these cells in LL nerve lesions. In the current study, we investigated the involvement of TLRs in the induction of LDs by M. leprae in SCs.…”

mentioning

confidence: 99%

TLR6-Driven Lipid Droplets in Mycobacterium leprae-Infected Schwann Cells: Immunoinflammatory Platforms Associated with Bacterial Persistence

Mattos

Oliveira

D’Avila

et al. 2011

The Journal of Immunology

123

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The mechanisms responsible for nerve injury in leprosy need further elucidation. We recently demonstrated that the foamy phenotype of Mycobacterium leprae-infected Schwann cells (SCs) observed in nerves of multibacillary patients results from the capacity of M. leprae to induce and recruit lipid droplets (LDs; also known as lipid bodies) to bacterial-containing phagosomes. In this study, we analyzed the parameters that govern LD biogenesis by M. leprae in SCs and how this contributes to the innate immune response elicited by M. leprae. Our observations indicated that LD formation requires the uptake of live bacteria and depends on host cell cytoskeleton rearrangement and vesicular trafficking. TLR6 deletion, but not TLR2, completely abolished the induction of LDs by M. leprae, as well as inhibited the bacterial uptake in SCs. M. leprae-induced LD biogenesis correlated with increased PGE2 and IL-10 secretion, as well as reduced IL-12 and NO production in M. leprae-infected SCs. Analysis of nerves from lepromatous leprosy patients showed colocalization of M. leprae, LDs, and cyclooxygenase-2 in SCs, indicating that LDs are sites for PGE2 synthesis in vivo. LD biogenesis Inhibition by the fatty acid synthase inhibitor C-75 abolished the effect of M. leprae on SC production of immunoinflammatory mediators and enhanced the mycobacterial-killing ability of SCs. Altogether, our data indicated a critical role for TLR6-dependent signaling in M. leprae–SC interactions, favoring phagocytosis and subsequent signaling for induction of LD biogenesis in infected cells. Moreover, our observations reinforced the role of LDs favoring mycobacterial survival and persistence in the nerve. These findings give further support to a critical role for LDs in M. leprae pathogenesis in the nerve.

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Expression of adipose differentiation-related protein (ADRP) and perilipin in macrophages infected withMycobacterium leprae

Cited by 59 publications

References 36 publications

Tryptophan aspartate-containing coat protein (CORO1A) suppresses Toll-like receptor signalling in Mycobacterium leprae infection

Tryptophan aspartate-containing coat protein (CORO1A) suppresses Toll-like receptor signalling in Mycobacterium leprae infection

Whole-Genome Tiling Array Analysis of Mycobacterium leprae RNA Reveals High Expression of Pseudogenes and Noncoding Regions

TLR6-Driven Lipid Droplets in Mycobacterium leprae-Infected Schwann Cells: Immunoinflammatory Platforms Associated with Bacterial Persistence

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