9 results on '"Nobile, Clarissa J."'
Search Results
2. Filamentous growth is a general feature of Candida auris clinical isolates
- Author
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Fan, Shuru, Yue, Huizhen, Zheng, Qiushi, Bing, Jian, Tian, Sufei, Chen, Jingjing, Ennis, Craig L, Nobile, Clarissa J, Huang, Guanghua, and Du, Han
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Drug Resistance ,Microbial Sensitivity Tests ,Moths ,Microbiology ,Vaccine Related ,Mice ,Biodefense ,Genetics ,Animals ,Humans ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Aetiology ,Candida ,Virulence ,Prevention ,Candidiasis ,Candida auris ,antifungal resistance ,filamentation ,virulence ,Fungal ,Phenotype ,Infectious Diseases ,Good Health and Well Being ,Medical Microbiology ,Larva ,morphological plasticity ,Antimicrobial Resistance ,Infection - Abstract
A striking feature of pathogenic Candida species is morphological plasticity that facilitates environmental adaptation and host infection. Candida auris is an emerging multidrug-resistant fungal pathogen first described in Japan in 2009. In this study, we demonstrate that clinical isolates of C. auris have multiple colony and cellular morphologies including the yeast, filamentous, aggregated, and elongated forms. This phenotypic diversity has been observed in eight clinical isolates of C. auris representing four major genetic clades, suggesting that it could be a general characteristic. We further demonstrate that different cell types of C. auris exhibit distinct antifungal resistance and virulence properties in a Galleria mellonella infection model. Our findings imply that morphological diversity is an important biological feature of C. auris and could be a contributor to its emergence and rapid prevalence worldwide.Lay summaryCandida auris is an emerging multidrug-resistant fungal pathogen. Morphological analyses indicate that filamentation is a general feature of clinical isolates of C. auris. This ability is associated with antifungal resistance and virulence.
- Published
- 2021
3. Photodynamic Therapy Is Effective Against Candida auris Biofilms
- Author
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Bapat, Priyanka S and Nobile, Clarissa J
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Antifungal Agents ,Microbial Sensitivity Tests ,red ,Microbiology ,Vaccine Related ,green and blue (RGB) visible lights ,Biodefense ,Humans ,photosensitizing compounds ,Candida ,non-drug antifungal strategies ,reactive oxygen species ,drug resistance ,Prevention ,non-drug therapeutic strategies ,Candidiasis ,Candida auris biofilms ,Good Health and Well Being ,Infectious Diseases ,Emerging Infectious Diseases ,Photochemotherapy ,photodynamic therapy ,5.1 Pharmaceuticals ,Biofilms ,Antimicrobial Resistance ,Biochemistry and Cell Biology ,Development of treatments and therapeutic interventions ,Infection - Abstract
Fungal infections are increasing in prevalence worldwide. The paucity of available antifungal drug classes, combined with the increased occurrence of multidrug resistance in fungi, has led to new clinical challenges in the treatment of fungal infections. Candida auris is a recently emerged multidrug resistant human fungal pathogen that has become a worldwide public health threat. C. auris clinical isolates are often resistant to one or more antifungal drug classes, and thus, there is a high unmet medical need for the development of new therapeutic strategies effective against C. auris. Additionally, C. auris possesses several virulence traits, including the ability to form biofilms, further contributing to its drug resistance, and complicating the treatment of C. auris infections. Here we assessed red, green, and blue visible lights alone and in combination with photosensitizing compounds for their efficacies against C. auris biofilms. We found that (1) blue light inhibited and disrupted C. auris biofilms on its own and that the addition of photosensitizing compounds improved its antibiofilm potential; (2) red light inhibited and disrupted C. auris biofilms, but only in combination with photosensitizing compounds; and (3) green light inhibited C. auris biofilms in combination with photosensitizing compounds, but had no effects on disrupting C. auris biofilms. Taken together, our findings suggest that photodynamic therapy could be an effective non-drug therapeutic strategy against multidrug resistant C. auris biofilm infections.
