58 results on '"David Kadosh"'
Search Results
2. Genome-wide translational response of Candida albicans to fluconazole treatment
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Saket Choudhary, Vasanthakrishna Mundodi, Andrew D. Smith, and David Kadosh
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fluconazole ,ribosome profiling ,translational control ,transcriptional profiling ,Candida albicans ,Microbiology ,QR1-502 - Abstract
ABSTRACT Azoles are commonly used for the treatment of fungal infections, and the ability of human fungal pathogens to rapidly respond to azole treatment is critical for the development of antifungal resistance. While the roles of genetic mutations, chromosomal rearrangements, and transcriptional mechanisms in azole resistance have been well-characterized, very little is known about post-transcriptional and translational mechanisms that drive this process. In addition, most previous genome-wide studies have focused on transcriptional responses to azole treatment and likely serve as inaccurate proxies for changes in protein expression due to extensive post-transcriptional and translational regulation. In this study, we use ribosome profiling to provide the first picture of the global translational response of a major human fungal pathogen, Candida albicans, to treatment with fluconazole (Flu), one of the most widely used azole drugs. We identify sets of genes showing significantly altered translational efficiency, including genes associated with a variety of biological processes such as the cell cycle, DNA repair, cell wall/cell membrane biosynthesis, transport, signaling, DNA- and RNA-binding activities, and protein synthesis. We observe both similarities and differences among the most highly represented gene categories (as defined by gene ontology) that are regulated by fluconazole at the translational vs transcriptional levels. Importantly, however, very few genes that are translationally regulated by fluconazole are also controlled transcriptionally under this condition. Our findings suggest that C. albicans possesses distinct translational mechanisms that are important for the response to antifungal treatment, which could eventually be targeted by novel antifungal therapies. IMPORTANCE Azoles are one of the most commonly used drug classes to treat human fungal pathogens. While point mutations, chromosomal rearrangements, and transcriptional mechanisms that drive azole resistance have been well-characterized, we know very little about the role of translational mechanisms. In this study, we determined the global translational profile of genes that are expressed in the major human fungal pathogen Candida albicans in response to fluconazole, one of the most widely used azole drugs. We find both similarities and differences among the most highly represented categories of genes regulated by fluconazole at the transcriptional and translational levels. Interestingly, however, many of the specific genes that are regulated by fluconazole at the translational level do not appear to be controlled by transcriptional mechanisms under this condition. Our results suggest that distinct C. albicans translational mechanisms control the response to antifungals and could eventually be targeted in the development of new therapies.
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- 2023
- Full Text
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3. Editorial: Omics-originated exploration of pathogenic patterns and molecular mechanisms in human and animal fungal pathogens
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Chuan Xu, David Kadosh, Donglei Sun, Guohong Zeng, and Yi-Zhou Gao
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omics ,genome-wide patterns ,pathogenic factors ,molecular regulatory mechanisms ,disease ,biocontrol ,Microbiology ,QR1-502 - Published
- 2023
- Full Text
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4. Perspective on the origin, resistance, and spread of the emerging human fungal pathogen Candida auris.
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Cheshta Sharma and David Kadosh
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Published
- 2023
- Full Text
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5. Erratum to: Global translational landscape of the Candida albicans morphological transition
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Vasanthakrishna Mundodi, Saket Choudhary, Andrew D Smith, and David Kadosh
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Genetics ,QH426-470 - Published
- 2021
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6. Global Transcriptomic Analysis of the Candida albicans Response to Treatment with a Novel Inhibitor of Filamentation
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Jesus A. Romo, Hao Zhang, Hong Cai, David Kadosh, Julia R. Koehler, Stephen P. Saville, Yufeng Wang, and Jose L. Lopez-Ribot
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Candida albicans ,candidiasis ,filamentation ,antivirulence ,Microbiology ,QR1-502 - Abstract
ABSTRACT The opportunistic pathogenic fungus Candida albicans can cause devastating infections in immunocompromised patients. Its ability to undergo a morphogenetic transition from yeast to filamentous forms allows it to penetrate tissues and damage tissues, and the expression of genes associated with a number of pathogenetic mechanisms is also coordinately regulated with the yeast-to-hypha conversion. Therefore, it is widely considered that filamentation represents one of the main virulence factors of C. albicans. We have previously identified N-[3-(allyloxy)-phenyl]-4-methoxybenzamide (compound 9029936) as the lead compound in a series of small-molecule inhibitors of C. albicans filamentation and characterized its activity both in vitro and in vivo. This compound appears to be a promising candidate for the development of alternative antivirulence strategies for the treatment of C. albicans infections. In this study, we performed RNA sequencing analysis of samples obtained from C. albicans cells grown under filament-inducing conditions in the presence or absence of this compound. Overall, treatment with compound 9029936 resulted in 618 upregulated and 702 downregulated genes. Not surprisingly, some of the most downregulated genes included well-characterized genes associated with filamentation and virulence such as SAP5, ECE1 (candidalysin), and ALS3, as well as genes that impact metal chelation and utilization. Gene ontology analysis revealed an overrepresentation of cell adhesion, iron transport, filamentation, biofilm formation, and pathogenesis processes among the genes downregulated during treatment with this leading compound. Interestingly, the top upregulated genes suggested an enhancement of vesicular transport pathways, particularly those involving SNARE interactions. IMPORTANCE These results from whole-genome transcriptional profiling provide further insights into the biological activity and mode of action of a small-molecule inhibitor of C. albicans filamentation. This information will assist in the development of novel antivirulence strategies against C. albicans infections.
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- 2019
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7. Filamentation Is Associated with Reduced Pathogenicity of Multiple Non-albicans Candida Species
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Mohua Banerjee, Anna L. Lazzell, Jesus A. Romo, Jose L. Lopez-Ribot, and David Kadosh
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candidiasis ,infectious disease ,mycology ,morphology ,pathogenicity ,Candida species ,Microbiology ,QR1-502 - Abstract
ABSTRACT Candidiasis affects a wide variety of immunocompromised and medically compromised patients. Candida albicans, a major human fungal pathogen, accounts for about 50% of all cases, while the remainder are caused by the less pathogenic non-albicans Candida species (NACS). These species are believed to be less pathogenic, in part, because they do not filament as readily or robustly as C. albicans, although definitive evidence is lacking. To address this question, we used strains for two NACS, Candida tropicalis and Candida parapsilosis, which were genetically engineered to constitutively express the key transcriptional regulator UME6 and drive strong filamentation both in vitro and during infection in vivo. Unexpectedly, both strains showed a dramatic reduction in organ fungal burden in response to UME6 expression. Consistent with these findings, we observed that a C. tropicalis hyperfilamentous mutant was significantly reduced and a filamentation-defective mutant was slightly increased for organ fungal burden. Comprehensive immune profiling generally did not reveal any significant changes in the host response to UME6 expression in the NACS that could explain the increased clearance of infection. Interestingly, whole-genome transcriptional profiling indicated that while genes important for filamentation were induced by UME6 expression in C. tropicalis and C. parapsilosis, other genes involved in a variety of processes important for pathogenesis were strongly downregulated. These findings suggest that there are fundamental evolutionary differences in the relationship between morphology and pathogenicity among Candida species and that NACS do not necessarily possess the same virulence properties as C. albicans. IMPORTANCE Many immunocompromised individuals, including HIV/AIDS and cancer patients, are susceptible to candidiasis. About half of all cases are caused by the major fungal pathogen Candida albicans, whereas the remainder are due to less pathogenic non-albicans Candida species (NACS). Generation of filamentous cells represents a major virulence property of C. albicans, and the NACS are believed to be less pathogenic, in part, because they do not filament as well as C. albicans does. To address this question, we determined the pathogenicity of two NACS strains that have been genetically engineered to promote filamentation during infection. Surprisingly, these strains showed a dramatic reduction in pathogenicity. The host immune response did not appear to be affected. However, unlike C. albicans, filamentation of the NACS was associated with downregulation of several genes important for pathogenicity processes. Our results suggest that there are fundamental evolutionary differences in the relationship between filamentation and pathogenesis in NACS compared to C. albicans.
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- 2019
- Full Text
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8. A Re-Evaluation of the Relationship between Morphology and Pathogenicity in Candida Species
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David Kadosh and Vasanthakrishna Mundodi
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candida species ,morphology ,pathogenesis ,yeast ,filaments ,Biology (General) ,QH301-705.5 - Abstract
Many pathogenic Candida species possess the ability to undergo a reversible morphological transition from yeast to filamentous cells. In Candida albicans, the most frequently isolated human fungal pathogen, multiple lines of evidence strongly suggest that this transition is associated with virulence and pathogenicity. While it has generally been assumed that non-albicans Candida species (NACS) are less pathogenic than C. albicans, in part, because they do not filament as well, definitive evidence is lacking. Interestingly, however, a recent study suggests that filamentation of NACS is associated with reduced, rather than increased, pathogenicity. These findings, in turn, challenge conventional views and suggest that there are fundamental evolutionary differences in the morphology−pathogenicity relationship in C. albicans vs. NACS. The findings also raise many new and intriguing questions and open new avenues for future research, which are discussed.
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- 2020
- Full Text
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9. Filament condition-specific response elements control the expression of NRG1 and UME6, key transcriptional regulators of morphology and virulence in Candida albicans.
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Delma S Childers and David Kadosh
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Medicine ,Science - Abstract
Candida albicans is the most frequently isolated human fungal pathogen and can cause a range of mucosal and systemic infections in immunocompromised individuals. Morphogenesis, the ability to undergo a reversible transition from budding yeast to elongated filaments, is an essential virulence trait. The yeast-to-filament transition is associated with expression of genes specifically important for filamentation as well as other virulence-related processes, and is controlled, in part, by the key transcriptional regulators Nrg1 and Ume6. Both of these regulators are themselves controlled at the transcriptional level by filament-inducing environmental cues, although little is known about how this process occurs. In order to address this question and determine whether environmental signals regulate transcription of UME6 and NRG1 via distinct and/or common promoter elements, we performed promoter deletion analyses. Strains bearing promoter deletion constructs were induced to form filaments in YEPD plus 10% serum at 37°C, Spider medium (nitrogen and carbon starvation) and/or Lee's medium pH 6.8 (neutral pH) and reporter gene expression was measured. In the NRG1 promoter we identified several distinct condition-specific response elements for YEPD plus 10% serum at 37°C and Spider medium. In the UME6 promoter we also identified response elements for YEPD plus 10% serum at 37°C. While a few of these elements are distinct, others overlap with those which respond to Lee's pH 6.8 medium. Consistent with UME6 possessing a very long 5' UTR, many response elements in the UME6 promoter are located significantly upstream from the coding sequence. Our data indicate that certain distinct condition-specific elements can control expression of C. albicans UME6 and NRG1 in response to key filament-inducing environmental cues. Because C. albicans encounters a variety of host microenvironments during infection, our results suggest that UME6 and NRG1 expression can be differentially modulated by multiple signaling pathways to control filamentation and virulence in vivo.
