scholarly journals Defective Hyphal Development and Avirulence Caused by a Deletion of the SSK1 Response Regulator Gene in Candida albicans

2000 ◽  
Vol 68 (2) ◽  
pp. 518-525 ◽  
Author(s):  
José Antonio Calera ◽  
Xiao-Jiong Zhao ◽  
Richard Calderone
Keyword(s):  
Candida Albicans ◽  
Nitrogen Availability ◽  
Response Regulator ◽  
Hyphal Development ◽  
Isolation And Characterization ◽  
Solid Media ◽  
Functional Homolog ◽  
Good Target ◽  
Two Component ◽  
Hyphal Formation

ABSTRACT In a previous study, we reported the isolation and characterization of the two-component response regulator SSK1 gene ofCandida albicans. This gene is a structural but not a functional homolog of the SSK1 andmcs4 + genes of Saccharomyces cerevisiae and Schizosaccharomyces pombe, respectively. In the present study, we have constructed and phenotypically characterized Δssk1 mutants of C. albicans. The results confirmed our previous observation thatCaSSK1, unlike SSK1 ormcs4 +, does not regulate cellular responses to either osmotic or oxidative stress. Instead, Δssk1 null strains showed severely reduced hyphal formation on serum agar and were totally defective in hyphal development on other solid media, such as medium 199 (pH 7.5) and Spider medium. In contrast, under conditions of low nitrogen availability on solid media, Δssk1 null strains dramatically hyperinvaded the agar. However, while forming germ tubes and hyphae in liquid media similar to those of the wild type, Δssk1 null strains flocculated in a manner similar to that of Δchk1 two-component histidine kinase mutants, which we have previously described. Finally, virulence studies indicated that SSK1 is essential for the pathogenesis ofC. albicans, suggesting that the Ssk1p response regulator could be a good target for antifungal therapy.

scholarly journals Roles of Three Histidine Kinase Genes in Hyphal Development and Virulence of the Pathogenic Fungus Candida albicans

1999 ◽  
Vol 181 (23) ◽  
pp. 7243-7247 ◽  
Author(s):  
Toshiko Yamada-Okabe ◽  
Toshiyuki Mio ◽  
Naomi Ono ◽  
Yuji Kashima ◽  
Mitsuaki Matsui ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Histidine Kinase ◽  
Response Regulator ◽  
Pathogenic Fungus ◽  
Signal Transmission ◽  
Systemic Candidiasis ◽  
Hyphal Development ◽  
Hyphal Formation ◽  
Transmission Pathways ◽  
Null Mutants

ABSTRACT The pathogenic fungus Candida albicans harbors three histidine kinase genes called CaSLN1, CaNIK1, and CaHK1. The disruption of any one of these three genes impaired the hyphal formation and attenuated the virulence of C. albicans in a mouse systemic candidiasis model. The effects of the disruption on hyphal formation and virulence were most severe in the cahk1Δ null mutants. Although the double disruption of CaSLN1 and CaNIK1 was impossible, further deletion of CaSLN1 or CaNIK1 in thecahk1Δ null mutants partially restored the serum-induced hypha-forming ability and virulence. When incubated with radiolabelled ATP, the recombinant CaSln1 and CaNik1 proteins, which contained their own kinase and response regulator domains, were autophosphorylated, whereas CaHk1p was not. These results imply that in C. albicans, CaSLN1 and CaNIK1 function upstream of CaHK1 but are in distinct signal transmission pathways.

scholarly journals Roles of Candida albicans Sfl1 in Hyphal Development

2007 ◽  
Vol 6 (11) ◽  
pp. 2112-2121 ◽  
Author(s):  
Yandong Li ◽  
Chang Su ◽  
Xuming Mao ◽  
Fang Cao ◽  
Jiangye Chen
Keyword(s):  
Candida Albicans ◽  
Growth Conditions ◽  
Filamentous Growth ◽  
Negative Regulator ◽  
Specific Gene ◽  
Environmental Cues ◽  
Dimorphic Fungi ◽  
Hyphal Development ◽  
Negative Factor ◽  
Functional Homolog