- Published
- 2021
4. An expanded cell wall damage signaling network is comprised of the transcription factors Rlm1 and Sko1 in Candida albicans
- Author
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Heredia, Marienela Y, Ikeh, Mélanie AC, Gunasekaran, Deepika, Conrad, Karen A, Filimonava, Sviatlana, Marotta, Dawn H, Nobile, Clarissa J, Rauceo, Jason M, and Butler, Geraldine
- Subjects
Saccharomyces cerevisiae Proteins ,Antifungal Agents ,MADS Domain Proteins ,Saccharomyces cerevisiae ,Fungal Proteins ,Repressor Proteins ,Fungal ,Basic-Leucine Zipper Transcription Factors ,Infectious Diseases ,Gene Expression Regulation ,Cell Wall ,Caspofungin ,Candida albicans ,Genetics ,Humans ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Phosphorylation ,Aetiology ,Transcription Factors ,Signal Transduction ,Biotechnology ,Developmental Biology - Abstract
The human fungal pathogen Candida albicans is constantly exposed to environmental challenges impacting the cell wall. Signaling pathways coordinate stress adaptation and are essential for commensalism and virulence. The transcription factors Sko1, Cas5, and Rlm1 control the response to cell wall stress caused by the antifungal drug caspofungin. Here, we expand the Sko1 and Rlm1 transcriptional circuit and demonstrate that Rlm1 activates Sko1 cell wall stress signaling. Caspofungin-induced transcription of SKO1 and several Sko1-dependent cell wall integrity genes are attenuated in an rlm1Δ/Δ mutant strain when compared to the treated wild-type strain but not in a cas5Δ/Δ mutant strain. Genome-wide chromatin immunoprecipitation (ChIP-seq) results revealed numerous Sko1 and Rlm1 directly bound target genes in the presence of caspofungin that were undetected in previous gene expression studies. Notable targets include genes involved in cell wall integrity, osmolarity, and cellular aggregation, as well as several uncharacterized genes. Interestingly, we found that Rlm1 does not bind to the upstream intergenic region of SKO1 in the presence of caspofungin, indicating that Rlm1 indirectly controls caspofungin-induced SKO1 transcription. In addition, we discovered that caspofungin-induced SKO1 transcription occurs through self-activation. Based on our ChIP-seq data, we also discovered an Rlm1 consensus motif unique to C. albicans. For Sko1, we found a consensus motif similar to the known Sko1 motif for Saccharomyces cerevisiae. Growth assays showed that SKO1 overexpression suppressed caspofungin hypersensitivity in an rlm1Δ/Δ mutant strain. In addition, overexpression of the glycerol phosphatase, RHR2, suppressed caspofungin hypersensitivity specifically in a sko1Δ/Δ mutant strain. Our findings link the Sko1 and Rlm1 signaling pathways, identify new biological roles for Sko1 and Rlm1, and highlight the complex dynamics underlying cell wall signaling.