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- 2015
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10. Shaping up for battle: morphological control mechanisms in human fungal pathogens.
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David Kadosh
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Published
- 2013
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11. Dispersion as an important step in the Candida albicans biofilm developmental cycle.
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Priya Uppuluri, Ashok K Chaturvedi, Anand Srinivasan, Mohua Banerjee, Anand K Ramasubramaniam, Julia R Köhler, David Kadosh, and Jose L Lopez-Ribot
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
Biofilms are dynamic microbial communities in which transitions between planktonic and sessile modes of growth occur interchangeably in response to different environmental cues. In the last decade, early events associated with C. albicans biofilm formation have received considerable attention. However, very little is known about C. albicans biofilm dispersion or the mechanisms and signals that trigger it. This is important because it is precisely C. albicans cells dispersed from biofilms that are the main culprits associated with candidemia and establishment of disseminated invasive disease, two of the gravest forms of candidiasis. Using a simple flow biofilm model recently developed by our group, we have performed initial investigations into the phenomenon of C. albicans biofilm dispersion, as well as the phenotypic characteristics associated with dispersed cells. Our results indicate that C. albicans biofilm dispersion is dependent on growing conditions, including carbon source and pH of the media used for biofilm development. C. albicans dispersed cells are mostly in the yeast form and display distinct phenotypic properties compared to their planktonic counterparts, including enhanced adherence, filamentation, biofilm formation and, perhaps most importantly, increased pathogenicity in a murine model of hematogenously disseminated candidiasis, thus indicating that dispersed cells are armed with a complete arsenal of "virulence factors" important for seeding and establishing new foci of infection. In addition, utilizing genetically engineered strains of C. albicans (tetO-UME6 and tetO-PES1) we demonstrate that C. albicans biofilm dispersion can be regulated by manipulating levels of expression of these key genes, further supporting the evidence for a strong link between biofilms and morphogenetic conversions at different stages of the C. albicans biofilm developmental cycle. Overall, our results offer novel and important insight into the phenomenon of C. albicans biofilm dispersion, a key part of the biofilm developmental cycle, and provide the basis for its more detailed analysis.
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- 2010
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12. Post-transcriptional control of antifungal resistance in human fungal pathogens
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Cheshta Sharma and David Kadosh
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General Medicine ,Applied Microbiology and Biotechnology ,Microbiology - Abstract
Global estimates suggest that over 300 million individuals of all ages are affected by serious fungal infections every year, culminating in about 1.7 million deaths. The societal and economic burden on the public health sector due to opportunistic fungal pathogens is quite significant, especially among immunocompromised patients. Despite the high clinical significance of these infectious agents, treatment options are limited with only three major classes of antifungal drugs approved for use. Clinical management of fungal diseases is further compromised by the emergence of antifungal resistant strains. Transcriptional and genetic mechanisms that control drug resistance in human fungal pathogens are well-studied and include drug target alteration, upregulation of drug efflux pumps as well as changes in drug affinity and abundance of target proteins. In this review, we highlight several recently discovered novel post-transcriptional mechanisms that control antifungal resistance, which involve regulation at the translational, post-translational, epigenetic, and mRNA stability levels. The discovery of many of these novel mechanisms has opened new avenues for the development of more effective antifungal treatment strategies and new insights, perspectives, and future directions that will facilitate this process are discussed.
- Published
- 2022
13. Endo-hepatology: An emerging field
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Michael Ma, David Kadosh, Daniel Hogan, Kana Chin, Arun Swaminath, and Alisha Menon
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Endoscopic ultrasound ,medicine.medical_specialty ,Hepatology ,medicine.diagnostic_test ,business.industry ,Portal venous pressure ,Minireviews ,Liver biopsy ,Gastric varices ,medicine.disease ,Therapeutic endoscopic ultrasound ,digestive system diseases ,Endoscopy ,Liver disease ,Internal medicine ,medicine ,Paracentesis ,Radiology ,business - Abstract
Gastroenterologists have long been spearheading the care of patients with various forms of liver disease. The diagnosis and management of liver disease has traditionally been a combination of clinical, laboratory, and imaging findings coupled with percutaneous and intravascular procedures with endoscopy largely limited to screening for and therapy of esophageal and gastric varices. As the applications of diagnostic and therapeutic endoscopic ultrasound (EUS) have evolved, it has found a particular niche within hepatology now coined endo-hepatology. Here we discuss several EUS-guided procedures such as liver biopsy, shear wave elastography, direct portal pressure measurement, paracentesis, as well as EUS-guided therapies for variceal hemorrhage.
- Published
- 2021
14. Brief Report: Chylothorax and Chylous Ascites During RET Tyrosine Kinase Inhibitor Therapy
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Or Kalchiem-Dekel, Christina J. Falcon, Christine M. Bestvina, Dazhi Liu, Lauren A. Kaplanis, Clare Wilhelm, Jordan Eichholz, Guilherme Harada, Lori J. Wirth, Subba R. Digumarthy, Robert P. Lee, David Kadosh, Robin B. Mendelsohn, Jessica Donington, Justin F. Gainor, Alexander Drilon, and Jessica J. Lin
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Pulmonary and Respiratory Medicine ,Lung Neoplasms ,Oncology ,Proto-Oncogene Proteins c-ret ,Humans ,Chylothorax ,Chylous Ascites ,Protein Kinase Inhibitors ,Retrospective Studies - Abstract
Spontaneous chylous effusions are rare; however, they have been observed by independent investigators in patients treated with RET tyrosine kinase inhibitors (TKIs).This multicenter, retrospective study evaluated the frequency of chylous effusions in patients treated with RET TKIs. Clinicopathologic features and management of patients with chylous effusions were evaluated.A pan-cancer cohort of 7517 patients treated with one or more multikinase inhibitor or selective RET TKI and a selective TKI cohort of 96 patients treated with selpercatinib or pralsetinib were analyzed. Chylous effusions were most common with selpercatinib (7%), followed by agerafenib (4%), cabozantinib (0.3%), and lenvatinib (0.02%); none were observed with pralsetinib. Overall, 12 patients had chylothorax, five had chylous ascites, and five had both. Time from TKI initiation to diagnosis ranged from 0.5 to 50 months. Median fluid triglyceride level was lower in chylothoraces than in chylous ascites (397 mg/dL [interquartile range: 304-4000] versus 3786 mg/dL [interquartile range: 842-6596], p = 0.035). Malignant cells were present in 13% (3 of 22) of effusions. Chyle leak was not identified by lymphangiography. After initial drainage, 76% of patients with chylothorax and 80% with chylous ascites required additional interventions. Selpercatinib dose reduction and discontinuation rates in those with chylous effusions were 47% and 0%, respectively. Median time from diagnosis to disease progression was not reached (95% confidence interval: 14.5-undefined); median time from diagnosis to TKI discontinuation was 11.4 months (95% confidence interval: 8.2-14.9).Chylous effusions can emerge during treatment with selected RET TKIs. Recognition of this side effect is key to prevent potential misattribution of worsening effusions to progressive malignancy.
- Published
- 2022
15. Regulatory mechanisms controlling morphology and pathogenesis in Candida albicans
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David Kadosh
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Microbiology (medical) ,Hyphae ,Virulence ,Microbiology ,Article ,03 medical and health sciences ,Gene Expression Regulation, Fungal ,Candida albicans ,Transcriptional regulation ,Animals ,Humans ,Transcription factor ,030304 developmental biology ,Genetics ,0303 health sciences ,biology ,030306 microbiology ,Candidiasis ,biology.organism_classification ,Corpus albicans ,Review article ,Infectious Diseases ,Signal transduction ,Functional genomics ,Signal Transduction - Abstract
Candida albicans, a major human fungal pathogen, can cause a wide variety of both mucosal and systemic infections, particularly in immunocompromised individuals. Multiple lines of evidence suggest a strong association between virulence and the ability of C. albicans to undergo a reversible morphological transition from yeast to filamentous cells in response to host environmental cues. Most previous studies on mechanisms important for controlling the C. albicans morphological transition have focused on signaling pathways and sequence-specific transcription factors. However, in recent years a variety of novel mechanisms have been reported, including those involving global transcriptional regulation and translational control. A large-scale functional genomics screen has also revealed new roles in filamentation for certain key biosynthesis pathways. This review article will highlight several of these exciting recent discoveries and discuss how they are relevant to the development of novel antifungal strategies. Ultimately, components of mechanisms that control C. albicans morphogenesis and pathogenicity could potentially serve as viable antifungal targets.