ABSTRACT The ability to switch between different morphological forms is an important feature of Candida albicans and is relevant to its pathogenesis. Many conserved positive and negative transcription factors are involved in morphogenetic regulation of the two dimorphic fungi Candida albicans and Saccharomyces cerevisiae. In S. cerevisiae, the transcriptional repressor Sfl1 and the activator Flo8 function antagonistically in invasive and filamentous growth. We have previously reported that Candida albicans Flo8 is a transcription factor essential for hyphal development and virulence in C. albicans. To determine whether a similar negative factor exists in C. albicans, we identified Candida albicans Sfl1 as a functional homolog of the S. cerevisiae sfl1 mutant. Sfl1 is a negative regulator of hyphal development in C. albicans. Deletion of C. albicans SFL1 enhanced filamentous growth and hypha-specific gene expression in several media and at several growth temperatures. Overexpression of the SFL1 led to a significant reduction of filament formation. Both deletion and overexpression of the SFL1 attenuated virulence of C. albicans in a mouse model. Deleting FLO8 in an sfl1/sfl1 mutant completely blocked hyphal development in various growth conditions examined, suggesting that C. albicans Sfl1 may act as a negative regulator of filamentous growth by antagonizing Flo8 functions. We suggest that, similar to the case for S. cerevisiae, a combination of dual control by activation and repression of Flo8 and Sfl1 may contribute to the fine regulatory network in C. albicans morphogenesis responding to different environmental cues.

scholarly journals Two-Component Histidine Phosphotransfer Protein Ypd1 Is Not Essential for Viability in Candida albicans

2014 ◽  
Vol 13 (4) ◽  
pp. 452-460 ◽  
Author(s):  
John Mavrianos ◽  
Chirayu Desai ◽  
Neeraj Chauhan
Keyword(s):  
Candida Albicans ◽  
Fluorescent Protein ◽  
Mapk Pathway ◽  
Response Regulator ◽  
Pathogenic Fungi ◽  
Mitogen Activated Protein Kinase ◽  
Wild Type ◽  
Signaling Mechanism ◽  
Content Type ◽  
Two Component

ABSTRACTProkaryotes and lower eukaryotes, such as yeasts, utilize two-component signal transduction pathways to adapt cells to environmental stress and to regulate the expression of genes associated with virulence. One of the central proteins in this type of signaling mechanism is the phosphohistidine intermediate protein Ypd1. Ypd1 is reported to be essential for viability in the model yeastSaccharomyces cerevisiae. We present data here showing that this is not the case forCandida albicans. Disruption ofYPD1causes cells to flocculate and filament constitutively under conditions that favor growth in yeast form. To determine the function of Ypd1 in the Hog1 mitogen-activated protein kinase (MAPK) pathway, we measured phosphorylation of Hog1 MAPK inypd1Δ/Δ and wild-type strains ofC. albicans. Constitutive phosphorylation of Hog1 was observed in theypd1Δ/Δ strain compared to the wild-type strain. Furthermore, fluorescence microscopy revealed that green fluorescent protein (GFP)-tagged Ypd1 is localized to both the nucleus and the cytoplasm. The subcellular segregation of GFP-tagged Ypd1 hints at an important role(s) of Ypd1 in regulation of Ssk1 (cytosolic) and Skn7 (nuclear) response regulator proteins via phosphorylation inC. albicans. Overall, our findings have profound implications for a mechanistic understanding of two-component signaling pathways inC. albicans, and perhaps in other pathogenic fungi.

scholarly journals Mss11, a Transcriptional Activator, Is Required for Hyphal Development in Candida albicans

2009 ◽  
Vol 8 (11) ◽  
pp. 1780-1791 ◽  
Author(s):  
Chang Su ◽  
Yandong Li ◽  
Yang Lu ◽  
Jiangye Chen
Keyword(s):  
Candida Albicans ◽  
Growth Conditions ◽  
Yeast Cells ◽  
Binding Partner ◽  
Hyphal Development ◽  
Functional Homolog ◽  
Upstream Activating Sequence ◽  
Enhanced Expression ◽  
Sequence Region

ABSTRACT Candida albicans undergoes a morphological transition from yeast to hyphae in response to a variety of stimuli and growth conditions. We previously isolated a LisH domain containing transcription factor Flo8, which is essential for hyphal development in C. albicans. To search the putative binding partner of Flo8 in C. albicans, we identified C. albicans Mss11, a functional homolog of Saccharomyces cerevisiae Mss11, which also contains a LisH motif at its N terminus. C. albicans Mss11 can interact with Flo8 via the LisH motif by in vivo coimmunoprecipitation. The results of a chromatin immunoprecipitation (ChIP) assay showed that more Mss11 and Flo8 proteins bound to the upstream activating sequence region of HWP1 promoter in hyphal cells than in yeast cells, and the increased binding of each of these two proteins responding to hyphal induction was dependent on the other. Overexpression of MSS11 enhanced filamentous growth. Deletion of MSS11 caused a profound defect in hyphal development and the induction of hypha-specific genes. Our data suggest that Mss11 functions as an activator in hyphal development of C. albicans. Furthermore, overexpression of FLO8 can bypass the requirement of Mss11 in filamentous formation, whereas overexpression of MSS11 failed to promote hyphae growth in flo8 mutants. In summary, we show that the expression level of MSS11 increases during hyphal induction, and the enhanced expression of MSS11 may contribute to cooperative binding of Mss11 and Flo8 to the HWP1 promoter.