- Published
- 2020
5. The Als3 Cell Wall Adhesin Plays a Critical Role in Human Serum Amyloid A1-Induced Cell Death and Aggregation in Candida albicans
- Author
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Gong, Jiao, Bing, Jian, Guan, Guobo, Nobile, Clarissa J, and Huang, Guanghua
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Cell Death ,Als3 ,antifungal activity ,Bacterial ,cell aggregation ,serum amyloid A ,Pharmacology and Pharmaceutical Sciences ,adhesins ,Microbiology ,Fungal Proteins ,Mice ,Infectious Diseases ,Cell Wall ,Medical Microbiology ,Biofilms ,Candida albicans ,Genetics ,Animals ,Humans ,2.1 Biological and endogenous factors ,2.2 Factors relating to the physical environment ,Aetiology ,Infection ,SAA1 - Abstract
Antimicrobial peptides and proteins play critical roles in the host defense against invading pathogens. We recently discovered that recombinantly expressed human and mouse serum amyloid A1 (rhSAA1 and rmSAA1, respectively) proteins have potent antifungal activities against the major human fungal pathogen Candida albicans At high concentrations, rhSAA1 disrupts C. albicans membrane integrity and induces rapid fungal cell death. In the present study, we find that rhSAA1 promotes cell aggregation and targets the C. albicans cell wall adhesin Als3. Inactivation of ALS3 in C. albicans leads to a striking decrease in cell aggregation and cell death upon rhSAA1 treatment, suggesting that Als3 plays a critical role in SAA1 sensing. We further demonstrate that deletion of the transcriptional regulators controlling the expression of ALS3, such as AHR1, BCR1, and EFG1, in C. albicans results in similar effects to that of the als3/als3 mutant upon rhSAA1 treatment. Global gene expression profiling indicates that rhSAA1 has a discernible impact on the expression of cell wall- and metabolism-related genes, suggesting that rhSAA1 treatment could lead to a nutrient starvation effect on C. albicans cells.
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- 2020
6. Visualization of Biofilm Formation in Candida albicans Using an Automated Microfluidic Device
- Author
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Gulati, Megha, Ennis, Craig L, Rodriguez, Diana L, and Nobile, Clarissa J
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Biofilm ,biofilm screens ,Bioengineering ,Issue 130 ,biofilm protocols ,biofilm methods ,Infectious Diseases ,laminar flow ,Biofilms ,Lab-On-A-Chip Devices ,Candida albicans ,Humans ,2.1 Biological and endogenous factors ,microfluidic device ,Psychology ,Cognitive Sciences ,Antimicrobial Resistance ,Biochemistry and Cell Biology ,Aetiology ,in vitro biofilm assays ,Infection ,visualization - Abstract
Candida albicans is the most common fungal pathogen of humans, causing about 15% of hospital-acquired sepsis cases. A major virulence attribute of C. albicans is its ability to form biofilms, structured communities of cells attached to biotic and abiotic surfaces. C. albicans biofilms can form on host tissues, such as mucosal layers, and on medical devices, such as catheters, pacemakers, dentures, and joint prostheses. Biofilms pose significant clinical challenges because they are highly resistant to physical and chemical perturbations, and can act as reservoirs to seed disseminated infections. Various in vitro assays have been utilized to study C. albicans biofilm formation, such as microtiter plate assays, dry weight measurements, cell viability assays, and confocal scanning laser microscopy. All of these assays are single end-point assays, where biofilm formation is assessed at a specific time point. Here, we describe a protocol to study biofilm formation in real-time using an automated microfluidic device under laminar flow conditions. This method allows for the observation of biofilm formation as the biofilm develops over time, using customizable conditions that mimic those of the host, such as those encountered in vascular catheters. This protocol can be used to assess the biofilm defects of genetic mutants as well as the inhibitory effects of antimicrobial agents on biofilm development in real-time.
- Published
- 2017
7. Lactic acid bacteria differentially regulate filamentation in two heritable cell types of the human fungal pathogen Candida albicans
- Author
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Liang, Weihong, Guan, Guobo, Dai, Yu, Cao, Chengjun, Tao, Li, Du, Han, Nobile, Clarissa J, Zhong, Jin, and Huang, Guanghua
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Pediatric Research Initiative ,Agricultural and Veterinary Sciences ,Biological Sciences ,Medical and Health Sciences ,Microbiology ,DNA-Binding Proteins ,Fungal Proteins ,Lactobacillus ,Infectious Diseases ,Candida albicans ,Genetics ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Lactic Acid ,Aetiology ,Infection ,Transcription Factors ,Signal Transduction - Abstract
Microorganisms rarely exist as single species in natural environments. The opportunistic fungal pathogen Candida albicans and lactic acid bacteria (LAB) are common members of the microbiota of several human niches such as the mouth, gut and vagina. Lactic acid bacteria are known to suppress filamentation, a key virulence feature of C. albicans, through the production of lactic acid and other metabolites. Here we report that C. albicans cells switch between two heritable cell types, white and opaque, to undergo filamentation to adapt to diversified environments. We show that acidic pH conditions caused by LAB and low temperatures support opaque cell filamentation, while neutral pH conditions and high temperatures promote white cell filamentation. The cAMP signalling pathway and the Rfg1 transcription factor play major roles in regulating the responses to these conditions. This cell type-specific response of C. albicans to different environmental conditions reflects its elaborate regulatory control of phenotypic plasticity.