- Published
- 2019
16. Rapid Proliferation Compensates for Defective Filamentation in Candida albicans Pathogenesis
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David Kadosh
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Microbiology (medical) ,Neutrophils ,Mutant ,Metabolic adaptation ,Hyphae ,Virulence ,Biology ,Microbiology ,Article ,Pathogenesis ,Fungal Proteins ,Filamentation ,Virology ,Gene Expression Regulation, Fungal ,Candida albicans ,Animals ,Humans ,Cellular microbiology ,Cell Proliferation ,Mice, Inbred BALB C ,Macrophages ,Candidiasis ,biology.organism_classification ,Corpus albicans ,Cell biology ,Disease Models, Animal ,Infectious Diseases ,Mutation ,Fungal pathogenesis ,Cytokines ,Female ,Pathogens ,Cell Division - Abstract
The ability of the fungal pathogen Candida albicans to undergo a yeast-to-hypha transition is believed to be a key virulence factor, as filaments mediate tissue damage. Here, we show that virulence is not necessarily reduced in filament-deficient strains, and the results depend on the infection model used. We generate a filament-deficient strain by deletion or repression of EED1 (known to be required for maintenance of hyphal growth). Consistent with previous studies, the strain is attenuated in damaging epithelial cells and macrophages in vitro and in a mouse model of intraperitoneal infection. However, in a mouse model of systemic infection, the strain is as virulent as the wild type when mice are challenged with intermediate infectious doses, and even more virulent when using low infectious doses. Retained virulence is associated with rapid yeast proliferation, likely the result of metabolic adaptation and improved fitness, leading to high organ fungal loads. Analyses of cytokine responses in vitro and in vivo, as well as systemic infections in immunosuppressed mice, suggest that differences in immunopathology contribute to some extent to retained virulence of the filament-deficient mutant. Our findings challenge the long-standing hypothesis that hyphae are essential for pathogenesis of systemic candidiasis by C. albicans., The ability of the fungal pathogen Candida albicans to undergo yeast-to-hypha transition is believed to be a key virulence factor. Here, Dunker et al. show that a filament-deficient strain is attenuated in a mouse model of intraperitoneal infection, but remains virulent in a mouse model of systemic candidiasis.
- Published
- 2021
17. Erratum to: Global translational landscape of the Candida albicans morphological transition
- Author
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Andrew Smith, Vasanthakrishna Mundodi, David Kadosh, and Saket Choudhary
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AcademicSubjects/SCI01140 ,biology ,Transition (genetics) ,Virulence ,AcademicSubjects/SCI00010 ,Computational biology ,QH426-470 ,biology.organism_classification ,AcademicSubjects/SCI01180 ,Fungal Proteins ,Gene Expression Regulation, Fungal ,Protein Biosynthesis ,Candida albicans ,Genetics ,Morphogenesis ,AcademicSubjects/SCI00960 ,Erratum ,Molecular Biology ,Genetics (clinical) - Abstract
Candida albicans, a major human fungal pathogen associated with high mortality and/or morbidity rates in a wide variety of immunocompromised individuals, undergoes a reversible morphological transition from yeast to filamentous cells that is required for virulence. While previous studies have identified and characterized global transcriptional mechanisms important for driving this transition, as well as other virulence properties, in C. albicans and other pathogens, considerably little is known about the role of genome-wide translational mechanisms. Using ribosome profiling, we report the first global translational profile associated with C. albicans morphogenesis. Strikingly, many genes involved in pathogenesis, filamentation, and the response to stress show reduced translational efficiency (TE). Several of these genes are known to be strongly induced at the transcriptional level, suggesting that a translational fine-tuning mechanism is in place. We also identify potential upstream open reading frames (uORFs), associated with genes involved in pathogenesis, and novel ORFs, several of which show altered TE during filamentation. Using a novel bioinformatics method for global analysis of ribosome pausing that will be applicable to a wide variety of genetic systems, we demonstrate an enrichment of ribosome pausing sites in C. albicans genes associated with protein synthesis and cell wall functions. Altogether, our results suggest that the C. albicans morphological transition, and most likely additional virulence processes in fungal pathogens, is associated with widespread global alterations in TE that do not simply reflect changes in transcript levels. These alterations affect the expression of many genes associated with processes essential for virulence and pathogenesis.
- Published
- 2021
18. Global translational landscape of the Candida albicans morphological transition
- Author
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David Kadosh, Saket Choudhary, Andrew D. Smith, and Vasanthakrishna Mundodi
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AcademicSubjects/SCI01140 ,Translational efficiency ,AcademicSubjects/SCI00010 ,Virulence ,AcademicSubjects/SCI01180 ,Ribosome ,03 medical and health sciences ,0302 clinical medicine ,Translational regulation ,Candida albicans ,morphology ,Genetics ,Ribosome profiling ,Molecular Biology ,Gene ,Genetics (clinical) ,030304 developmental biology ,ribosome profiling ,0303 health sciences ,biology ,fungal pathogenesis ,biology.organism_classification ,Corpus albicans ,translational regulation ,Fungal Genetics and Genomics ,AcademicSubjects/SCI00960 ,030217 neurology & neurosurgery - Abstract
Candida albicans, a major human fungal pathogen associated with high mortality and/or morbidity rates in a wide variety of immunocompromised individuals, undergoes a reversible morphological transition from yeast to filamentous cells that is required for virulence. While previous studies have identified and characterized global transcriptional mechanisms important for driving this transition, as well as other virulence properties, in C. albicans and other pathogens, considerably little is known about the role of genome-wide translational mechanisms. Using ribosome profiling, we report the first global translational profile associated with C. albicans morphogenesis. Strikingly, many genes involved in pathogenesis, filamentation, and the response to stress show reduced translational efficiency (TE). Several of these genes are known to be strongly induced at the transcriptional level, suggesting that a translational fine-tuning mechanism is in place. We also identify potential upstream open reading frames (uORFs), associated with genes involved in pathogenesis, and novel ORFs, several of which show altered TE during filamentation. Using a novel bioinformatics method for global analysis of ribosome pausing that will be applicable to a wide variety of genetic systems, we demonstrate an enrichment of ribosome pausing sites in C. albicans genes associated with protein synthesis and cell wall functions. Altogether, our results suggest that the C. albicans morphological transition, and most likely additional virulence processes in fungal pathogens, is associated with widespread global alterations in TE that do not simply reflect changes in transcript levels. These alterations affect the expression of many genes associated with processes essential for virulence and pathogenesis.
- Published
- 2020
19. A Re-Evaluation of the Relationship between Morphology and Pathogenicity in
- Author
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David, Kadosh and Vasanthakrishna, Mundodi
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pathogenesis ,morphology ,Candida species ,Review ,yeast ,filaments - Abstract
Many pathogenic Candida species possess the ability to undergo a reversible morphological transition from yeast to filamentous cells. In Candida albicans, the most frequently isolated human fungal pathogen, multiple lines of evidence strongly suggest that this transition is associated with virulence and pathogenicity. While it has generally been assumed that non-albicans Candida species (NACS) are less pathogenic than C. albicans, in part, because they do not filament as well, definitive evidence is lacking. Interestingly, however, a recent study suggests that filamentation of NACS is associated with reduced, rather than increased, pathogenicity. These findings, in turn, challenge conventional views and suggest that there are fundamental evolutionary differences in the morphology–pathogenicity relationship in C. albicans vs. NACS. The findings also raise many new and intriguing questions and open new avenues for future research, which are discussed.
- Published
- 2019
20. S5 Prevalence and Growth Rates of Pancreatic Cysts in Patients With Diabetes Mellitus
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David P. Robbins, Sohil Khurana, David Kadosh, and Benjamin Ascherman
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medicine.medical_specialty ,Hepatology ,business.industry ,Internal medicine ,Diabetes mellitus ,Gastroenterology ,medicine ,In patient ,Pancreatic cysts ,business ,medicine.disease - Published
- 2021
21. Dynamics of Mixed–Candida Species Biofilms in Response to Antifungals
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Geethanjali Vipulanandan, X. Li, Monica L. Herrera, Brian L. Wickes, Nathan P. Wiederhold, J. Mintz, and David Kadosh
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0301 basic medicine ,Antifungal Agents ,030106 microbiology ,Candida glabrata ,Biology ,Polymerase Chain Reaction ,Microbiology ,Candida tropicalis ,03 medical and health sciences ,chemistry.chemical_compound ,Candidiasis, Oral ,Amphotericin B ,medicine ,Humans ,Candida albicans ,Fluconazole ,General Dentistry ,Candida ,Coinfection ,Biofilm ,Research Reports ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Corpus albicans ,chemistry ,Biofilms ,Caspofungin ,medicine.drug - Abstract
Oral infections caused by Candida species, the most commonly isolated human fungal pathogen, are frequently associated with biofilms. Although Candida albicans is the predominant organism found in patients with oral thrush, a biofilm infection, there is an increasing incidence of oral colonization and infections caused by non- albicans Candida species, including C. glabrata, C. dubliniensis, and C. tropicalis, which are frequently more resistant to antifungal treatment. While single-species Candida biofilms have been well studied, considerably less is known about the dynamics of mixed– Candida species biofilms and how these dynamics are altered by antifungal treatment. To address these questions, we developed a quantitative polymerase chain reaction–based approach to determine the precise species composition of mixed– Candida species biofilms formed by clinical isolates and laboratory strains in the presence and absence of clinically relevant concentrations of 3 commonly used antifungals: fluconazole, caspofungin, and amphotericin B. In monospecies biofilms, fluconazole exposure favored growth of C. glabrata and C. tropicalis, while caspofungin generally favored significant growth of all species to a varying degree. Fluconazole was not effective against preformed mixed– Candida species biofilms while amphotericin B was potent. As a general trend, in mixed– Candida species biofilms, C. albicans lost dominance in the presence of antifungals. Interestingly, presence in mixed versus monospecies biofilms reduced susceptibility to amphotericin B for C. tropicalis and C. glabrata. Overall, our data suggest that antifungal treatment favors the growth of specific non- albicans Candida species in mixed– Candida species biofilms.
