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Journal ArticleDOI

Passage through the mammalian gut triggers a phenotypic switch that promotes Candida albicans commensalism.

01 Sep 2013-Nature Genetics (Nature Publishing Group)-Vol. 45, Iss: 9, pp 1088-1091
TL;DR: It is reported that exposure of C. albicans to the mammalian gut triggers a developmental switch, driven by the Wor1 transcription factor, to a commensal cell type, and the resulting GUT cells differ morphologically and functionally from previously defined cell types, and express a transcriptome that is optimized for the digestive tract.
Abstract: Suzanne Noble and colleagues show that the passage of Candida albicans through the mammalian gut induces expression of the Wor1 transcription factor, triggering a developmental switch that promotes commensal fitness.

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Citations
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Journal ArticleDOI
TL;DR: What is currently known about the makeup of fungal communities in the body and the features of the immune system that are particularly important for interacting with fungi at these sites are discussed.
Abstract: The body is host to a wide variety of microbial communities from which the immune system protects us and that are important for the normal development of the immune system and for the maintenance of healthy tissues and physiological processes. Investigators have mostly focused on the bacterial members of these communities, but fungi are increasingly being recognized to have a role in defining these communities and to interact with immune cells. In this Review, we discuss what is currently known about the makeup of fungal communities in the body and the features of the immune system that are particularly important for interacting with fungi at these sites.

506 citations

Journal ArticleDOI
TL;DR: The characteristics of the classic cell types — yeast, hyphae, pseudohyphae and chlamydospores — as well as the newly identified yeast-like morphotypes are explored, highlighting emerging knowledge about the associations of these different morphotypes with different host niches and virulence potential.
Abstract: Candida albicans is a ubiquitous commensal of the mammalian microbiome and the most prevalent fungal pathogen of humans. A cell-type transition between yeast and hyphal morphologies in C. albicans was thought to underlie much of the variation in virulence observed in different host tissues. However, novel yeast-like cell morphotypes, including opaque(a/α), grey and gastrointestinally induced transition (GUT) cell types, were recently reported that exhibit marked differences in vitro and in animal models of commensalism and disease. In this Review, we explore the characteristics of the classic cell types - yeast, hyphae, pseudohyphae and chlamydospores - as well as the newly identified yeast-like morphotypes. We highlight emerging knowledge about the associations of these different morphotypes with different host niches and virulence potential, as well as the environmental cues and signalling pathways that are involved in the morphological transitions.

353 citations

Journal ArticleDOI
TL;DR: In this paper, extensive genomic and phenotypic analyses were performed on 21 clinical C. albicans isolates, revealing a natural mutation that alters the balance between commensalism and pathogenicity.
Abstract: Candida albicans is a commensal fungus of the human gastrointestinal tract and a prevalent opportunistic pathogen. To examine diversity within this species, extensive genomic and phenotypic analyses were performed on 21 clinical C. albicans isolates. Genomic variation was evident in the form of polymorphisms, copy number variations, chromosomal inversions, subtelomeric hypervariation, loss of heterozygosity (LOH), and whole or partial chromosome aneuploidies. All 21 strains were diploid, although karyotypic changes were present in eight of the 21 isolates, with multiple strains being trisomic for Chromosome 4 or Chromosome 7. Aneuploid strains exhibited a general fitness defect relative to euploid strains when grown under replete conditions. All strains were also heterozygous, yet multiple, distinct LOH tracts were present in each isolate. Higher overall levels of genome heterozygosity correlated with faster growth rates, consistent with increased overall fitness. Genes with the highest rates of amino acid substitutions included many cell wall proteins, implicating fast evolving changes in cell adhesion and host interactions. One clinical isolate, P94015, presented several striking properties including a novel cellular phenotype, an inability to filament, drug resistance, and decreased virulence. Several of these properties were shown to be due to a homozygous nonsense mutation in the EFG1 gene. Furthermore, loss of EFG1 function resulted in increased fitness of P94015 in a commensal model of infection. Our analysis therefore reveals intra-species genetic and phenotypic differences in C. albicans and delineates a natural mutation that alters the balance between commensalism and pathogenicity.

231 citations


Cites methods or result from "Passage through the mammalian gut t..."

  • ...It should be noted, however, that in both our experiments and in another study using SC5314 (Pande et al. 2013), loss of EFG1 function con-...

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  • ...Previous studies demonstrated that commensal fitness in SC5314 was enhanced by deletion of EFG1 (Pierce and Kumamoto 2012; Pande et al. 2013; Pierce et al. 2013)....

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  • ...white and opaque cells (Pande et al. 2013; Tao et al. 2014)....

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  • ...For in vivo commensal experiments, an antibiotic-treated murine model of commensalism was used (Pande et al. 2013)....

