The Human Gut Microbial Metabolome Modulates Fungal Growth via the TOR Signaling Pathway

ABSTRACT Candida albicans is a natural component of the human microbiota but also an opportunistic pathogen that causes life-threatening infections. The human gastrointestinal tract is the main reservoir of C. albicans, from where systemic infections originate as a consequence of the disruption of the intestinal mucosal barrier. Recent studies provided convincing evidence that overgrowth of C. albicans and other related species in the gut is predominantly associated with chronic intestinal inflammatory bowel diseases. Here, we showed, for the first time, the antagonistic interkingdom interactions between C. albicans and common intestinal commensal bacteria. From a therapeutic perspective, administering a defined bacterial community, such as the one described here with anti-Candida activity, could provide potential therapeutic protection against gastrointestinal inflammatory diseases. Candida albicans is well known as a major human fungal pathogen, but it is also a permanent resident of healthy gastrointestinal tracts. Recent studies have shown that the human gut microbial metabolome represents an interesting source of bioactive molecules with a significant degree of chemical diversity. Some of these bioactive molecules may have useful antivirulence activities. For instance, intestinal bacterial species belonging to the Lachnospiraceae family were found to secrete molecules that attenuate Salmonella pathogenicity and repress the expression of virulence genes. Here, we have investigated whether the microbial gut metabolome (GM) contains molecules that might promote the commensal lifestyle and/or inhibit the expression of virulence of C. albicans in the intestine. We found that metabolites from human feces inhibited the growth of C. albicans and other opportunistic yeasts. A genetic screen in C. albicans suggested that TOR is the molecular target of the antifungal molecule(s) of the GM. In addition, we found that the GM metabolites inhibit both C. albicans hyphal growth and the invasion of human enterocytes. The antigrowth and antivirulence activities were partially recapitulated by secretions from Roseburia spp. and Bacteroides ovatus strains, respectively. This study demonstrates that the antimicrobial activity of the GM can be extended to a eukaryotic pathogen, C. albicans, illuminating the antagonistic interkingdom interactions between a fungus and intestinal commensal bacteria. IMPORTANCE Candida albicans is a natural component of the human microbiota but also an opportunistic pathogen that causes life-threatening infections. The human gastrointestinal tract is the main reservoir of C. albicans, from where systemic infections originate as a consequence of the disruption of the intestinal mucosal barrier. Recent studies provided convincing evidence that overgrowth of C. albicans and other related species in the gut is predominantly associated with chronic intestinal inflammatory bowel diseases. Here, we showed, for the first time, the antagonistic interkingdom interactions between C. albicans and common intestinal commensal bacteria. From a therapeutic perspective, administering a defined bacterial community, such as the one described here with anti-Candida activity, could provide potential therapeutic protection against gastrointestinal inflammatory diseases.

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A Novel Function for Hog1 Stress-Activated Protein Kinase in Controlling White-Opaque Switching and Mating in Candida albicans

Eukaryotic Cell ◽

10.1128/ec.00235-14 ◽

2014 ◽

Vol 13 (12) ◽

pp. 1557-1566 ◽

Cited By ~ 20

Author(s):

Shen-Huan Liang ◽

Jen-Hua Cheng ◽

Fu-Sheng Deng ◽

Pei-An Tsai ◽

Ching-Hsuan Lin

Keyword(s):

Candida Albicans ◽

Protein Kinase ◽

Synthetic Medium ◽

Opportunistic Pathogen ◽

Phenotypic Switch ◽

Content Type ◽

Host Interactions ◽

Main Pathway ◽

Phenotypic Transition ◽

External Stimuli

ABSTRACTCandida albicansis a commensal in heathy people but has the potential to become an opportunistic pathogen and is responsible for half of all clinical infections in immunocompromised patients. Central to understandingC. albicansbehavior is the white-opaque phenotypic switch, in which cells can undergo an epigenetic transition between the white state and the opaque state. The phenotypic switch regulates multiple properties, including biofilm formation, virulence, mating, and fungus-host interactions. Switching between the white and opaque states is associated with many external stimuli, such as oxidative stress, pH, andN-acetylglucosamine, and is directly regulated by the Wor1 transcriptional circuit. The Hog1 stress-activated protein kinase (SAPK) pathway is recognized as the main pathway for adapting to environmental stress inC. albicans. In this work, we first show that loss of theHOG1gene ina/aand α/α cells, but nota/α cells, results in 100% white-to-opaque switching when cells are grown on synthetic medium, indicating that switching is repressed by thea1/α2 heterodimer that repressesWOR1gene expression. Indeed, switching in thehog1Δ strain was dependent on the presence ofWOR1, as ahog1Δwor1Δ strain did not show switching to the opaque state. Deletion ofPBS2andSSK2also resulted inC. albicanscells switching from white to opaque with 100% efficiency, indicating that the entire Hog1 SAPK pathway is involved in regulating this unique phenotypic transition. Interestingly, all Hog1 pathway mutants also caused defects in shmoo formation and mating efficiencies. Overall, this work reveals a novel role for the Hog1 SAPK pathway in regulating white-opaque switching and sexual behavior inC. albicans.