- Published
- 2016
8. S-nitrosomycothiol reductase and mycothiol are required for survival under aldehyde stress and biofilm formation in Mycobacterium smegmatis
- Author
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Vargas, Derek, Hageman, Samantha, Gulati, Megha, Nobile, Clarissa J, and Rawat, Mamta
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Aldehydes ,Cysteine Synthase ,Mycobacterium Infections ,Biochemistry & Molecular Biology ,S-Nitrosothiols ,Nontuberculous ,mycobacteria ,Mycobacterium smegmatis ,Glycopeptides ,ergothioneine ,Medical Biochemistry and Metabolomics ,Aldehyde Oxidoreductases ,formaldehyde dehydrogenase ,nitrosative stress ,Biofilms ,S-nitrosothiol reductase ,Genetics ,Cysteine ,mycothiol ,Biochemistry and Cell Biology ,Inositol - Abstract
We show that Mycobacterium smegmatis mutants disrupted in mscR, coding for a dual function S-nitrosomycothiol reductase and formaldehyde dehydrogenase, and mshC, coding for a mycothiol ligase and lacking mycothiol (MSH), are more susceptible to S-nitrosoglutathione (GSNO) and aldehydes than wild type. MSH is a cofactor for MscR, and both mshC and mscR are induced by GSNO and aldehydes. We also show that a mutant disrupted in egtA, coding for a γ-glutamyl cysteine synthetase and lacking in ergothioneine, is sensitive to nitrosative stress but not to aldehydes. In addition, we find that MSH and S-nitrosomycothiol reductase are required for normal biofilm formation in M. smegmatis, suggesting potential new therapeutic pathways to target to inhibit or disrupt biofilm formation. © 2016 IUBMB Life, 68(8):621-628, 2016.
- Published
- 2016
9. An expanded regulatory network temporally controls Candida albicans biofilm formation
- Author
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Fox, Emily P, Bui, Catherine K, Nett, Jeniel E, Hartooni, Nairi, Mui, Michael C, Andes, David R, Nobile, Clarissa J, and Johnson, Alexander D
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Fungal Proteins ,Agricultural and Veterinary Sciences ,Biofilms ,Candida albicans ,Gene Expression ,biochemical phenomena, metabolism, and nutrition ,Biological Sciences ,Microbiology ,Medical and Health Sciences - Abstract
Candida albicans biofilms are composed of highly adherent and densely arranged cells with properties distinct from those of free-floating (planktonic) cells. These biofilms are a significant medical problem because they commonly form on implanted medical devices, are drug resistant and are difficult to remove. C. albicans biofilms are not static structures; rather they are dynamic and develop over time. Here we characterize gene expression in biofilms during their development, and by comparing them to multiple planktonic reference states, we identify patterns of gene expression relevant to biofilm formation. In particular, we document time-dependent changes in genes involved in adhesion and metabolism, both of which are at the core of biofilm development. Additionally, we identify three new regulators of biofilm formation, Flo8, Gal4, and Rfx2, which play distinct roles during biofilm development over time. Flo8 is required for biofilm formation at all time points, and Gal4 and Rfx2 are needed for proper biofilm formation at intermediate time points.
- Published
- 2015
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