- Published
- 2017
22. S3063 Air on the Side of Caution: A Case of Gastric Emphysema
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David Kadosh, Anjali Mone, Petros C. Benias, Vinayak Shenoy, Arun Swaminath, Megan C. Buckley, and Daniel F. Hogan
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Pancolitis ,medicine.medical_specialty ,Hepatology ,Diabetic ketoacidosis ,business.industry ,Stomach ,Gastroenterology ,Abdominal distension ,medicine.disease ,Curvatures of the stomach ,medicine.anatomical_structure ,Polyuria ,Internal medicine ,medicine ,Abdomen ,Gastroparesis ,medicine.symptom ,business - Abstract
INTRODUCTION: Gastric pneumatosis, the presence of intramural gas in the stomach, is a rare but alarming radiographic finding Gastric emphysema (GE) and emphysematous gastritis remain the two most important differential diagnoses of gastric pneumatosis, both differing vastly in their management and prognosis Due to these differences, it is essential to reach an accurate clinical diagnosis early Here we describe the case of a young male with GE due to severe gastroparesis from uncontrolled diabetes CASE DESCRIPTION/METHODS: A 36 year-old COVID-19 positive male with a history of uncontrolled Type 1 Diabetes, Hepatitis C, and Hirschsprung disease presented with generalized weakness, fatigue, polyuria, and polydipsia for two days Laboratory work revealed diabetic ketoacidosis which improved with intravenous (IV) fluids and insulin However, his course was complicated by persistent nausea, inability to tolerate oral diet, abdominal distension, and worsening leukocytosis Computed Tomography (CT) of the abdomen demonstrated a markedly distended stomach containing air and undigested food, air in the gastric wall, gas and thrombus in the left portal vein, and pancolitis He remained afebrile, hemodynamically stable with negative blood cultures and was initially treated conservatively with fluconazole and piperacillin-tazobactam, nasogastric suction and supportive care Repeat CT of the abdomen two days later showed improvement in gastric pneumatosis and portal venous gas Subsequent EGD revealed retained gastric contents, an open pylorus, and large necroticappearing ulcerations extending most of the lesser curvature and fundus of the stomach These findings were consistent with GE, likely a chronic issue from longstanding gastroparesis However microvascular thrombi related to COVID remain on the differential as there is a known propensity for a procoagulable state in these patients DISCUSSION: GE can be due to an increase in intraluminal pressure or mucosal injury that leads to intramural gas formation In our patient, we suspect his GE was due to uncontrolled diabetes, causing severe gastroparesis and gastric wall distention GE is benign and managed with observation and conservative treatment Comparatively emphysematous gastritis is often associated with systemic toxicity, is potentially fatal, and often requires more aggressive therapy including surgery As in the majority of GE cases, our patient's symptoms improved with conservative treatment and follow-up imaging revealed interval improvement
- Published
- 2020
23. Effect of Antifungal Treatment in a Diet-Based Murine Model of Disseminated Candidiasis Acquired via the Gastrointestinal Tract
- Author
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Marcos Olivo, Rosie Bocanegra, Thomas F. Patterson, David Kadosh, Nathan P. Wiederhold, Laura K. Najvar, and William R. Kirkpatrick
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Antifungal Agents ,Prednisolone ,medicine.medical_treatment ,030106 microbiology ,Colony Count, Microbial ,Clinical Therapeutics ,Organ transplantation ,Echinocandins ,Immunocompromised Host ,Lipopeptides ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Caspofungin ,Candida albicans ,medicine ,Animals ,Humans ,Pharmacology (medical) ,Cyclophosphamide ,Fluconazole ,Pharmacology ,Mice, Inbred BALB C ,Gastrointestinal tract ,biology ,business.industry ,Candidiasis ,Immunosuppression ,biology.organism_classification ,Disseminated Candidiasis ,Survival Analysis ,Corpus albicans ,Diet ,Gastrointestinal Tract ,Disease Models, Animal ,030104 developmental biology ,Infectious Diseases ,chemistry ,Immunology ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
Candida albicans , normally found as a commensal in the gut, is a major human fungal pathogen responsible for both mucosal and systemic infections in a wide variety of immunocompromised individuals, including cancer patients and organ transplant recipients. The gastrointestinal tract represents a major portal of entry for the establishment of disseminated candidiasis in many of these individuals. Here we report the development of a diet-based mouse model for disseminated candidiasis acquired via the gastrointestinal tract. Using this model, as well as an appropriate immunosuppression regimen, we demonstrate that dissemination of C. albicans from the gastrointestinal tract can result in mortality within 30 days postinfection. We also show a significant increase in fungal burden in systemic organs, but not gastrointestinal tract organs, upon immunosuppression. Importantly, we demonstrate that the administration of two widely used antifungals, fluconazole and caspofungin, either pre- or postimmunosuppression, significantly reduces fungal burdens. This model should prove to be of significant value for testing the ability of both established and experimental therapeutics to inhibit C. albicans dissemination from the gastrointestinal tract in an immunocompromised host as well as the subsequent mortality that can result from disseminated candidiasis.
- Published
- 2016
24. Global Transcriptomic Analysis of the <named-content content-type='genus-species'>Candida albicans</named-content> Response to Treatment with a Novel Inhibitor of Filamentation
- Author
-
Hong Cai, Jose L. Lopez-Ribot, Hao Zhang, Stephen P. Saville, Yufeng Wang, Julia Koehler, Jesus A. Romo, and David Kadosh
- Subjects
Molecular Biology and Physiology ,Antifungal Agents ,Virulence Factors ,lcsh:QR1-502 ,Hyphae ,Virulence ,Down-Regulation ,Microbiology ,lcsh:Microbiology ,Transcriptome ,03 medical and health sciences ,Filamentation ,Gene Expression Regulation, Fungal ,Candida albicans ,antivirulence ,Molecular Biology ,Gene ,030304 developmental biology ,0303 health sciences ,biology ,030306 microbiology ,Gene Expression Profiling ,Biofilm ,biology.organism_classification ,Editor's Pick ,candidiasis ,Corpus albicans ,QR1-502 ,Up-Regulation ,filamentation ,Biofilms ,Genome, Fungal ,Candidalysin ,Research Article - Abstract
These results from whole-genome transcriptional profiling provide further insights into the biological activity and mode of action of a small-molecule inhibitor of C. albicans filamentation. This information will assist in the development of novel antivirulence strategies against C. albicans infections., The opportunistic pathogenic fungus Candida albicans can cause devastating infections in immunocompromised patients. Its ability to undergo a morphogenetic transition from yeast to filamentous forms allows it to penetrate tissues and damage tissues, and the expression of genes associated with a number of pathogenetic mechanisms is also coordinately regulated with the yeast-to-hypha conversion. Therefore, it is widely considered that filamentation represents one of the main virulence factors of C. albicans. We have previously identified N-[3-(allyloxy)-phenyl]-4-methoxybenzamide (compound 9029936) as the lead compound in a series of small-molecule inhibitors of C. albicans filamentation and characterized its activity both in vitro and in vivo. This compound appears to be a promising candidate for the development of alternative antivirulence strategies for the treatment of C. albicans infections. In this study, we performed RNA sequencing analysis of samples obtained from C. albicans cells grown under filament-inducing conditions in the presence or absence of this compound. Overall, treatment with compound 9029936 resulted in 618 upregulated and 702 downregulated genes. Not surprisingly, some of the most downregulated genes included well-characterized genes associated with filamentation and virulence such as SAP5, ECE1 (candidalysin), and ALS3, as well as genes that impact metal chelation and utilization. Gene ontology analysis revealed an overrepresentation of cell adhesion, iron transport, filamentation, biofilm formation, and pathogenesis processes among the genes downregulated during treatment with this leading compound. Interestingly, the top upregulated genes suggested an enhancement of vesicular transport pathways, particularly those involving SNARE interactions. IMPORTANCE These results from whole-genome transcriptional profiling provide further insights into the biological activity and mode of action of a small-molecule inhibitor of C. albicans filamentation. This information will assist in the development of novel antivirulence strategies against C. albicans infections.
- Published
- 2019
25. Control of Candida albicans morphology and pathogenicity by post-transcriptional mechanisms
- Author
-
David Kadosh
- Subjects
0301 basic medicine ,Antifungal Agents ,Transcription, Genetic ,RNA Stability ,030106 microbiology ,Morphogenesis ,Virulence ,Morphology (biology) ,Article ,Microbiology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Candida albicans ,Molecular Biology ,Pharmacology ,biology ,Translation (biology) ,Cell Biology ,Fungal pathogen ,Pathogenicity ,biology.organism_classification ,Corpus albicans ,Alternative Splicing ,Protein Biosynthesis ,Molecular Medicine - Abstract
Candida albicans is a major human fungal pathogen responsible for both systemic and mucosal infections in a wide variety of immunocompromised individuals. Because the ability of C. albicans to undergo a reversible morphological transition from yeast to filaments is important for virulence, significant research efforts have focused on mechanisms that control this transition. While transcriptional and post-translational mechanisms have been well-studied, considerably less is known about the role of post-transcriptional mechanisms. However, in recent years several discoveries have begun to shed light on this important, but understudied, area. Here, I will review a variety of post-transcriptional mechanisms that have recently been shown to control C. albicans morphology, virulence and/or virulence-related processes, including those involving alternative transcript localization, mRNA stability and translation. I will also discuss the role that these mechanisms play in other pathogens as well as the potential they may hold to serve as targets for new antifungal strategies. Ultimately, gaining a better understanding of C. albicans post-transcriptional mechanisms will significantly improve our knowledge of how morphogenesis and virulence are controlled in fungal pathogens and open new avenues for the development of novel and more effective antifungals.
- Published
- 2016
26. Regulatory roles of phosphorylation in model and pathogenic fungi
- Author
-
Mohammad T. Albataineh and David Kadosh
- Subjects
0301 basic medicine ,Antifungal ,Proteome ,medicine.drug_class ,030106 microbiology ,Review Article ,Computational biology ,Biology ,Bioinformatics ,human fungal pathogens ,Fungal Proteins ,03 medical and health sciences ,medicine ,Humans ,phosphatases ,phosphorylation ,Kinase ,Phosphotransferases ,phosphoproteome ,Fungi ,General Medicine ,Phosphoproteins ,Phosphoric Monoester Hydrolases ,Pathogenic organism ,kinases ,Infectious Diseases ,Mycoses ,Phosphorylation - Abstract
Over the past 20 years, considerable advances have been made toward our understanding of how post-translational modifications affect a wide variety of biological processes, including morphology and virulence, in medically important fungi. Phosphorylation stands out as a key molecular switch and regulatory modification that plays a critical role in controlling these processes. In this article, we first provide a comprehensive and up-to-date overview of the regulatory roles that both Ser/Thr and non-Ser/Thr kinases and phosphatases play in model and pathogenic fungi. Next, we discuss the impact of current global approaches that are being used to define the complete set of phosphorylation targets (phosphoproteome) in medically important fungi. Finally, we provide new insights and perspectives into the potential use of key regulatory kinases and phosphatases as targets for the development of novel and more effective antifungal strategies.