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Identification of a Cell Death Pathway in Candida albicans during the Response to Pheromone

Eukaryotic Cell ◽

10.1128/ec.00155-10 ◽

2010 ◽

Vol 9 (11) ◽

pp. 1690-1701 ◽

Cited By ~ 12

Author(s):

Kevin Alby ◽

Dana Schaefer ◽

Racquel Kim Sherwood ◽

Stephen K. Jones ◽

Richard J. Bennett

Keyword(s):

Cell Death ◽

Candida Albicans ◽

Laboratory Strain ◽

Opportunistic Pathogen ◽

Cell Types ◽

Yeast Cells ◽

Phenotypic Switching ◽

Morphological Response ◽

Content Type ◽

Cell Death Pathway

ABSTRACT Mating in hemiascomycete yeasts involves the secretion of pheromones that induce sexual differentiation in cells of the opposite mating type. Studies in Saccharomyces cerevisiae have revealed that a subpopulation of cells experiences cell death during exposure to pheromone. In this work, we tested whether the phenomenon of pheromone-induced death (PID) also occurs in the opportunistic pathogen Candida albicans. Mating in C. albicans is uniquely regulated by white-opaque phenotypic switching; both cell types respond to pheromone, but only opaque cells undergo the morphological transition and cell conjugation. We show that approximately 20% of opaque cells, but not white cells, of laboratory strain SC5314 experience pheromone-induced death. Furthermore, analysis of mutant strains revealed that PID was significantly reduced in strains lacking Fig1 or Fus1 transmembrane proteins that are induced during the mating process and, we now show, are necessary for efficient mating in C. albicans. The level of PID was also Ca2+ dependent, as chelation of Ca2+ ions increased cell death to almost 50% of the population. However, in contrast to S. cerevisiae PID, pheromone-induced killing of C. albicans cells was largely independent of signaling via the Ca2+-dependent protein phosphatase calcineurin, even when combined with the loss of Cmk1 and Cmk2 proteins. Finally, we demonstrate that levels of PID vary widely between clinical isolates of C. albicans, with some strains experiencing close to 70% cell death. We discuss these findings in light of the role of prodeath and prosurvival pathways operating in yeast cells undergoing the morphological response to pheromone.

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The Genomic Landscape of the Fungus-Specific SWI/SNF Complex Subunit, Snf6, in Candida albicans

mSphere ◽

10.1128/msphere.00497-17 ◽

2017 ◽

Vol 2 (6) ◽

Cited By ~ 10

Author(s):

Faiza Tebbji ◽

Yaolin Chen ◽

Adnane Sellam ◽

Malcolm Whiteway

Keyword(s):