scholarly journals Mitochondrial Two-Component Signaling Systems in Candida albicans

2013 ◽  
Vol 12 (6) ◽  
pp. 913-922 ◽  
Author(s):  
John Mavrianos ◽  
Elizabeth L. Berkow ◽  
Chirayu Desai ◽  
Alok Pandey ◽  
Mona Batish ◽  
...  
Keyword(s):  
Cell Death ◽  
Candida Albicans ◽  
Response Regulator ◽  
Wild Type ◽  
Content Type ◽  
Cell Death Pathway ◽  
Regulator Protein ◽  
Two Component ◽  
In The Wild ◽  
Response Regulator Protein

ABSTRACTTwo-component signal transduction pathways are one of the primary means by which microorganisms respond to environmental signals. These signaling cascades originated in prokaryotes and were inherited by eukaryotes via endosymbiotic lateral gene transfer from ancestral cyanobacteria. We report here that the nuclear genome of the pathogenic fungusCandida albicanscontains elements of a two-component signaling pathway that seem to be targeted to the mitochondria. TheC. albicanstwo-component response regulator protein Srr1 (stressresponseregulator 1) contains a mitochondrial targeting sequence at the N terminus, and fluorescence microscopy reveals mitochondrial localization of green fluorescent protein-tagged Srr1. Moreover, phylogenetic analysis indicates thatC. albicansSrr1 is more closely related to histidine kinases and response regulators found in marine bacteria than are other two-component proteins present in the fungi. These data suggest conservation of this protein during the evolutionary transition from endosymbiont to a subcellular organelle. We used microarray analysis to determine whether the phenotypes observed with asrr1Δ/Δmutant could be correlated with gene transcriptional changes. The expression of mitochondrial genes was altered in thesrr1Δ/Δnull mutant in comparison to their expression in the wild type. Furthermore, apoptosis increased significantly in thesrr1Δ/Δmutant strain compared to the level of apoptosis in the wild type, suggesting the activation of a mitochondrion-dependent apoptotic cell death pathway in thesrr1Δ/Δmutant. Collectively, this study shows for the first time that a lower eukaryote likeC. albicanspossesses a two-component response regulator protein that has survived in mitochondria and regulates a subset of genes whose functions are associated with the oxidative stress response and programmed cell death (apoptosis).

scholarly journals Functional analysis of the phospholipase C gene CaPLC1 and two unusual phospholipase C genes, CaPLC2 and CaPLC3, of Candida albicans

Microbiology ◽  
2005 ◽  
Vol 151 (10) ◽  
pp. 3381-3394 ◽  
Author(s):  
Donika Kunze ◽  
Inga Melzer ◽  
Désirée Bennett ◽  
Dominique Sanglard ◽  
Donna MacCallum ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Phospholipase C ◽  
Essential Gene ◽  
Pathogenic Fungus ◽  
Systemic Infection ◽  
Cellular Processes ◽  
Solid Media ◽  
Transcriptional Pattern ◽  
Human Pathogenic Fungus ◽  
Hyphal Formation

Phospholipases C are known to be important regulators of cellular processes but may also act as virulence factors of pathogenic microbes. At least three genes in the genome of the human-pathogenic fungus Candida albicans encode phospholipases with conserved phospholipase C (Plc) motifs. None of the deduced protein sequences contain N-terminal signal peptides, suggesting that these phospholipases are not secreted. In contrast to its orthologue in Sacharomyces cerevisiae, CaPLC1 seems to be an essential gene. However, a conditional mutant with reduced transcript levels of CaPLC1 had phenotypes similar to Plc1p-deficient mutants in S. cerevisiae, including reduced growth on media causing increased osmotic stress, on media with a non-glucose carbon source, or at elevated or lower temperatures, suggesting that CaPlc1p, like the Plc1p counterpart in S. cerevisiae, may be involved in multiple cellular processes. Furthermore, phenotypic screening of the heterozygous ΔCaplc1/CaPLC1 mutant showed additional defects in hyphal formation. The loss of CaPLC1 cannot be compensated by two additional PLC genes of C. albicans (CaPLC2 and CaPLC3) encoding two almost identical phospholipases C with no counterpart in S. cerevisiae but containing structural elements found in bacterial phospholipases C. Although the promoter sequences of CaPLC2 and CaPLC3 differed dramatically, the transcriptional pattern of both genes was similar. In contrast to CaPLC1, CaPLC2 and CaPLC3 are not essential. Although Caplc2/3 mutants had reduced abilities to produce hyphae on solid media, these mutants were as virulent as the wild-type in a model of systemic infection. These data suggest that C. albicans contains two different classes of phospholipases C which are involved in cellular processes but which have no specific functions in pathogenicity.