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Journal ArticleDOI
TL;DR: It is proposed that gut microbiota dysbiosis is a collective feature of complex interactions between prokaryotic and eukaryotic microbial communities that can affect immunity and that can influence health and disease.
Abstract: Fungi and mammals share a co-evolutionary history and are involved in a complex web of interactions. Studies focused on commensal bacteria suggest that pathological changes in the microbiota, historically known as dysbiosis, are at the root of many inflammatory diseases of non-infectious origin. However, the importance of dysbiosis in the fungal community - the mycobiota - was only recently acknowledged to have a pathological role, as novel findings have suggested that mycobiota disruption can have detrimental effects on host immunity. Fungal dysbiosis and homeostasis are dynamic processes that are probably more common than actual fungal infections, and therefore constantly shape the immune response. In this Review, we summarize specific mycobiota patterns that are associated with fungal dysbiosis, and discuss how mucosal immunity has evolved to distinguish fungal infections from dysbiosis and how it responds to these different conditions. We propose that gut microbiota dysbiosis is a collective feature of complex interactions between prokaryotic and eukaryotic microbial communities that can affect immunity and that can influence health and disease.

227 citations

Journal ArticleDOI
TL;DR: Carbon sources influence virulence factor expression and innate immune surveillance and nutrients also affect stress resistance and antifungal drug susceptibility, which impacts Candida pathogenicity at multiple levels.

192 citations

References
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Journal ArticleDOI
TL;DR: Concurrent surveillance for nosocomial bloodstream infections at 49 hospitals over a 3-year period detected >10,000 infections, and coagulase-negative staphylococci were the most common pathogens on all clinical services except obstetrics, where Escherichia coli was most common.
Abstract: Nosocomial bloodstream infections are important causes of morbidity and mortality. In this study, concurrent surveillance for nosocomial bloodstream infections at 49 hospitals over a 3-year period detected >10,000 infections. Gram-positive organisms accounted for 64% of cases, gram-negative organisms accounted for 27%, and 8% were caused by fungi. The most common organisms were coagulase-negative staphylococci (32%), Staphylococcus aureus (16%), and enterococci (11%). Enterobacter, Serratia, coagulase-negative staphylococci, and Candida were more likely to cause infections in patients in critical care units. In patients with neutropenia, viridans streptococci were significantly more common. Coagulase-negative staphylococci were the most common pathogens on all clinical services except obstetrics, where Escherichia coli was most common. Methicillin resistance was detected in 29% of S. aureus isolates and 80% of coagulase-negative staphylococci. Vancomycin resistance in enterococci was species-dependent-3% of Enterococcus faecalis strains and 50% of Enterococcus faecium isolates displayed resistance. These data may allow clinicians to better target empirical therapy for hospital-acquired cases of bacteremia.

1,396 citations

Journal ArticleDOI
TL;DR: A gene bank of Sau3A partially digested Candida albicans DNA in vector YEp13 was used to complement a ura3 mutation, OMPdecase, which was sufficient to allow complementation in S. cerevisiae with integrating as well as high copy number vectors.
Abstract: A gene bank of Sau3A partially digested Candida albicans DNA in vector YEp13 was used to complement a ura3 mutation (orotidine-5'-phosphate decarboxylase, OMPdecase) in S. cerevisiae. Two plasmids which complemented ura3 and showed clear linkage of Ura+ and plasmid markers were selected for further study. Both plasmids also complemented the corresponding OMPdecase mutation (pyrF) in E. coli. Restriction mapping and subcloning studies localized the OMPdecase complementing activity to a region common to both plasmids. Probes prepared from this common region hybridized specifically to C. albicans DNA and not to E. coli or S. cerevisiae DNA. Southern blot analysis also showed that the restriction map of the ura3 complementing region of one plasmid was colinear with C. albicans genomic DNA. Expression of the OMPdecase complementing gene in E. coli and S. cerevisiae was not dependent upon orientation relative to vector sequences, suggesting that promotion could be occurring within the C. albicans fragment. Expression was sufficient to allow complementation in S. cerevisiae with integrating as well as high copy number vectors.

