Role of trehalose in resistance to macrophage killing: study with a tps1/tps1 trehalose-deficient mutant of Candida albicans

Martínez‐Esparza, María; Aguinaga, Ana; Gónzalez-Párraga, Pilar; García‐Peñarrubia, Pilar; Jouault, Thierry; Argüelles, Juan-Carlos

doi:10.1111/j.1469-0691.2007.01663.x

Cited by 47 publications

(32 citation statements)

References 38 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5). Recently it has been shown that mutants with a deletion of TPS1, encoding the first enzyme of the trehalose biosynthesis pathway, are more easily killed by macrophages than wild-type control cells (23).…”

Section: Vol 76 2008 Combined Inactivation Of C Albicans Gpr1 and mentioning

confidence: 99%

Combined Inactivation of the Candida albicans GPR1 and TPS2 Genes Results in Avirulence in a Mouse Model for Systemic Infection

et al. 2008

View full text Add to dashboard Cite

Inhibition of the biosynthesis of trehalose, a well-known stress protectant in pathogens, is an interesting approach for antifungal or antibacterial therapy. Deletion of TPS2, encoding trehalose-6-phosphate (T6P) phosphatase, results in strongly reduced virulence of Candida albicans due to accumulation of T6P instead of trehalose in response to stress. To further aggravate the deregulation in the pathogen, we have additionally deleted the GPR1 gene, encoding the nutrient receptor that activates the cyclic AMP-protein kinase A signaling pathway, which negatively regulates trehalose accumulation in yeasts. A gpr1 mutant is strongly affected in morphogenesis on solid media as well as in vivo in a mouse model but has only a slightly decreased virulence. The gpr1 tps2 double mutant, on the other hand, is completely avirulent in a mouse model for systemic infection. This strain accumulates very high T6P levels under stress conditions and has a growth defect at higher temperatures. We also show that a tps2 mutant is more sensitive to being killed by macrophages than the wild type or the gpr1 mutant. A double mutant has susceptibility similar to that of the single tps2 mutant. For morphogenesis on solid media, on the other hand, the gpr1 tps2 mutant shows a phenotype similar to that of the single gpr1 mutant. Taken together these results show that there is synergism between Gpr1 and Tps2 and that their combined inactivation results in complete avirulence. Combination therapy targeting both proteins may prove highly effective against pathogenic fungi with increased resistance to the currently used antifungal drugs.Trehalose is known as a stress-protective sugar synthesized under unfavorable growth conditions in a variety of microorganisms (4). It can be synthesized by several pathways (1), but in yeasts it is made only in a two-step process carried out by trehalose-6-phosphate (T6P) synthase (Tps1) and T6P phosphatase (Tps2). Tps1 catalyzes the conversion of UDP-glucose and glucose-6-phosphate into T6P. The second enzyme, Tps2, dephosphorylates T6P to produce trehalose. In Saccharomyces cerevisiae, these enzymes have been studied extensively (4). Apart from a catalytic function in the biosynthesis of trehalose, the ScTps1 enzyme also plays a crucial role in controlling the influx of glucose into glycolysis (5). As a consequence, a yeast tps1⌬ mutant is not able to grow on glucose because of a very fast deregulation of metabolism due to strong accumulation of sugar phosphates in the first part of glycolysis (31). Deletion of the yeast TPS2 gene results in a thermosensitivity phenotype, which is also caused by deregulation of trehalose metabolism. At higher temperatures (or under any other stress condition), the Sctps2⌬ mutant accumulates a high level of T6P, resulting in rapid deprivation of free phosphate (9, 28). Because the enzymes of trehalose metabolism are not present in humans and because trehalose is an important stress-protecting molecule in many fungi, these enzymes have been investigated as potential targets fo...

show abstract

Section: Vol 76 2008 Combined Inactivation Of C Albicans Gpr1 and mentioning

confidence: 99%

Combined Inactivation of the Candida albicans GPR1 and TPS2 Genes Results in Avirulence in a Mouse Model for Systemic Infection

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Little is known about the mechanisms by which A. fumigatus survives under these conditions. One possible mechanism by which A. fumigatus adapts to environmental stress is via the biosynthesis of the carbohydrate trehalose, which is involved in mediating the stress response and virulence of other pathogenic fungi such as Candida albicans and Cryptococcus neoformans (1,22,30,48). The trehalose content of these fungal cells may increase up to 50-fold in response to oxidative stress, osmotic stress, and heat shock (27).…”

mentioning

confidence: 99%

“…In the pathogenic yeasts C. albicans and C. neoformans, the single-copy trehalose-6-phosphate synthase Tps1 is required for normal oxidative stress response and hyphal development and has a role in mediating virulence (1,22,30,48). In Aspergillus nidulans, the trehalose-6-phosphate synthase TpsA is necessary for normal fungal development, thermosensitive growth and response to sublethal exposure to oxidative stress (16).…”