Candida Albicans ◽

Chromatin Remodeling ◽

Opportunistic Pathogen ◽

Resistance Mechanisms ◽

Phenotypic Data ◽

Content Type ◽

Chromatin Remodeling Complex ◽

Clinical Resistance ◽

Immunosuppressed Patients

ABSTRACT Candida albicans is a natural component of the human microbiota but also an opportunistic pathogen that causes life-threatening infections in immunosuppressed patients. Current therapeutics include a limited number of molecules that suffer from limitations, including growing clinical resistance and toxicity. New molecules are being clinically investigated; however, the majority of these potential antifungals target the same processes as do the standard antifungals and might confront the same problems of toxicity and loss of efficiency due to the common resistance mechanisms. Here, we characterized the role of Snf6, a fungus-specific subunit of the chromatin-remodeling complex SWI/SNF. Our genomic and phenotypic data demonstrated a central role of Snf6 in biological processes that are critical for a fungal pathogen to colonize its host and cause disease, suggesting Snf6 as a possible antifungal target. SWI/SNF is an ATP-dependent chromatin-remodeling complex that is required for the regulation of gene expression in eukaryotes. While most of the fungal SWI/SNF components are evolutionarily conserved with those of the metazoan SWI/SNF, subunits such as Snf6 are specific to certain fungi and thus represent potential antifungal targets. We have characterized the role of the Snf6 protein in Candida albicans. Our data showed that although there was low conservation of its protein sequence with other fungal orthologs, Snf6 was copurified with bona fide SWI/SNF complex subunits. The role of Snf6 in C. albicans was investigated by determining its genome-wide occupancy using chromatin immunoprecipitation coupled to tiling arrays in addition to transcriptional profiling of the snf6 conditional mutant. Snf6 directs targets that were enriched in functions related to carbohydrate and amino acid metabolic circuits, to cellular transport, and to heat stress responses. Under hypha-promoting conditions, Snf6 expanded its set of targets to include promoters of genes related to respiration, ribosome biogenesis, mating, and vesicle transport. In accordance with the genomic occupancy data, an snf6 doxycycline-repressible mutant exhibited growth defects in response to heat stress and also when grown in the presence of different fermentable and nonfermentable carbon sources. Snf6 was also required to differentiate invasive hyphae in response to different cues. This study represents the first comprehensive characterization, at the genomic level, of the role of SWI/SNF in the pathogenic yeast C. albicans and uncovers functions that are essential for fungal morphogenesis and metabolic flexibility. IMPORTANCE Candida albicans is a natural component of the human microbiota but also an opportunistic pathogen that causes life-threatening infections in immunosuppressed patients. Current therapeutics include a limited number of molecules that suffer from limitations, including growing clinical resistance and toxicity. New molecules are being clinically investigated; however, the majority of these potential antifungals target the same processes as do the standard antifungals and might confront the same problems of toxicity and loss of efficiency due to the common resistance mechanisms. Here, we characterized the role of Snf6, a fungus-specific subunit of the chromatin-remodeling complex SWI/SNF. Our genomic and phenotypic data demonstrated a central role of Snf6 in biological processes that are critical for a fungal pathogen to colonize its host and cause disease, suggesting Snf6 as a possible antifungal target.

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Put3 Positively Regulates Proline Utilization in Candida albicans

mSphere ◽

10.1128/msphere.00354-17 ◽

2017 ◽

Vol 2 (6) ◽

Cited By ~ 9

Author(s):

Walters Aji Tebung ◽

Raha Parvizi Omran ◽

Debra L. Fulton ◽

Joachim Morschhäuser ◽

Malcolm Whiteway

Keyword(s):

Saccharomyces Cerevisiae ◽

Transcription Factor ◽

Candida Albicans ◽

Nitrogen Source ◽

Opportunistic Pathogen ◽

Baker's Yeast ◽

Null Mutant ◽

Multiple Sources ◽

Content Type ◽

Proline Catabolism

ABSTRACT Candida albicans poses a significant threat to the lives of immunocompromised people. Historically, knowledge has been drawn from studies on Saccharomyces cerevisiae to understand the pathogen, and many Candida albicans genes are named after their S. cerevisiae orthologs. Direct studies on the pathogen have, however, revealed differences in the roles of some orthologous proteins in the two yeasts. We show that the Put3 transcription factor allows the pathogen to completely degrade proline to usable nitrogen and carbon by evading regulatory restrictions imposed on its S. cerevisiae ortholog, which mandates conditional use of proline only as a nitrogen source in the baker’s yeast. The ability of Candida albicans to freely obtain nutrients from multiple sources may help it thrive as a commensal and opportunistic pathogen. The zinc cluster transcription factor Put3 was initially characterized in Saccharomyces cerevisiae as the transcriptional activator of PUT1 and PUT2, two genes acting early in the proline assimilation pathway. We have used phenotypic studies, transcription profiling, and chromatin immunoprecipitation with microarray technology (ChIP-chip) to establish that unlike S. cerevisiae, which only uses proline as a nitrogen source, Candida albicans can use proline as a nitrogen source, a carbon source, or a source of both nitrogen and carbon. However, a C. albicans put3 null mutant cannot grow on proline, suggesting that as in S. cerevisiae, C. albicans Put3 (CaPut3) is required for proline catabolism, and because the C. albicans put3 null mutant grew efficiently on glutamate as the sole carbon or nitrogen source, it appears that CaPut3 also regulates the early genes of the pathway. CaPut3 showed direct binding to the CaPUT1 promoter, and both PUT1 and PUT2 were upregulated in response to proline addition in a Put3-dependent manner, as well as in a C. albicans strain expressing a hyperactive Put3. CaPut3 directs proline degradation even in the presence of a good nitrogen source such as ammonia, which contrasts with S. cerevisiae Put3 (ScPut3)-regulated proline catabolism, which only occurs in the absence of a rich nitrogen source. Thus, while overall proline regulatory circuitry differs between S. cerevisiae and C. albicans, the specific role of Put3 appears fundamentally conserved. IMPORTANCE Candida albicans poses a significant threat to the lives of immunocompromised people. Historically, knowledge has been drawn from studies on Saccharomyces cerevisiae to understand the pathogen, and many Candida albicans genes are named after their S. cerevisiae orthologs. Direct studies on the pathogen have, however, revealed differences in the roles of some orthologous proteins in the two yeasts. We show that the Put3 transcription factor allows the pathogen to completely degrade proline to usable nitrogen and carbon by evading regulatory restrictions imposed on its S. cerevisiae ortholog, which mandates conditional use of proline only as a nitrogen source in the baker’s yeast. The ability of Candida albicans to freely obtain nutrients from multiple sources may help it thrive as a commensal and opportunistic pathogen.

