Limits...
Comparative analysis of calcineurin signaling between Candida dubliniensis and Candida albicans.

Zhang J, Heitman J, Chen YL - Commun Integr Biol (2012)

Bottom Line: Despite the fact that these two species share > 80% genome sequence identity, they exhibit distinct properties such as less hyphal growth, reduced pathogenicity and increased sensitivity to sodium stress and elevated temperatures in C. dubliniensis compared with C. albicans.Furthermore, we demonstrate that azole or echinocandin drugs in combination with the calcineurin inhibitor FK506 exhibit a synergistic effect against C. dubliniensis wild-type and echinocandin-resistant strains.The involvement of calcineurin in a variety of fungal virulence attributes and as a target for fungicidal synergism with azoles and echinocandins highlights the potential of combination therapy with calcineurin inhibitors for treating Candida infections.

View Article: PubMed Central - PubMed

ABSTRACT
Candida dubliniensis, an emerging fungal pathogen, is the closest known species to the established pathogenic species Candida albicans. Despite the fact that these two species share > 80% genome sequence identity, they exhibit distinct properties such as less hyphal growth, reduced pathogenicity and increased sensitivity to sodium stress and elevated temperatures in C. dubliniensis compared with C. albicans. It is, however, largely unknown whether signaling pathways are conserved in the two Candida species. Calcineurin signaling is known to be required for hyphal growth in Cryptococcus neoformans and Aspergillus fumigatus but remains elusive in C. albicans. Our recent study showed that calcineurin plays a clearly demonstrable role in controlling hyphal growth, drug tolerance and virulence in C. dubliniensis. Here, we extend our studies and show that calcineurin is conserved in controlling endoplasmic reticulum stress but distinct in governing pH homeostasis. Furthermore, we demonstrate that azole or echinocandin drugs in combination with the calcineurin inhibitor FK506 exhibit a synergistic effect against C. dubliniensis wild-type and echinocandin-resistant strains. The involvement of calcineurin in a variety of fungal virulence attributes and as a target for fungicidal synergism with azoles and echinocandins highlights the potential of combination therapy with calcineurin inhibitors for treating Candida infections.

No MeSH data available.


Related in: MedlinePlus

Figure 2. Calcineurin functions are conserved whereas Crz1 has different roles during ER stress in C. albicans and C. dubliniensis. C. dubliniensis and C. albicans calcineurin mutants were hypersensitive to the ER stress inducers tunicamycin (TM) and dithiothreitol (DTT). The C. albicans crz1/crz1 mutants, but not C. dubliniensis crz1/crz1 mutants, exhibit TM sensitivity intermediate between wild-type and calcineurin mutants. Cells were grown overnight in YPD medium at 24°C, washed twice in dH2O, 5-fold serially diluted, and spotted onto YPD medium containing TM (1 µg/ml) or DTT (45 mM). All strains were spotted on the same media. Strains tested are described in reference.9
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3376044&req=5

Figure 2: Figure 2. Calcineurin functions are conserved whereas Crz1 has different roles during ER stress in C. albicans and C. dubliniensis. C. dubliniensis and C. albicans calcineurin mutants were hypersensitive to the ER stress inducers tunicamycin (TM) and dithiothreitol (DTT). The C. albicans crz1/crz1 mutants, but not C. dubliniensis crz1/crz1 mutants, exhibit TM sensitivity intermediate between wild-type and calcineurin mutants. Cells were grown overnight in YPD medium at 24°C, washed twice in dH2O, 5-fold serially diluted, and spotted onto YPD medium containing TM (1 µg/ml) or DTT (45 mM). All strains were spotted on the same media. Strains tested are described in reference.9

Mentions: ER stress due to an accumulation of unfolded or misfolded proteins activates the unfolded protein response (UPR) signaling pathway in eukaryotic cells15,16 and has been shown to be involved in C. albicans morphogenesis.17 UPR signaling activates a variety of downstream transcripts, including the bZIP transcription factor Hac1 that impacts C. albicans hyphal growth in response to ER stress.17 Tunicamycin (TM) and dithiothreitol (DTT) induce the UPR by inhibiting N-linked glycosylation of secreted proteins and preventing disulfide bond formation, respectively.16 We found that C. albicans and C. dubliniensis calcineurin mutants are hypersensitive to tunicamycin and DTT compared with the wild-type (Fig. 2). Furthermore, the role of Crz1 in ER stress is different in C. albicans compared with C. dubliniensis (Fig. 2). While C. dubliniensis crz1/crz1, crz2/crz2, and crz1/crz1 crz2/crz2 double mutants grew similarly to wild-type in the presence of TM, the C. albicans crz1/crz1 mutant exhibited attenuated growth that was intermediate between wild-type and calcineurin mutants (Figs. 1and2), indicating a divergent function of Crz1 in ER stress responses in both Candida species. Interestingly, we found that the C. dubliniensis wild-type strainis hypersensitive to the ER stress inducer DTT compared with the C. albicans wild-type strain (Fig. 2), indicating that the tolerance to protein misfolding has been reduced in C. dubliniensis compared with C. albicans.


