Comparative host transcriptome in response to pathogenic fungi identifies common and species-specific transcriptional antifungal host response pathways
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE162746 | GEO | 2021/01/31
REPOSITORIES: GEO
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Project description:Candida albicans is the major invasive fungal pathogen of humans, causing diseases ranging from superficial mucosal infections to disseminated, systemic infections which are often life threatening. Hematogenously disseminated candidiasis (HDC) has a 47% mortality rate despite current antifungal therapy. An increase in prevalence, as well as an increasing resistance to most of the clinically important antifungal therapies, provides a strong impetus to understand the molecular mechanisms of pathogenesis and the acquisition of drug resistance. This information holds promise to identify novel therapeutic targets. A complete and accurate characterization of how the transcriptome of C. albicans responds to its interaction with cells from the host is an absolute necessity to accomplish this goal. RNA-seq (deep-sequencing of cDNA) provides an unbiased method to define comprehensively and systematically the transcriptome of an organism. We propose a comprehensive characterization of the C. albicans transcriptome in two different human tissue culture models, using RNA-seq. Such a characterization will shed unprecedented light on how fungal pathogens sense and respond to the host environment and how the host tissue responds to fungal invasion. We performed a comprehensive characterization of the C. albicans transcriptome in two different murine models of candidiasis (HDC and oropharyngeal candidiasis (OPC)), and two different human tissue culture models, using RNA-seq. Because the two murine models accurately recapitulate the pathology that is observed in clinical cases of candidiasis, we are confident that gene expression levels will provide an accurate representation of what occurs during the course of an infection in humans. Such a characterization of the in vivo transcriptome will shed unprecedented light on how fungal pathogens sense and respond to the host environment and how the host tissue responds to fungal invasion. PRJNA86065 Two different strains of C. albicans (SC5314 or WO-1) were used to infect two different types of human tissue culture monolayers (HUVECs or OKF6-TERT2). RNA from the infection mixtures were harvested at 90 minutes, 5 hours and 8 hours post infection. Experiments were performed in biological duplicate.
2014-03-30 | E-GEOD-56091 | biostudies-arrayexpress
Project description:Candida albicans is the major invasive fungal pathogen of humans, causing diseases ranging from superficial mucosal infections to disseminated, systemic infections which are often life threatening. Hematogenously disseminated candidiasis (HDC) has a 47% mortality rate despite current antifungal therapy. An increase in prevalence, as well as an increasing resistance to most of the clinically important antifungal therapies, provides a strong impetus to understand the molecular mechanisms of pathogenesis and the acquisition of drug resistance. This information holds promise to identify novel therapeutic targets. A complete and accurate characterization of how the transcriptome of C. albicans responds to its interaction with cells from the host is an absolute necessity to accomplish this goal. RNA-seq (deep-sequencing of cDNA) provides an unbiased method to define comprehensively and systematically the transcriptome of an organism. We propose a comprehensive characterization of the C. albicans transcriptome in two different human tissue culture models, using RNA-seq. Such a characterization will shed unprecedented light on how fungal pathogens sense and respond to the host environment and how the host tissue responds to fungal invasion. We performed a comprehensive characterization of the C. albicans transcriptome in two different murine models of candidiasis (HDC and oropharyngeal candidiasis (OPC)), and two different human tissue culture models, using RNA-seq. Because the two murine models accurately recapitulate the pathology that is observed in clinical cases of candidiasis, we are confident that gene expression levels will provide an accurate representation of what occurs during the course of an infection in humans. Such a characterization of the in vivo transcriptome will shed unprecedented light on how fungal pathogens sense and respond to the host environment and how the host tissue responds to fungal invasion. PRJNA211732 C. albicans strain SC5314 was used to infect mice in a murine model of systemic candidiasis as well as a murine model of oropharyngeal candidiasis. For the disseminated model, kidneys were harvested at 6 hours, 12 hours, 24 hours and 48 hours after infection. For the oropharyngeal model, tongues were harvest at 1 day, 2 days, 3 days, and 5 days after infection. Total RNA was extracted from all harvested tissues and subject to RNA-seq. We also tested 3 C. albicans mutants in the disseminated model. For the infections with the mutant strains, only 1 timepoint (24 hours post-infection) was analyzed.