- Published
- 2015
27. S1244 Following the Paper Trail: The Perils of Self-Reported Colonoscopy Documentation in the Outpatient Office
- Author
-
David Kadosh, Jeffrey Shenfeld, Rebecca Mazurkiewicz, and David B. Huang
- Subjects
Documentation ,Hepatology ,medicine.diagnostic_test ,business.industry ,Gastroenterology ,medicine ,Colonoscopy ,Medical emergency ,medicine.disease ,business - Published
- 2020
28. S1221 Bundle Payments for Care Improvement in Patients With Gastrointestinal Hemorrhage: Reducing Costs and Readmission Rates at a Single Hospital Center
- Author
-
Nazish Ilyas, Vinayak Shenoy, Connie Park, David Kadosh, Elena Ivanina, and Isabella Bergagnini
- Subjects
medicine.medical_specialty ,Hepatology ,business.industry ,media_common.quotation_subject ,Bundle ,Emergency medicine ,Gastroenterology ,Medicine ,In patient ,Center (algebra and category theory) ,business ,Payment ,media_common - Published
- 2020
29. S1695 Acute Large Bowel Ischemia After a Bupropion Overdose
- Author
-
Berta Shamuilova, Elena Ivanina, David Kadosh, and Daniel Hogan
- Subjects
Bupropion ,Hepatology ,Bowel ischemia ,business.industry ,Anesthesia ,Gastroenterology ,Medicine ,business ,medicine.drug - Published
- 2020
30. 2244 Getting to the Root of the Matter: A Case of Valerian Root-Induced Hepatitis and Pancreatitis
- Author
-
Andrew Nguyen, Isabella Bergagnini, Arun Swaminath, and David Kadosh
- Subjects
Hepatitis ,medicine.medical_specialty ,Root (linguistics) ,Hepatology ,business.industry ,Internal medicine ,Valerian Root ,Gastroenterology ,medicine ,Pancreatitis ,medicine.disease ,business - Published
- 2019
31. Ppg1, a PP2A-Type Protein Phosphatase, Controls Filament Extension and Virulence in Candida albicans
- Author
-
Mohammad T. Albataineh, David Kadosh, Jose L. Lopez-Ribot, and Anna L. Lazzell
- Subjects
Neuregulin-1 ,Phosphatase ,Down-Regulation ,Gene Expression ,Virulence ,macromolecular substances ,Microbiology ,Fungal Proteins ,Catalytic Domain ,Gene Expression Regulation, Fungal ,Candida albicans ,medicine ,Animals ,Protein Phosphatase 2 ,Molecular Biology ,Mice, Inbred BALB C ,Fungal protein ,biology ,Candidiasis ,Articles ,General Medicine ,Protein phosphatase 2 ,biology.organism_classification ,medicine.disease ,Corpus albicans ,Cell biology ,Female ,Systemic candidiasis ,Signal transduction ,Signal Transduction - Abstract
Candida albicans , a major human fungal pathogen, is the primary cause of invasive candidiasis in a wide array of immunocompromised patients. C. albicans virulence requires the ability to undergo a reversible morphological transition from yeast to filaments in response to a variety of host environmental cues. These cues are sensed by the pathogen and activate multiple signal transduction pathways to induce filamentation. Reversible phosphorylation events are critical for regulation of many of these pathways. While a variety of protein kinases are known to function as components of C. albicans filamentous growth signal transduction pathways, considerably little is known about the role of phosphatases. Here we demonstrate that PPG1 , encoding a putative type 2A-related protein phosphatase, is important for C. albicans filament extension, invasion, and virulence in a mouse model of systemic candidiasis. PPG1 is also important for downregulation of NRG1 , a key transcriptional repressor of C. albicans filamentous growth, and is shown to affect the expression of several filament-specific target genes. An epistasis analysis suggests that PPG1 controls C. albicans filamentation via the cyclic AMP-protein kinase A (cAMP-PKA) signaling pathway. We demonstrate that Ppg1 possesses phosphatase activity and that a ppg1 catalytic mutant shows nearly equivalent filamentation, invasion, and virulence defects compared to those of a ppg1 Δ/Δ strain. Overall, our results suggest that phosphatases, such as Ppg1, play critical roles in controlling and fine-tuning C. albicans filament extension and virulence as well as signal transduction pathways, transcriptional regulators, and target genes associated with these processes.
- Published
- 2014
32. An Efficient, Rapid, and Recyclable System for CRISPR-Mediated Genome Editing in Candida albicans
- Author
-
Namkha Nguyen, Morgan M. F. Quail, Aaron D. Hernday, Aaron P. Mitchell, Karl Kuchler, David Kadosh, and Brendan Cormack
- Subjects
0301 basic medicine ,lcsh:QR1-502 ,Locus (genetics) ,Biology ,gene addback ,2.2 Factors relating to physical environment ,Microbiology ,Genome ,lcsh:Microbiology ,gene knockout ,03 medical and health sciences ,0302 clinical medicine ,Genome editing ,Candida albicans ,Genetics ,genome editing ,2.2 Factors relating to the physical environment ,CRISPR ,genetics ,Cas9 ,Molecular Biology ,Gene ,markerless ,Selectable marker ,Gene knockout ,Human Genome ,QR1-502 ,Infectious Diseases ,030104 developmental biology ,Infection ,030217 neurology & neurosurgery ,Biotechnology - Abstract
Candida albicans is the most common fungal pathogen of humans. Historically, molecular genetic analysis of this important pathogen has been hampered by the lack of stable plasmids or meiotic cell division, limited selectable markers, and inefficient methods for generating gene knockouts. The recent development of clustered regularly interspaced short palindromic repeat(s) (CRISPR)-based tools for use with C.albicans has opened the door to more efficient genome editing; however, previously reported systems have specific limitations. We report the development of an optimized CRISPR-based genome editing system for use with C.albicans. Our system is highly efficient, does not require molecular cloning, does not leave permanent markers in the genome, and supports rapid, precise genome editing in C.albicans. We also demonstrate the utility of our system for generating two independent homozygous gene knockouts in a single transformation and present a method for generating homozygous wild-type gene addbacks at the native locus. Furthermore, each step of our protocol is compatible with high-throughput strain engineering approaches, thus opening the door to the generation of a complete C.albicans gene knockout library. IMPORTANCECandida albicans is the major fungal pathogen of humans and is the subject of intense biomedical and discovery research. Until recently, the pace of research in this field has been hampered by the lack of efficient methods for genome editing. We report the development of a highly efficient and flexible genome editing system for use with C.albicans. This system improves upon previously published C.albicans CRISPR systems and enables rapid, precise genome editing without the use of permanent markers. This new tool kit promises to expedite the pace of research on this important fungal pathogen.
- Published
- 2017
33. Morphogenesis in C. albicans
- Author
-
David Kadosh
- Subjects
0301 basic medicine ,Hyphal growth ,Genetics ,Candida glabrata ,Morphogenesis ,Virulence ,Biology ,medicine.disease ,biology.organism_classification ,Corpus albicans ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine ,Systemic candidiasis ,Candida albicans ,Pathogen ,030217 neurology & neurosurgery - Abstract
Many human fungal pathogens possess the ability to grow in a variety of different morphologies and Candida albicans is no exception. In dimorphic fungal pathogens, such as Histoplasma capsulatum and Coccidioides immitis, morphological transitions are critical for virulence (Klein and Tebbets, Curr Opin Microbiol, 10(4):314–319, 2007). However, other pathogens, such as Candida glabrata, rarely alter their morphology and the ability to change shape appears to play little, if any, role in their pathogenicity (Do Carmo-Sousa 1969; Fidel et al., Clin Microbiol Rev 12:80–96, 1999; Csank and Haynes, FEMS Microbiol Lett 189(1):115–120, 2000). The ability of Candida albicans to undergo a reversible morphological transition from yeast to filamentous form represents a fundamental aspect of this pathogen’s biology. This transition is typically correlated with pathogenicity and important for a wide variety of virulence-related processes (Lo et al., Cell 90(5):939–949, 1997; Braun and Johnson, Science 277(5322):105–109, 1997; Braun et al., Genetics 156(1):31–44, 2000; Saville et al., Eukaryot Cell 2(5):1053–1060, 2003; Carlisle et al., Proc Natl Acad Sci USA 106:599–604, 2009; Kumamoto and Vinces, Proc Natl Acad Sci USA 102(15):5576–5581, 2005; Korting et al., J Med Microbiol 52(Pt 8):623–632, 2003; Gow et al., Curr opin microbiol 5(4):366–371, 2002). As a consequence, a significant amount of research, mostly over the past 25 years, has focused on signaling pathways, regulators, and mechanisms that are involved in controlling the C. albicans morphological transition. In this chapter we will first describe the major C. albicans morphologies and the relationship between C. albicans morphology and virulence. Next, we will discuss the mechanics of hyphal growth as well as a variety of signaling pathways, regulators, and mechanisms important for regulating C. albicans morphogenesis in response to host environmental cues. Finally, we will discuss recent insights gained from genome-wide studies of the C. albicans morphological transition as well as the potential that this transition may hold to serve as a target for new therapeutic strategies.
- Published
- 2017
34. A 5′ UTR-mediated translational efficiency mechanism inhibits theCandida albicansmorphological transition
- Author
-
David Kadosh, Vasanthakrishna Mundodi, Mohua Banerjee, and Delma S. Childers
- Subjects
Regulation of gene expression ,Hyphal growth ,Untranslated region ,Genetics ,Translational efficiency ,Five prime untranslated region ,biology ,Transcriptional regulation ,Virulence ,Candida albicans ,biology.organism_classification ,Molecular Biology ,Microbiology - Abstract
Summary While virulence properties of Candida albicans, the most commonly isolated human fungal pathogen, are controlled by transcriptional and post-translational mechanisms, considerably little is known about the role of post-transcriptional, and particularly translational, mechanisms. We demonstrate that UME6, a key filament-specific transcriptional regulator whose expression level is sufficient to determine C. albicans morphology and promote virulence, has one of the longest 5′ untranslated regions (UTRs) identified in fungi to date, which is predicted to form a complex and extremely stable secondary structure. The 5′ UTR inhibits the ability of UME6, when expressed at constitutive high levels, to drive complete hyphal growth, but does not cause a reduction in UME6 transcript. Deletion of the 5′ UTR increases C. albicans filamentation under a variety of conditions but does not affect UME6 transcript level or induction kinetics. We show that the 5′ UTR functions to inhibit Ume6 protein expression under several filament-inducing conditions and specifically reduces association of the UME6 transcript with polysomes. Overall, our findings suggest that translational efficiency mechanisms, known to regulate diverse biological processes in bacterial and viral pathogens as well as higher eukaryotes, have evolved to inhibit and fine-tune morphogenesis, a key virulence trait of many human fungal pathogens.