Comparative analysis of calcineurin signaling between Candida dubliniensis and Candida albicans.

Zhang J, Heitman J, Chen YL - Commun Integr Biol (2012)

Figure 2. Calcineurin functions are conserved whereas Crz1 has different roles during ER stress in C. albicans and C. dubliniensis. C. dubliniensis and C. albicans calcineurin mutants were hypersensitive to the ER stress inducers tunicamycin (TM) and dithiothreitol (DTT). The C. albicans crz1/crz1 mutants, but not C. dubliniensis crz1/crz1 mutants, exhibit TM sensitivity intermediate between wild-type and calcineurin mutants. Cells were grown overnight in YPD medium at 24°C, washed twice in dH2O, 5-fold serially diluted, and spotted onto YPD medium containing TM (1 µg/ml) or DTT (45 mM). All strains were spotted on the same media. Strains tested are described in reference.9
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3376044&req=5

Figure 2: Figure 2. Calcineurin functions are conserved whereas Crz1 has different roles during ER stress in C. albicans and C. dubliniensis. C. dubliniensis and C. albicans calcineurin mutants were hypersensitive to the ER stress inducers tunicamycin (TM) and dithiothreitol (DTT). The C. albicans crz1/crz1 mutants, but not C. dubliniensis crz1/crz1 mutants, exhibit TM sensitivity intermediate between wild-type and calcineurin mutants. Cells were grown overnight in YPD medium at 24°C, washed twice in dH2O, 5-fold serially diluted, and spotted onto YPD medium containing TM (1 µg/ml) or DTT (45 mM). All strains were spotted on the same media. Strains tested are described in reference.9
Mentions: ER stress due to an accumulation of unfolded or misfolded proteins activates the unfolded protein response (UPR) signaling pathway in eukaryotic cells15,16 and has been shown to be involved in C. albicans morphogenesis.17 UPR signaling activates a variety of downstream transcripts, including the bZIP transcription factor Hac1 that impacts C. albicans hyphal growth in response to ER stress.17 Tunicamycin (TM) and dithiothreitol (DTT) induce the UPR by inhibiting N-linked glycosylation of secreted proteins and preventing disulfide bond formation, respectively.16 We found that C. albicans and C. dubliniensis calcineurin mutants are hypersensitive to tunicamycin and DTT compared with the wild-type (Fig. 2). Furthermore, the role of Crz1 in ER stress is different in C. albicans compared with C. dubliniensis (Fig. 2). While C. dubliniensis crz1/crz1, crz2/crz2, and crz1/crz1 crz2/crz2 double mutants grew similarly to wild-type in the presence of TM, the C. albicans crz1/crz1 mutant exhibited attenuated growth that was intermediate between wild-type and calcineurin mutants (Figs. 1and2), indicating a divergent function of Crz1 in ER stress responses in both Candida species. Interestingly, we found that the C. dubliniensis wild-type strainis hypersensitive to the ER stress inducer DTT compared with the C. albicans wild-type strain (Fig. 2), indicating that the tolerance to protein misfolding has been reduced in C. dubliniensis compared with C. albicans.

Bottom Line: Despite the fact that these two species share > 80% genome sequence identity, they exhibit distinct properties such as less hyphal growth, reduced pathogenicity and increased sensitivity to sodium stress and elevated temperatures in C. dubliniensis compared with C. albicans.Furthermore, we demonstrate that azole or echinocandin drugs in combination with the calcineurin inhibitor FK506 exhibit a synergistic effect against C. dubliniensis wild-type and echinocandin-resistant strains.The involvement of calcineurin in a variety of fungal virulence attributes and as a target for fungicidal synergism with azoles and echinocandins highlights the potential of combination therapy with calcineurin inhibitors for treating Candida infections.

View Article: PubMed Central - PubMed

ABSTRACT
Candida dubliniensis, an emerging fungal pathogen, is the closest known species to the established pathogenic species Candida albicans. Despite the fact that these two species share > 80% genome sequence identity, they exhibit distinct properties such as less hyphal growth, reduced pathogenicity and increased sensitivity to sodium stress and elevated temperatures in C. dubliniensis compared with C. albicans. It is, however, largely unknown whether signaling pathways are conserved in the two Candida species. Calcineurin signaling is known to be required for hyphal growth in Cryptococcus neoformans and Aspergillus fumigatus but remains elusive in C. albicans. Our recent study showed that calcineurin plays a clearly demonstrable role in controlling hyphal growth, drug tolerance and virulence in C. dubliniensis. Here, we extend our studies and show that calcineurin is conserved in controlling endoplasmic reticulum stress but distinct in governing pH homeostasis. Furthermore, we demonstrate that azole or echinocandin drugs in combination with the calcineurin inhibitor FK506 exhibit a synergistic effect against C. dubliniensis wild-type and echinocandin-resistant strains. The involvement of calcineurin in a variety of fungal virulence attributes and as a target for fungicidal synergism with azoles and echinocandins highlights the potential of combination therapy with calcineurin inhibitors for treating Candida infections.

No MeSH data available.


Related in: MedlinePlus