mentioning

confidence: 99%

Role of Trehalose Biosynthesis in Aspergillus fumigatus Development, Stress Response, and Virulence

et al. 2010

View full text Add to dashboard Cite

Aspergillus fumigatus is a pathogenic mold which causes invasive, often fatal, pulmonary disease in immunocompromised individuals. Recently, proteins involved in the biosynthesis of trehalose have been linked with virulence in other pathogenic fungi. We found that the trehalose content increased during the developmental life cycle of A. fumigatus, throughout which putative trehalose synthase genes tpsA and tpsB were significantly expressed. The trehalose content of A. fumigatus hyphae also increased after heat shock but not in response to other stressors. This increase in trehalose directly correlated with an increase in expression of tpsB but not tpsA. However, deletion of both tpsA and tpsB was required to block trehalose accumulation during development and heat shock. The ⌬tpsAB double mutant had delayed germination at 37°C, suggesting a developmental defect. At 50°C, the majority of ⌬tpsAB spores were found to be nonviable, and those that were viable had severely delayed germination, growth, and subsequent sporulation. ⌬tpsAB spores were also susceptible to oxidative stress. Surprisingly, the ⌬tpsAB double mutant was hypervirulent in a murine model of invasive aspergillosis, and this increased virulence was associated with alterations in the cell wall and resistance to macrophage phagocytosis. Thus, while trehalose biosynthesis is required for a number of biological processes that both promote and inhibit virulence, in A. fumigatus the predominant effect is a reduction in pathogenicity. This finding contrasts sharply with those for other fungi, in which trehalose biosynthesis acts to enhance virulence.

show abstract

“…Biosynthesis of trehalose also provides protection against oxidant stress (4,27,41). Of the mitogen-activated protein kinase (MAPK) signal pathways that regulate new gene transcription during stress, the MKC1 MAPK and HOG1 MAPK (for hyperosmotic glycerol) pathways are prominent in a number of yeasts and filamentous fungi in regard to adaptation to hyperosmotic and/or oxidant stress (2, 3, 5, 6, 11, 12, 18-21, 29, 44, 50, 52, 55).…”

mentioning

confidence: 99%

Goa1p of Candida albicans Localizes to the Mitochondria during Stress and Is Required for Mitochondrial Function and Virulence

et al. 2009

View full text Add to dashboard Cite

Using a Tn7 transposon library of Candida albicans, we have identified a mutant that exhibited sensitivity in drop plate assays to oxidants such as menadione and hydrogen peroxide. To verify the role of the mutated gene in stress adaptation, null mutants were constructed and phenotypically characterized. Because of its apparent functions in growth and oxidant adaptation, we have named the gene GOA1. Goa1p appears to be unique to the CTG subclade of the Saccharomycotina, including C. albicans. Mutants of C. albicans lacking goa1 (strain GOA31) were more sensitive to 6 mM H 2 O 2 and 0.125 mM menadione than the wild type (wt) or a genereconstituted (GOA32) strain. The sensitivity to oxidants correlated with reduced survival of the GOA31 mutant in human neutrophils and avirulence compared to control strains. Other phenotypes of GOA31 include reduced growth and filamentation in 10% serum, Spider, and SLAD agar media and an inability to form chlamydospores. Since Goa1p has an N-terminal mitochondrion localization site, we also show that green fluorescent protein-tagged Goa1p shows a mitochondrionlike distribution during oxidant or osmotic stress. Further, the inability of GOA31 to grow in medium containing lactate, ethanol, or glycerol as the sole carbon source indicates that the mitochondria are defective in the mutant. To determine how Goa1p contributes to mitochondrial function, we compared the wt, GOA32, and GOA31 strains for mitochondrial electrical membrane potential, respiration, and oxidative phosphorylation. We now show that GOA31, but not the wt or GOA32, had decreased respiration and mitochondrial membrane potential such that mutant cells are unable to drive oxidative phosphorylation. This is the first report in C. albicans of a respiratory defect caused by a loss of mitochondrial membrane potential.

show abstract

Role of trehalose in resistance to macrophage killing: study with a tps1/tps1 trehalose-deficient mutant of Candida albicans

Cited by 47 publications

References 38 publications

Combined Inactivation of the Candida albicans GPR1 and TPS2 Genes Results in Avirulence in a Mouse Model for Systemic Infection

Combined Inactivation of the Candida albicans GPR1 and TPS2 Genes Results in Avirulence in a Mouse Model for Systemic Infection

Role of Trehalose Biosynthesis in Aspergillus fumigatus Development, Stress Response, and Virulence

Goa1p of Candida albicans Localizes to the Mitochondria during Stress and Is Required for Mitochondrial Function and Virulence

Contact Info

Product

Resources

About