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Candidalysin Crucially Contributes to Nlrp3 Inflammasome Activation by Candida albicans Hyphae

mBio ◽

10.1128/mbio.02221-18 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 24

Author(s):

Ona Rogiers ◽

Ulrika C. Frising ◽

Soňa Kucharíková ◽

Mary Ann Jabra-Rizk ◽

Geert van Loo ◽

...

Keyword(s):

Candida Albicans ◽

Nlrp3 Inflammasome ◽

Molecular Mechanisms ◽

Myeloid Cell ◽

Opportunistic Pathogen ◽

Cell Immune Response ◽

Inflammasome Activation ◽

Dependent Manner ◽

Morphological Transformation ◽

Content Type

ABSTRACT Candida albicans is an opportunistic fungal pathogen that can cause life-threatening infections, particularly in immunocompromised patients. C. albicans induced activation of the Nlrp3 inflammasome, leading to secretion of bioactive interleukin 1β (IL-1β) is a crucial myeloid cell immune response needed for antifungal host defense. Being a pleiomorphic fungus, C. albicans can provoke Nlrp3 inflammasome responses only upon morphological transformation to its hyphal appearance. However, the specific hyphal factors that enable C. albicans to activate the Nlrp3 inflammasome in primary macrophages remain to be revealed. Here, we identify candidalysin, a peptide derived from the hypha-specific ECE1 gene, as a fungal trigger for Nlrp3 inflammasome-mediated maturation and secretion of IL-1β from primary macrophages. Direct peptide administration experiments showed that candidalysin was sufficient for inducing secretion of mature IL-1β from macrophages in an Nlrp3 inflammasome-dependent manner. Conversely, infection experiments using candidalysin-deficient C. albicans showed that candidalysin crucially contributed to the capacity of this fungus to induce maturation and secretion of IL-1β from primary macrophages. These complementary observations identify the expression of candidalysin as one of the molecular mechanisms by which hyphal transformation equips C. albicans with its proinflammatory capacity to elicit the release of bioactive IL-1β from macrophages. IMPORTANCE Candidiasis is a potentially lethal condition that is caused by systemic dissemination of Candida albicans, a common fungal commensal residing mostly on mucosal surfaces. The transition of C. albicans from an innocuous commensal to an opportunistic pathogen goes hand in hand with its morphological transformation from a fungus to a hyphal appearance. On the one hand, the latter manifestation enables C. albicans to penetrate tissues, while on the other hand, the expression of many hypha-specific genes also endows it with the capacity to trigger particular cytokine responses. The Nlrp3 inflammasome is a crucial component of the innate immune system that provokes release of the IL-1β cytokine from myeloid cells upon encountering C. albicans hyphae. Our study reveals the peptide candidalysin as one of the hypha-derived drivers of Nlrp3 inflammasome responses in primary macrophages and, thus, contributes to better understanding the fungal mechanisms that determine the pathogenicity of C. albicans.

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Are Patients with Inflammatory Bowel Disease at Increased Risk for Covid-19 Infection?