scholarly journals SKN7 of Candida albicans: Mutant Construction and Phenotype Analysis

2004 ◽  
Vol 72 (4) ◽  
pp. 2390-2394 ◽  
Author(s):  
Praveen Singh ◽  
Neeraj Chauhan ◽  
Anup Ghosh ◽  
Freddie Dixon ◽  
Richard Calderone
Keyword(s):  
Candida Albicans ◽  
Response Regulator ◽  
Regulator Gene ◽  
Wild Type ◽  
Response Regulators ◽  
Two Component ◽  
Phenotype Analysis

ABSTRACT The SKN7 two-component response regulator gene of Candida albicans was deleted, and the phenotype of the mutant was established. This mutant exhibited impaired growth on Spider agar and 10% serum agar compared to wild-type and gene-reconstituted strains. The skn7 mutant was sensitive to H2O2 in vitro, but its virulence was only mildly attenuated. A comparison of the Skn7p and Ssk1p response regulators of C. albicans is discussed.

Candida albicans IRS4 contributes to hyphal formation and virulence after the initial stages of disseminated candidiasis

Microbiology ◽  
2005 ◽  
Vol 151 (9) ◽  
pp. 2923-2931 ◽  
Author(s):  
Hassan Badrane ◽  
Shaoji Cheng ◽  
M. Hong Nguyen ◽  
Hong Yan Jia ◽  
Zongde Zhang ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Bloodstream Infections ◽  
Screening Strategy ◽  
Expression Library ◽  
Genomic Expression ◽  
Disseminated Candidiasis ◽  
Solid Media ◽  
Hyphal Formation ◽  
Intravenous Inoculation

Candida albicans is a common cause of mucosal and bloodstream infections. As a screening strategy to identify novel candidal virulence factors, sera recovered from HIV-infected patients with active oropharyngeal candidiasis (OPC) were previously used to probe a C. albicans genomic expression library. IRS4 was identified as a gene that encodes an immunogenic protein. In the present study, the presence of IRS4 transcripts was verified within OPC pseudomembranes recovered from patients. Having confirmed that the gene is expressed during human candidiasis, gene disruption strains were created and this implicated IRS4 in diverse processes, including hyphal formation on solid media and under embedded conditions, cell wall integrity and structure, and adherence to human epithelial cells in vitro. IRS4 disruption, however, did not influence hyphal formation or virulence in a murine model of OPC. Rather, the gene was found to be necessary for normal morphogenesis and full virulence during murine intravenously disseminated candidiasis (DC). IRS4's effects on hyphal formation and virulence during DC were not evident on the first day after intravenous inoculation, even though transcripts were detected within murine kidneys. After 4 days, however, an irs4 null mutant strain was associated with attenuated mortality, diminished tissue burdens, less extensive infections, impaired C. albicans hyphal formation and decreased kidney damage. Taken together, these findings suggest that IRS4 makes distinct temporal-spatial contributions to the pathogenesis of candidiasis, which appear to vary between different tissue sites as well as within a given tissue over time.

scholarly journals Candida albicans SRR1 , a Putative Two-Component Response Regulator Gene, Is Required for Stress Adaptation, Morphogenesis, and Virulence

2011 ◽  
Vol 10 (10) ◽  
pp. 1370-1374 ◽  
Author(s):  
Chirayu Desai ◽  
John Mavrianos ◽  
Neeraj Chauhan
Keyword(s):  
Candida Albicans ◽  
Response Regulator ◽  
Stress Adaptation ◽  
Regulator Gene ◽  
Content Type ◽  
Virulence Attenuation ◽  
Two Component ◽  
Resistance To Stress ◽  
Identification And Characterization

ABSTRACT We report here the identification and characterization of a previously uncharacterized, two-component response regulator gene (orf19.5843) from Candida albicans . Because of its apparent functions in stress adaptation, we have named this gene SRR1 ( s tress r esponse r egulator 1). Disruption of SRR1 causes defects in hyphal development, reduced resistance to stress, and severe virulence attenuation in the mouse model of disseminated candidiasis.

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