- Published
- 2014
35. 1985 A Case of Spontaneous Hemoperitoneum in a Patient With Decompensated Alcoholic Cirrhosis
- Author
-
Kathy N. Williams, David Kadosh, Elena Ivanina, and Richa Bhardwaj
- Subjects
Alcoholic liver disease ,medicine.medical_specialty ,Hepatology ,business.industry ,Internal medicine ,Gastroenterology ,medicine ,Spontaneous hemoperitoneum ,medicine.disease ,business - Published
- 2019
36. A genome-wide transcriptional analysis of morphology determination in Candida albicans
- Author
-
Patricia L. Carlisle and David Kadosh
- Subjects
Hyphae ,Microbiology ,Transcriptome ,Fungal Proteins ,03 medical and health sciences ,Gene Expression Regulation, Fungal ,Gene expression ,Candida albicans ,Morphogenesis ,Cluster Analysis ,Molecular Biology ,Gene ,030304 developmental biology ,0303 health sciences ,Fungal protein ,biology ,030306 microbiology ,Gene Expression Profiling ,fungi ,Cell Biology ,Articles ,biology.organism_classification ,Corpus albicans ,Yeast ,Cell biology ,Biosynthetic Pathways ,Gene expression profiling ,Cell Motility ,Protein Biosynthesis ,Genome, Fungal ,Transcription Factors - Abstract
Morphology determination is critical for virulence of the human fungal pathogen Candida albicans. A genome-wide transcriptional analysis shows that genes associated with specifying the C. albicans pseudohyphal morphology represent a subset of hyphal genes and reveals fundamental differences between forward and reverse morphological transitions., Candida albicans, the most common cause of human fungal infections, undergoes a reversible morphological transition from yeast to pseudohyphal and hyphal filaments, which is required for virulence. For many years, the relationship among global gene expression patterns associated with determination of specific C. albicans morphologies has remained obscure. Using a strain that can be genetically manipulated to sequentially transition from yeast to pseudohyphae to hyphae in the absence of complex environmental cues and upstream signaling pathways, we demonstrate by whole-genome transcriptional profiling that genes associated with pseudohyphae represent a subset of those associated with hyphae and are generally expressed at lower levels. Our results also strongly suggest that in addition to dosage, extended duration of filament-specific gene expression is sufficient to drive the C. albicans yeast-pseudohyphal-hyphal transition. Finally, we describe the first transcriptional profile of the C. albicans reverse hyphal-pseudohyphal-yeast transition and demonstrate that this transition involves not only down-regulation of known hyphal-specific, genes but also differential expression of additional genes that have not previously been associated with the forward transition, including many involved in protein synthesis. These findings provide new insight into genome-wide expression patterns important for determining fungal morphology and suggest that in addition to similarities, there are also fundamental differences in global gene expression as pathogenic filamentous fungi undergo forward and reverse morphological transitions.
- Published
- 2013
37. Expression levels of a filament-specific transcriptional regulator are sufficient to determine Candida albicans morphology and virulence
- Author
-
David Kadosh, Anna L. Lazzell, Patricia L. Carlisle, Carlos Monteagudo, Mohua Banerjee, and Jose L. Lopez-Ribot
- Subjects
Transcription, Genetic ,Population ,Hyphae ,Virulence ,Microbiology ,Mice ,Candida albicans ,Gene expression ,Transcriptional regulation ,medicine ,Animals ,education ,education.field_of_study ,Multidisciplinary ,biology ,Candidiasis ,medicine.disease ,biology.organism_classification ,Yeast ,Corpus albicans ,Disease Models, Animal ,Commentary ,Systemic candidiasis ,Transcription Factors - Abstract
Candida albicans , the major human fungal pathogen, undergoes a reversible morphological transition from single yeast cells to pseudohyphal and hyphal filaments (elongated cells attached end-to-end). Because typical C. albicans infections contain a mixture of these morphologies it has, for many years, been difficult to assess the relative contribution of each form to virulence. In addition, the regulatory mechanisms that determine growth in pseudohyphal and hyphal morphologies are largely unknown. To address these questions we have generated a C. albicans strain that can be genetically manipulated to grow completely in the hyphal form under non-filament-inducing conditions in vitro. This was achieved by inducing high-level constitutive expression of UME6 , a recently identified filament-specific transcriptional regulator of C. albicans hyphal extension. We show that high-level UME6 expression significantly increases hyphal formation and promotes virulence in a mouse model of systemic candidiasis. Our results strongly suggest that shifting the morphology of a C. albicans population toward the hyphal form, and/or increasing hyphal-specific gene expression, during the course of infection is sufficient to improve virulence potential. We also demonstrate that lower levels of UME6 expression specify growth largely in the pseudohyphal form and that increasing UME6 levels is sufficient to cause cells to gradually shift from pseudohyphal to hyphal morphology. In addition, we show that UME6 levels differentially induce the expression of several known filament-specific transcripts. These findings suggest that a common transcriptional regulatory mechanism functions to specify both pseudohyphal and hyphal morphologies in a dosage-dependent manner.
- Published
- 2009
38. UME6, a Novel Filament-specific Regulator ofCandida albicansHyphal Extension and Virulence
- Author
-
Patricia L. Carlisle, Carlos Monteagudo, Mohua Banerjee, Delma S. Thompson, Christopher G. Pierce, Jose L. Lopez-Ribot, David Kadosh, and Anna L. Lazzell
- Subjects
Hypha ,Genes, Fungal ,Regulator ,Germ tube ,Virulence ,Biology ,medicine.disease_cause ,Models, Biological ,Microbiology ,Fungal Proteins ,Protein filament ,Mice ,Gene Expression Regulation, Fungal ,Candida albicans ,medicine ,Animals ,Humans ,DNA, Fungal ,Molecular Biology ,Oligonucleotide Array Sequence Analysis ,Mice, Inbred BALB C ,Fungal protein ,Mutation ,Candidiasis ,Gene Expression Regulation, Developmental ,Articles ,Cell Biology ,biology.organism_classification ,Repressor Proteins ,Disease Models, Animal ,Female ,Transcription Factors - Abstract
The specific ability of the major human fungal pathogen Candida albicans, as well as many other pathogenic fungi, to extend initial short filaments (germ tubes) into elongated hyphal filaments is important for a variety of virulence-related processes. However, the molecular mechanisms that control hyphal extension have remained poorly understood for many years. We report the identification of a novel C. albicans transcriptional regulator, UME6, which is induced in response to multiple host environmental cues and is specifically important for hyphal extension. Although capable of forming germ tubes, the ume6Δ/ume6Δ mutant exhibits a clear defect in hyphal extension both in vitro and during infection in vivo and is attenuated for virulence in a mouse model of systemic candidiasis. We also show that UME6 is an important downstream component of both the RFG1-TUP1 and NRG1-TUP1 filamentous growth regulatory pathways, and we provide evidence to suggest that Nrg1 and Ume6 function together by a negative feedback loop to control the level and duration of filament-specific gene expression in response to inducing conditions. Our results suggest that hyphal extension is controlled by a specific transcriptional regulatory mechanism and is correlated with the maintenance of high-level expression of genes in the C. albicans filamentous growth program.
- Published
- 2008
39. Shaping up for battle: morphological control mechanisms in human fungal pathogens
- Author
-
David Kadosh
- Subjects
lcsh:Immunologic diseases. Allergy ,Battle ,media_common.quotation_subject ,Immunology ,Biology ,Microbiology ,Histoplasma capsulatum ,Pearls ,03 medical and health sciences ,Virology ,Candida albicans ,Genetics ,Animals ,Humans ,lcsh:QH301-705.5 ,Molecular Biology ,030304 developmental biology ,media_common ,0303 health sciences ,Virulence ,030306 microbiology ,Extramural ,Fungi ,biology.organism_classification ,Chromatin ,lcsh:Biology (General) ,Parasitology ,lcsh:RC581-607 - Published
- 2014
40. Rfg1, a Protein Related to the Saccharomyces cerevisiae Hypoxic Regulator Rox1, Controls Filamentous Growth and Virulence in Candida albicans
- Author
-
Alexander D. Johnson and David Kadosh
- Subjects
Saccharomyces cerevisiae Proteins ,Molecular Sequence Data ,Saccharomyces cerevisiae ,Regulator ,Virulence ,Repressor ,Microbiology ,Fungal Proteins ,Candida albicans ,Amino Acid Sequence ,Cell Growth and Development ,Molecular Biology ,Cytoskeleton ,Regulation of gene expression ,Fungal protein ,biology ,Cell Biology ,biology.organism_classification ,Corpus albicans ,DNA-Binding Proteins ,Repressor Proteins ,Sequence Alignment ,Transcription Factors - Abstract
Candida albicans, the major fungal pathogen in humans, can undergo a reversible transition from ellipsoidal single cells (blastospores) to filaments composed of elongated cells attached end to end. This transition is thought to allow for rapid colonization of host tissues, facilitating the spread of infection. Here, we report the identification of Rfg1, a transcriptional regulator that controls filamentous growth of C. albicans in an environment-dependent manner. Rfg1 is important for virulence of C. albicans in a mouse model and is shown to control a number of genes that have been implicated in this process. The closest relative to Rfg1 in Saccharomyces cerevisiae is Rox1, a key repressor of hypoxic genes. However, Rfg1 does not appear to play a role in the regulation of hypoxic genes in C. albicans. These results demonstrate that a regulatory protein that controls the hypoxic response in S. cerevisiae controls filamentous growth and virulence in C. albicans. The observations described in this paper raise new and intriguing questions about the evolutionary relationship between these processes.