1,172 citations

Journal ArticleDOI
TL;DR: Critically discussed the data relevant to each of these seven criteria, with specific emphasis on how this proteinase family could contribute to Candida virulence and pathogenesis.
Abstract: Candida albicans is the most common fungal pathogen of humans and has developed an extensive repertoire of putative virulence mechanisms that allows successful colonization and infection of the host under suitable predisposing conditions. Extracellular proteolytic activity plays a central role in Candida pathogenicity and is produced by a family of 10 secreted aspartyl proteinases (Sap proteins). Although the consequences of proteinase secretion during human infections is not precisely known, in vitro, animal, and human studies have implicated the proteinases in C. albicans virulence in one of the following seven ways: (i) correlation between Sap production in vitro and Candida virulence, (ii) degradation of human proteins and structural analysis in determining Sap substrate specificity, (iii) association of Sap production with other virulence processes of C. albicans, (iv) Sap protein production and Sap immune responses in animal and human infections, (v) SAP gene expression during Candida infections, (vi) modulation of C. albicans virulence by aspartyl proteinase inhibitors, and (vii) the use of SAP-disrupted mutants to analyze C. albicans virulence. Sap proteins fulfill a number of specialized functions during the infective process, which include the simple role of digesting molecules for nutrient acquisition, digesting or distorting host cell membranes to facilitate adhesion and tissue invasion, and digesting cells and molecules of the host immune system to avoid or resist antimicrobial attack by the host. We have critically discussed the data relevant to each of these seven criteria, with specific emphasis on how this proteinase family could contribute to Candida virulence and pathogenesis.

1,111 citations

Journal ArticleDOI
TL;DR: Technological advances make it possible to apply molecular methods to develop a stable classification and to discover and identify fungal taxa, revealing a monophyletic kingdom and increased diversity among early-diverging lineages.
Abstract: Premise of the study Fungi are major decomposers in certain ecosystems and essential associates of many organisms. They provide enzymes and drugs and serve as experimental organisms. In 1991, a landmark paper estimated that there are 1.5 million fungi on the Earth. Because only 70000 fungi had been described at that time, the estimate has been the impetus to search for previously unknown fungi. Fungal habitats include soil, water, and organisms that may harbor large numbers of understudied fungi, estimated to outnumber plants by at least 6 to 1. More recent estimates based on high-throughput sequencing methods suggest that as many as 5.1 million fungal species exist. Methods Technological advances make it possible to apply molecular methods to develop a stable classification and to discover and identify fungal taxa. Key results Molecular methods have dramatically increased our knowledge of Fungi in less than 20 years, revealing a monophyletic kingdom and increased diversity among early-diverging lineages. Mycologists are making significant advances in species discovery, but many fungi remain to be discovered. Conclusions Fungi are essential to the survival of many groups of organisms with which they form associations. They also attract attention as predators of invertebrate animals, pathogens of potatoes and rice and humans and bats, killers of frogs and crayfish, producers of secondary metabolites to lower cholesterol, and subjects of prize-winning research. Molecular tools in use and under development can be used to discover the world's unknown fungi in less than 1000 years predicted at current new species acquisition rates.

1,094 citations

Journal ArticleDOI
TL;DR: The impact of candidemia on excess mortality, increased length of stay, and the burden of cost of hospitalization underscores the need for improved means of prevention and treatment ofCandida species in adults and children.
Abstract: Background Candida species are the fourth most common cause of bloodstream infection and are the leading cause of invasive fungal infection among hospitalized patients in the United States. However, the frequency and outcomes attributable to the infection are uncertain. This retrospective study set out to estimate the incidence of candidemia in hospitalized adults and children in the United States and to determine attributable mortality, length of hospital stay, and hospital charges related to candidemia. Methods We used the Nationwide Inpatient Sample 2000 for adult patients and the Kids' Inpatient Database 2000 for pediatric patients. We matched candidemia-exposed and candidemia-unexposed patients by the propensity scores for the probability of candidemia exposure, which were derived from patient characteristics. Attributable outcomes were calculated as the differences in estimates of outcomes between propensity score-matched patients with and without candidemia. Results In the United States in 2000, candidemia was diagnosed in an estimated 1118 hospital admissions of pediatric patients and 8949 hospital admissions of adult patients, yielding a frequency of 43 cases per 100,000 pediatric admissions (95% confidence interval [CI], 35-52 cases per 100,000 pediatric admissions) and 30 cases per 100,000 adult admissions (95% CI, 26-34 cases per 100,000 adult admissions). In pediatric patients, candidemia was associated with a 10.0% increase in mortality (95% CI, 6.2%-13.8%), a mean 21.1-day increase in length of stay (95% CI, 14.4-27.8 days), and a mean increase in total per-patient hospital charges of 92,266 dollars (95% CI, 65,058 dollars-119,474 dollars). In adult patients, candidemia was associated with a 14.5% increase in mortality (95% CI, 12.1%-16.9%), a mean 10.1-day increase in length of stay (95% CI, 8.9-11.3 days), and a mean increase in hospital charges of 39,331 dollars (95% CI, 33,604 dollars-45,602 dollars). Conclusion The impact of candidemia on excess mortality, increased length of stay, and the burden of cost of hospitalization underscores the need for improved means of prevention and treatment of candidemia in adults and children.

765 citations