2014-03-30 | E-GEOD-56092 | biostudies-arrayexpress
Project description:Candida albicans is the major invasive fungal pathogen of humans, causing diseases ranging from superficial mucosal infections to disseminated, systemic infections which are often life threatening. Hematogenously disseminated candidiasis (HDC) has a 47% mortality rate despite current antifungal therapy. An increase in prevalence, as well as an increasing resistance to most of the clinically important antifungal therapies, provides a strong impetus to understand the molecular mechanisms of pathogenesis and the acquisition of drug resistance. This information holds promise to identify novel therapeutic targets. A complete and accurate characterization of how the transcriptome of C. albicans responds to its interaction with cells from the host is an absolute necessity to accomplish this goal. RNA-seq (deep-sequencing of cDNA) provides an unbiased method to define comprehensively and systematically the transcriptome of an organism. We propose a comprehensive characterization of the C. albicans transcriptome in two different human tissue culture models, using RNA-seq. Such a characterization will shed unprecedented light on how fungal pathogens sense and respond to the host environment and how the host tissue responds to fungal invasion. We performed a comprehensive characterization of the C. albicans transcriptome in two different murine models of candidiasis (HDC and oropharyngeal candidiasis (OPC)), and two different human tissue culture models, using RNA-seq. Because the two murine models accurately recapitulate the pathology that is observed in clinical cases of candidiasis, we are confident that gene expression levels will provide an accurate representation of what occurs during the course of an infection in humans. Such a characterization of the in vivo transcriptome will shed unprecedented light on how fungal pathogens sense and respond to the host environment and how the host tissue responds to fungal invasion. PRJNA86065
2014-03-30 | GSE56091 | GEO
Project description:Candida albicans is the major invasive fungal pathogen of humans, causing diseases ranging from superficial mucosal infections to disseminated, systemic infections which are often life threatening. Hematogenously disseminated candidiasis (HDC) has a 47% mortality rate despite current antifungal therapy. An increase in prevalence, as well as an increasing resistance to most of the clinically important antifungal therapies, provides a strong impetus to understand the molecular mechanisms of pathogenesis and the acquisition of drug resistance. This information holds promise to identify novel therapeutic targets. A complete and accurate characterization of how the transcriptome of C. albicans responds to its interaction with cells from the host is an absolute necessity to accomplish this goal. RNA-seq (deep-sequencing of cDNA) provides an unbiased method to define comprehensively and systematically the transcriptome of an organism. We propose a comprehensive characterization of the C. albicans transcriptome in two different human tissue culture models, using RNA-seq. Such a characterization will shed unprecedented light on how fungal pathogens sense and respond to the host environment and how the host tissue responds to fungal invasion. We performed a comprehensive characterization of the C. albicans transcriptome in two different murine models of candidiasis (HDC and oropharyngeal candidiasis (OPC)), and two different human tissue culture models, using RNA-seq. Because the two murine models accurately recapitulate the pathology that is observed in clinical cases of candidiasis, we are confident that gene expression levels will provide an accurate representation of what occurs during the course of an infection in humans. Such a characterization of the in vivo transcriptome will shed unprecedented light on how fungal pathogens sense and respond to the host environment and how the host tissue responds to fungal invasion. PRJNA211732
2014-03-30 | GSE56092 | GEO
Project description:Amphotericin B (AMB) is the most widely used polyene antifungal drug for the treatment of systemic fungal infections including invasive aspergillosis. We aimed to understand molecular targets of AMB in Aspergillus fumigatus (Afu) by genomic approaches. Amphotericin B (AMB) is the most widely used polyene antifungal drug for the treatment of systemic fungal infections including invasive aspergillosis. We aimed to understand molecular targets of AMB in Aspergillus fumigatus (Afu) by microarray and proteomic methods. Keywords: Aspergillus fumigatus treated with amphotericin B for 24 hours Experiment was performed in dye swap manner from two different biological replicates
2010-05-26 | E-GEOD-10505 | biostudies-arrayexpress
Project description:Mucormycosis is an increasingly common, life-threatening fungal infection caused by fungi belonging to the subphylum Mucormycotina, order Mucorales. The major risk factors for mucormycosis include uncontrolled diabetes mellitus, treatment with corticosteroids, organ or bone marrow transplantation, neutropenia, trauma and burns, malignant hematological disorders, and deferoxamine-therapy in patients receiving hemodialysis. Amphotericin B (AmB) remains the only antifungal agent approved for the treatment of invasive mucormycosis. Because fungi belonging to the mucorales order are relatively resistant to AmB, high doses are required, which frequently causes nephrotoxicity and other adverse effects. In the absence of surgical removal of the infected focus (such as excision of the eye in patients with rhinocerebral mucormycosis), antifungal therapy alone is rarely curative. Even when surgical debridement is combined with high-dose AmB, the mortality associated with mucor¬mycosis is >50%. In patients with prolonged neutropenia or disseminated disease, mortality is 90-100%. Rhizopus oryzae is by far the most common organism isolated from patients with mucormycosis, and is responsible for approximately 70% of all cases of mucormycosis. Recent epidemiological data collected from transplant centers have demonstrated a striking increase in the number of reported cases of mucormycosis. Furthermore, mucormycosis outbreaks are also known to follow natural disasters as was the case following the tsunami that devastated Indonesia in 2004 and the tornadoes that destroyed Joplin, Missouri in June 2011. Hence, there exists a large impetus to identify particular virulence factors and biomarkers associated with mucormycosis, which would lead to a rational approach to develop new antifungals and vaccines to prevent deaths specifically due to mucormycosis. In order to better understand the complex nature of the host pathogen interaction during mucormycosis, we performed dual species RNA-seq on 5 different Mucorales strains during in vitro infection of endothelial or epithelial cells.