- Published
- 2001
41. Histone deacetylase activity of Rpd3 is important for transcriptional repression in vivo
- Author
-
Kevin Struhl and David Kadosh
- Subjects
Saccharomyces cerevisiae Proteins ,Transcription, Genetic ,Molecular Sequence Data ,Saccharomyces cerevisiae ,SAP30 ,Biology ,Catalysis ,Histone Deacetylases ,Fungal Proteins ,Gene Expression Regulation, Fungal ,Genetics ,Amino Acid Sequence ,Histone deacetylase 5 ,Binding Sites ,Sequence Homology, Amino Acid ,Histone deacetylase 2 ,HDAC11 ,HDAC10 ,HDAC9 ,Acetylation ,HDAC4 ,Biochemistry ,Mutation ,Histone deacetylase activity ,Research Paper ,Transcription Factors ,Developmental Biology - Abstract
Eukaryotic organisms from yeast to human contain a multiprotein complex that includes Rpd3 histone deacetylase and Sin3 corepressor. The Sin3-Rpd3 complex, when recruited to promoters by specific DNA-binding proteins, can direct transcriptional repression of specific classes of target genes. It has been proposed that the histone deacetylase activity of Rpd3 is important for repression, but direct evidence is lacking. Here, we describe four Rpd3 derivatives with mutations in evolutionarily invariant histidine residues in a putative deacetylation motif. These Rpd3 mutants lack detectable histone deacetylase activity in vitro, but interact normally with Sin3 in vivo. In yeast cells, these catalytically inactive mutants are defective for transcriptional repression. They retain some residual Rpd3 function in vivo, however, suggesting that repression by the Sin3-Rpd3 complex may not be attributable exclusively to its intrinsic histone deacetylase activity. Finally, we show that a human Rpd3 homolog can interact with yeast Sin3 and repress transcription when artificially recruited to a promoter. These results suggest that the histone deacetylase activity of Rpd3 is important, but perhaps not absolutely required, for transcriptional repression in vivo.
- Published
- 1998
42. Activation and Repression Mechanisms in Yeast
- Author
-
Marie Keaveney, David Kadosh, Zarmik Moqtaderi, Kevin Struhl, and Laurent Kuras
- Subjects
Transcription, Genetic ,Saccharomyces cerevisiae ,RNA polymerase II ,Biochemistry ,DNA-binding protein ,Transcription Factors, TFII ,Transcription (biology) ,Gene Expression Regulation, Fungal ,Genetics ,Molecular Biology ,Psychological repression ,Transcription factor ,Regulation of gene expression ,Models, Genetic ,biology ,Chemistry ,TATA-Box Binding Protein ,biology.organism_classification ,TATA Box ,Yeast ,Cell biology ,DNA-Binding Proteins ,Enhancer Elements, Genetic ,biology.protein ,Transcription Factor TFIID ,RNA Polymerase II ,Transcription Factors - Published
- 1998
43. Comparative evolution of morphological regulatory functions in Candida species
- Author
-
Geethanjali Vipulanandan, Delma S. Childers, Erika Lackey, and David Kadosh
- Subjects
Genetics ,biology ,Mycelium ,Biofilm ,Repressor ,Virulence ,General Medicine ,macromolecular substances ,Articles ,biology.organism_classification ,Microbiology ,Corpus albicans ,Evolution, Molecular ,Fungal Proteins ,Filamentation ,Gene expression ,Candida albicans ,Molecular Biology ,Gene ,Candida - Abstract
Morphological transitions play an important role in virulence and virulence-related processes in a wide variety of pathogenic fungi, including the most commonly isolated human fungal pathogen Candida albicans . While environmental signals, transcriptional regulators, and target genes associated with C. albicans morphogenesis are well-characterized, considerably little is known about morphological regulatory mechanisms and the extent to which they are evolutionarily conserved in less pathogenic and less filamentous non- albicans Candida species (NACS). We have identified specific optimal filament-inducing conditions for three NACS ( C. tropicalis , C. parapsilosis , and C. guilliermondii ), which are very limited, suggesting that these species may be adapted for niche-specific filamentation in the host. Only a subset of evolutionarily conserved C. albicans filament-specific target genes were induced upon filamentation in C. tropicalis , C. parapsilosis , and C. guilliermondii . One of the genes showing conserved expression was UME6 , a key filament-specific regulator of C. albicans hyphal development. Constitutive high-level expression of UME6 was sufficient to drive increased filamentation as well as biofilm formation and partly restore conserved filament-specific gene expression in both C. tropicalis and C. parapsilosis , suggesting that evolutionary differences in filamentation ability among pathogenic Candida species may be partially attributed to alterations in the expression level of a conserved filamentous growth machinery. In contrast to UME6 , NRG1 , an important repressor of C. albicans filamentation, showed only a partly conserved role in controlling NACS filamentation. Overall, our results suggest that C. albicans morphological regulatory functions are partially conserved in NACS and have evolved to respond to more specific sets of host environmental cues.
- Published
- 2013
44. Expression of UME6, a key regulator of Candida albicans hyphal development, enhances biofilm formation via Hgc1- and Sun41-dependent mechanisms
- Author
-
Priya Uppuluri, Cristina Cunha Villar, Geethanjali Vipulanandan, David Kadosh, Jose L. Lopez-Ribot, Mohua Banerjee, Patricia L. Carlisle, and Xiang R. Zhao
- Subjects
Hyphal growth ,Transcriptional Activation ,Hypha ,Glycoside Hydrolases ,Hyphae ,Biology ,Microbiology ,Cell wall ,Fungal Proteins ,Cyclins ,Gene Expression Regulation, Fungal ,Candida albicans ,Humans ,Molecular Biology ,Cells, Cultured ,Fungal protein ,Biofilm ,Mouth Mucosa ,Epithelial Cells ,General Medicine ,Articles ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Yeast ,Corpus albicans ,Coculture Techniques ,Cell biology ,Biofilms ,Transcription Factors - Abstract
Biofilm formation is associated with the ability of Candida albicans , the major human fungal pathogen, to resist antifungal therapies and grow on tissues, catheters, and medical devices. In order to better understand the relationship between C. albicans morphology and biofilm formation, we examined biofilms generated in response to expression of UME6 , a key filament-specific transcriptional regulator. As UME6 levels rise, C. albicans cells are known to transition from yeast to hyphae, and we also observed a corresponding increase in the level of biofilm formation in vitro . In addition to forming a biofilm, we observed that a C. albicans strain expressing constitutive high levels of UME6 promoted tissue invasion in a reconstituted human three-dimensional model of oropharyngeal candidiasis. Confocal microscopy indicated that both the top and bottom layers of the biofilm generated upon high-level constitutive UME6 expression consist primarily of hyphal cells. UME6 -driven biofilm formation was reduced upon deletion of Hgc1, a cyclin-related protein important for hyphal development, as well as Sun41, a putative cell wall glycosidase. Constitutive high-level UME6 expression was also able to completely bypass both the filamentation and biofilm defects of a strain deleted for Efg1, a key transcriptional regulator of these processes. Finally, we show that both Sun41 and Efg1 affect the ability of UME6 to induce certain filament-specific transcripts. Overall, these findings indicate a strong correlation between increased C. albicans hyphal growth and enhanced biofilm formation and also suggest functional relationships between UME6 and other regulators of biofilm development.
- Published
- 2012
45. Coevolution of morphology and virulence in Candida species
- Author
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David Kadosh, Patricia L. Carlisle, and Delma S. Thompson
- Subjects
Virulence ,Ecology ,Extramural ,Virulence Factors ,Candidiasis ,Fungi ,Hyphae ,Gene Expression ,Morphology (biology) ,Minireviews ,General Medicine ,Biology ,Microbiology ,Phenotype ,Models, Biological ,Evolutionary biology ,Yeasts ,Humans ,Molecular Biology ,Coevolution ,Candida - Abstract
Many of the major human fungal pathogens are known to undergo morphological changes, which in certain cases are associated with virulence. Although there has been an intense research focus on morphology in fungi, very little is known about how morphology evolved in conjunction with a variety of other virulence properties. However, several recent important discoveries, primarily in Candida species, are beginning to shed light on this important area and answer many longstanding questions. In this minireview, we first provide a description of the major fungal morphologies, as well as the roles of morphology and morphology-associated gene expression in virulence. Next, focusing largely on Candida species, we examine the evolutionary relationships among specific morphological forms. Finally, drawing on recent findings, we begin to address the question of how specific morphological changes came to be associated with virulence of Candida species during evolution.
- Published
- 2011
46. Candida albicans Ume6, a Filament-Specific Transcriptional Regulator, Directs Hyphal Growth via a Pathway Involving Hgc1 Cyclin-Related Protein▿†
- Author
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Patricia L. Carlisle and David Kadosh
- Subjects
Hyphal growth ,fungi ,Regulator ,Morphogenesis ,Hyphae ,General Medicine ,macromolecular substances ,Articles ,Biology ,biology.organism_classification ,Microbiology ,Yeast ,Cell biology ,Fungal Proteins ,Repressor Proteins ,Gene Expression Regulation, Fungal ,Candida albicans ,Transcriptional regulation ,Molecular Biology ,Transcription factor ,Cyclin - Abstract
The ability of Candida albicans , the most common human fungal pathogen, to transition from yeast to hyphae is essential for pathogenicity. While a variety of transcription factors important for filamentation have been identified and characterized, links between transcriptional regulators of C. albicans morphogenesis and molecular mechanisms that drive hyphal growth are not well defined. We have previously observed that constitutive expression of UME6 , which encodes a filament-specific transcriptional regulator, is sufficient to direct hyphal growth in the absence of filament-inducing conditions. Here we show that HGC1 , encoding a cyclin-related protein necessary for hyphal growth under filament-inducing conditions, is specifically important for agar invasion, hyphal extension, and formation of true septa in response to constitutive UME6 expression under non-filament-inducing conditions. HGC1 -dependent inactivation of Rga2, a Cdc42 GTPase activating protein (GAP), also appears to be important for these processes. In response to filament-inducing conditions, HGC1 is induced prior to UME6 although UME6 controls the level and duration of HGC1 expression, which are likely to be important for hyphal extension. Interestingly, an epistasis analysis suggests that UME6 and HGC1 play distinct roles during early filament formation. These findings establish a link between a key regulator of filamentation and a downstream mechanism important for hyphal formation. In addition, this study demonstrates that a strain expressing constitutive high levels of UME6 provides a powerful strategy to specifically dissect downstream mechanisms important for hyphal development in the absence of complex filament-inducing conditions.
- Published
- 2010
47. Dispersion as an important step in the Candida albicans biofilm developmental cycle
- Author
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Anand Srinivasan, Ashok K. Chaturvedi, Julia R. Köhler, Mohua Banerjee, Anand K. Ramasubramaniam, David Kadosh, Priya Uppuluri, and Jose L. Lopez-Ribot
- Subjects
Umbilical Cord ,Mice ,Filamentation ,Gene Expression Regulation, Fungal ,Candida albicans ,lcsh:QH301-705.5 ,0303 health sciences ,Fungal protein ,Mice, Inbred BALB C ,biology ,Virulence ,Candidiasis ,Hydrogen-Ion Concentration ,Phenotype ,Corpus albicans ,Diffusion Chambers, Culture ,Research Article ,lcsh:Immunologic diseases. Allergy ,Immunology ,Models, Biological ,Microbiology ,Fungal Proteins ,03 medical and health sciences ,Infectious Diseases/Fungal Infections ,Virology ,Genetics ,Cell Adhesion ,Animals ,Humans ,Molecular Biology ,030304 developmental biology ,Microbiology/Microbial Growth and Development ,030306 microbiology ,Biofilm ,Endothelial Cells ,Microbiology/Medical Microbiology ,biochemical phenomena, metabolism, and nutrition ,Disseminated Candidiasis ,biology.organism_classification ,Carbon ,Disease Models, Animal ,lcsh:Biology (General) ,Biofilms ,Microscopy, Electron, Scanning ,Parasitology ,Stress, Mechanical ,lcsh:RC581-607 - Abstract
Biofilms are dynamic microbial communities in which transitions between planktonic and sessile modes of growth occur interchangeably in response to different environmental cues. In the last decade, early events associated with C. albicans biofilm formation have received considerable attention. However, very little is known about C. albicans biofilm dispersion or the mechanisms and signals that trigger it. This is important because it is precisely C. albicans cells dispersed from biofilms that are the main culprits associated with candidemia and establishment of disseminated invasive disease, two of the gravest forms of candidiasis. Using a simple flow biofilm model recently developed by our group, we have performed initial investigations into the phenomenon of C. albicans biofilm dispersion, as well as the phenotypic characteristics associated with dispersed cells. Our results indicate that C. albicans biofilm dispersion is dependent on growing conditions, including carbon source and pH of the media used for biofilm development. C. albicans dispersed cells are mostly in the yeast form and display distinct phenotypic properties compared to their planktonic counterparts, including enhanced adherence, filamentation, biofilm formation and, perhaps most importantly, increased pathogenicity in a murine model of hematogenously disseminated candidiasis, thus indicating that dispersed cells are armed with a complete arsenal of “virulence factors” important for seeding and establishing new foci of infection. In addition, utilizing genetically engineered strains of C. albicans (tetO-UME6 and tetO-PES1) we demonstrate that C. albicans biofilm dispersion can be regulated by manipulating levels of expression of these key genes, further supporting the evidence for a strong link between biofilms and morphogenetic conversions at different stages of the C. albicans biofilm developmental cycle. Overall, our results offer novel and important insight into the phenomenon of C. albicans biofilm dispersion, a key part of the biofilm developmental cycle, and provide the basis for its more detailed analysis., Author Summary Candida albicans is the main causative agent of candidiasis, a difficult-to-treat infection that occurs mostly in severely immunosuppressed and other at-risk patients. Candidiasis is often associated with the formation of biofilms (attached microbial communities encapsulated within a protective matrix) on host surfaces and/or implantable medical devices, most notably intravascular catheters. In recent years, for C. albicans, the process of biofilm formation has received much attention. However, the same is not true for biofilm dispersion (the release of cells from the biofilm). This is important since these dispersed cells are responsible for the subsequent establishment of disseminated candidiasis at distal organs. Here we have taken advantage of a model of biofilm formation under conditions of flow recently described by our group to study and characterize the phenomenon of C. albicans biofilm dispersion. Rather than an end-stage process, our results indicate that dispersion occurs at all different stages of the biofilm developmental cycle and is influenced by nutritional and other physiochemical conditions. In addition, our findings provide initial insights into how this process is regulated at the molecular level. We also demonstrate that dispersed cells display distinct phenotypic properties that are associated with increased virulence, with important clinical repercussions.
- Published
- 2010
48. Induction of the Candida albicans filamentous growth program by relief of transcriptional repression: a genome-wide analysis
- Author
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Alexander D. Johnson and David Kadosh
- Subjects
Budding ,Fungal protein ,Transition (genetics) ,biology ,Models, Genetic ,Virulence ,Microarray analysis techniques ,Genes, Fungal ,Repressor ,Cell Biology ,Articles ,biology.organism_classification ,Microarray Analysis ,Microbiology ,Fungal Proteins ,Repressor Proteins ,Transcriptional repression ,Gene Expression Regulation, Fungal ,Candida albicans ,Genome, Fungal ,Molecular Biology - Abstract
Candida albicans, the major human fungal pathogen, undergoes a reversible morphological transition from blastospores (round budding cells) to filaments (elongated cells attached end-to-end). This transition, which is induced upon exposure of C. albicans cells to a number of host conditions, including serum and body temperature (37 degrees C), is required for virulence. Using whole-genome DNA microarray analysis, we describe 61 genes that are significantly induced (or =2-fold) during the blastospore to filament transition that takes place in response to exposure to serum and 37 degrees C. We next show that approximately half of these genes are transcriptionally repressed in the blastospore state by three transcriptional repressors, Rfg1, Nrg1, and Tup1. We conclude that the relief of this transcriptional repression plays a key role in bringing the C. albicans filamentous growth program into play, and we describe the framework of this transcriptional circuit.
- Published
- 2005
49. The histone deacetylase RPD3 counteracts genomic silencing in Drosophila and yeast
- Author
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Gunter Reuter, David Kadosh, Francesco De Rubertis, Kevin Struhl, Sandra Henchoz, Daniel Pauli, and Pierre Spierer
- Subjects
Transcription Factors/chemistry/genetics/metabolism ,Saccharomyces cerevisiae Proteins ,Molecular Sequence Data ,Genes, Insect ,Histone Deacetylase 1 ,Saccharomyces cerevisiae ,Fungal Proteins/chemistry/genetics/metabolism ,Biology ,Histone Deacetylases ,Fungal Proteins ,ddc:590 ,Histone H1 ,Gene Expression Regulation, Fungal ,Histone H2A ,Animals ,Drosophila Proteins ,Humans ,Histone code ,Amino Acid Sequence ,Cloning, Molecular ,Genetics ,Histone deacetylase 5 ,Multidisciplinary ,HDAC11 ,Histone deacetylase 2 ,Histone Deacetylases/chemistry/genetics/metabolism ,fungi ,Telomere/physiology ,Telomere ,HDAC4 ,Repressor Proteins ,Mutagenesis, Insertional ,Drosophila melanogaster ,Gene Expression Regulation ,Histone methyltransferase ,DNA Transposable Elements ,Transcription Factors - Abstract
Both position-effect variegation (PEV) in Drosophila and telomeric position-effect in yeast (TPE) result from the mosaic inactivation of genes relocated next to a block of centromeric heterochromatin or next to telomeres. In many aspects, these phenomena are analogous to other epigenetic silencing mechanisms, such as the control of homeotic gene clusters, X-chromosome inactivation and imprinting in mammals, and mating-type control in yeast. Dominant mutations that suppress or enhance PEV are thought to encode either chromatin proteins or factors that directly affect chromatin structure. We have identified an insertional mutation in Drosophila that enhances PEV and reduces transcription of the gene in the eye-antenna imaginal disc. The gene corresponds to that encoding the transcriptional regulator RPD3 in yeast, and to a human histone deacetylase. In yeast, RRD3-deletion strains show enhanced TPE, suggesting a conserved role of the histone deacetylase RPD3 in counteracting genomic silencing. This function of RPD3, which is in contrast to the general correlation between histone acetylation and increased transcription, might be due to a specialized chromatin structure at silenced loci.
- Published
- 1996
50. NRG1, a repressor of filamentous growth in C.albicans, is down-regulated during filament induction
- Author
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Burkhard R. Braun, David Kadosh, and Alexander D. Johnson
- Subjects
Saccharomyces cerevisiae Proteins ,Hypha ,Transcription, Genetic ,Mutant ,Molecular Sequence Data ,Filamentous haemagglutinin adhesin ,Repressor ,macromolecular substances ,Saccharomyces cerevisiae ,DNA-binding protein ,General Biochemistry, Genetics and Molecular Biology ,Article ,Fungal Proteins ,Transcription (biology) ,Gene Expression Regulation, Fungal ,mental disorders ,Amino Acid Sequence ,Candida albicans ,Promoter Regions, Genetic ,Molecular Biology ,Gene ,Candida ,Binding Sites ,Membrane Glycoproteins ,General Immunology and Microbiology ,biology ,Sequence Homology, Amino Acid ,Virulence ,General Neuroscience ,Zinc Fingers ,biology.organism_classification ,Molecular biology ,Culture Media ,DNA-Binding Proteins ,Repressor Proteins ,Sequence Alignment ,Gene Deletion - Abstract
In response to a variety of external signals, the fungal pathogen Candida albicans undergoes a transition between ellipsoidal single cells (blastospores) and filaments composed of elongated cells attached end-to-end. Here we identify a DNA-binding protein, Nrg1, that represses filamentous growth in Candida probably by acting through the co-repressor Tup1. nrg1 mutant cells are predominantly filamentous under non-filament-inducing conditions and their colony morphology resembles that of tup1 mutants. We also identify two filament-specific genes, ECE1 and HWP1, whose transcription is repressed by Nrg1 under non-inducing conditions. These genes constitute a subset of those under Tup1 control, providing further evidence that Nrg1 acts by recruiting Tup1 to target genes. We show that growth in serum at 37 degrees C, a potent inducer of filamentous growth, causes a reduction of NRG1 mRNA, suggesting that filamentous growth is induced by the down-regulation of NRG1. Consistent with this idea, expression of NRG1 from a non-regulated promoter partially blocks the induction of filamentous growth.
- Published
- 2001
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