2014-06-19 | GSE58634 | GEO
Project description:Amphotericin B (AMB) is the most widely used polyene antifungal drug for the treatment of systemic fungal infections including invasive aspergillosis. We aimed to understand molecular targets of AMB in Aspergillus fumigatus (Afu) by genomic approaches. Keywords: Aspergillus fumigatus treated with amphotericin B for 24 hours
2008-02-14 | GSE10505 | GEO
Project description:The coronavirus pandemic (COVID-19) is associated with secondary bacterial and fungal infections globally. In India, inappropriate use of glucocorticoids, high prevalence of diabetes mellitus and a conducive environment for fungal growth are considered as the main factors for increased incidence of COVID-19 associated mucormycosis (CAM). Few cases of CAM without steroid abuse and normal blood glucose levels were also reported during the pandemic. This study was designed to explore whether altered immune responses due to severe COVID-19 infection predisposes towards development of mucormycosis. The global transcriptome profiling of monocytes and granulocytic cells derived from CAM, Mucormycosis, COVID-19 and healthy control groups were performed to identify the differentially expressed genes (DEGs) involved in dysregulated host immune response towards respective diseased and healthy conditions.
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Project description:6-Nonadecynoic acid (6-NDA), a plant-derived acetylenic acid, exhibits strong inhibitory activity against the human fungal pathogens Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model organism Saccharomyces cerevisiae to investigate the mechanism of action of this compound. 6-NDA elicited a transcriptome response indicative of fatty acid stress, altering the expression of genes known to be affected when yeast cells are grown in the presence of oleate. Mutants of S. cerevisiae lacking transcription factors that regulate fatty acid beta-oxidation showed increased sensitivity to 6-NDA. Fatty acid profile analysis indicated that 6-NDA inhibited the formation of fatty acids longer than 14 carbons in length. In addition, the growth inhibitory effect of 6-NDA was rescued in the presence of exogenously supplied oleate. To investigate the response of a pathogenic fungal species to 6-NDA, transcriptional profiling and biochemical analyses were also conducted in C. albicans. The transcriptional response and fatty acid profile of C. albicans were comparable to those obtained in S. cerevisiae, and the rescue of growth inhibition with exogenous oleate was also observed in C. albicans. In addition, 6-NDA enhanced the potency of the antifungal drug fluconazole in a fluconazole-resistant clinical isolate of C. albicans. Collectively, our results indicate that the antifungal activity of 6-NDA is mediated by a disruption in fatty acid homeostasis, and that this compound has potential utility in combination therapy in the treatment of drug-resistant fungal infections.
2012-02-08 | GSE35604 | GEO
Project description:Candida albicans is the most common human fungal pathogen causing mucosal and systemic infections. However, human antifungal immunity remains poorly defined. By integrating transcriptional analysis and functional genomics we identified Candida-specific host defense mechanisms in humans. Candida induced significant (p<10-35) expression of genes from the type I interferon (IFN) pathway in human peripheral blood mononuclear cells. This unexpectedly prominent role of type I IFN pathway in anti-Candida host defense was supported by additional evidence. Polymorphisms in type I IFN genes modulated Candida-induced cytokine production and were correlated with susceptibility to systemic candidiasis. In in-vitro experiments, type I IFNs skewed Candida-induced inflammation from a Th17-response toward a Th1-response. Patients with chronic mucocutaneaous candidiasis displayed defective expression of genes in the type I IFN pathway. These findings indicate that the type I IFN pathway is a main signature of Candida-induced inflammation and plays a crucial role in anti-Candida host defense in humans. 3 healthy controls and 2 CMC patients
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