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjaa061 ◽

2020 ◽

Vol 14 (9) ◽

pp. 1334-1336 ◽

Cited By ~ 55

Author(s):

Giovanni Monteleone ◽

Sandro Ardizzone

Keyword(s):

Intestinal Inflammation ◽

Inflammatory Diseases ◽

Convincing Evidence ◽

Complex Interaction ◽

The Novel ◽

Relevant Today ◽

Increased Risk ◽

Bowel Diseases ◽

Patients At Risk ◽

Inflammatory Bowel

Abstract Crohn’s disease [CD] and ulcerative colitis [UC], the main inflammatory bowel diseases [IBD] in humans, are chronic, immune-inflammatory diseases, the pathogenesis of which suggests a complex interaction between environmental factors and genetic susceptibility. These disabling conditions affect millions of individuals and, together with the drugs used to treat them, can put patients at risk of developing complications and other conditions. This is particularly relevant today, as coronavirus disease [Covid-19] has rapidly spread from China to countries where IBD are more prevalent, and there is convincing evidence that Covid-19-mediated morbidity and mortality are higher in subjects with comorbidities. The primary objectives of this Viewpoint are to provide a focused overview of the factors and mechanisms by which the novel severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infects cells and to illustrate the link between such determinants and intestinal inflammation. We also provide clues about the reasons why the overall IBD population might have no increased risk of developing SARS-CoV-2 infection and highlight the potential of cytokine blockers, used to treat IBD patients, to prevent Covid-driven pneumonia.

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Corynebacterium pseudodiphtheriticumExploitsStaphylococcus aureusVirulence Components in a Novel Polymicrobial Defense Strategy

mBio ◽

10.1128/mbio.02491-18 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 24

Author(s):

Britney L. Hardy ◽

Seth W. Dickey ◽

Roger D. Plaut ◽

Daniel P. Riggins ◽

Scott Stibitz ◽

...

Keyword(s):

Nasal Cavity ◽

Bactericidal Activity ◽

Low Frequency ◽

Opportunistic Pathogen ◽

Commensal Bacteria ◽

Nasal Colonization ◽

Antimicrobial Compounds ◽

Content Type ◽

Corynebacterium Pseudodiphtheriticum ◽

The Cost

ABSTRACTCommensal bacteria in the human nasal cavity are known to suppress opportunistic pathogen colonization by competing for limited space and nutrients. It has become increasingly apparent that some commensal bacteria also produce toxic compounds that directly inhibit or kill incoming competitors. Numerous studies suggest that microbial species-specific interactions can affect human nasal colonization by the opportunistic pathogenStaphylococcus aureus. However, the complex and dynamic molecular interactions that mediate these effects onS. aureusnasal colonization are often difficult to study and remain poorly understood. Here, we show thatCorynebacterium pseudodiphtheriticum, a common member of the normal nasal microbiota, mediates contact-independent bactericidal activity againstS. aureus, including methicillin-resistantS. aureus(MRSA). Bacterial interaction assays revealed thatS. aureusisolates that were spontaneously resistant toC. pseudodiphtheriticumkilling could be recovered at a low frequency. To better understand the pathways associated with killing and resistance, aS. aureustransposon mutant library was utilized to select for resistant mutant strains. We found that insertional inactivation ofagrC, which codes for the sensor kinase of the Agr quorum sensing (Agr QS) system that regulates expression of many virulence factors inS. aureus, conferred resistance to killing. Analysis of the spontaneously resistantS. aureusisolates revealed that each showed decreased expression of the Agr QS components. Targeted analysis of pathways regulated by Agr QS revealed that loss of the phenol-soluble modulins (PSMs), which are effectors of Agr QS, also conferred resistance to bactericidal activity. Transmission electron microscopy analysis revealed thatC. pseudodiphtheriticuminduced dramatic changes toS. aureuscell surface morphology that likely resulted in cell lysis. Taken together, these data suggest thatC. pseudodiphtheriticum-mediated killing ofS. aureusrequiresS. aureusvirulence components. WhileS. aureuscan overcome targeted killing, this occurs at the cost of attenuated virulence; loss of Agr QS activity would phenotypically resemble aS. aureuscommensal state that would be unlikely to be associated with disease. Commensal competition resulting in dampened virulence of the competitor may represent an exciting and unexplored possibility for development of novel antimicrobial compounds.IMPORTANCEWhile some individuals are nasally colonized withS. aureus, the underlying factors that determine colonization are not understood. There is increasing evidence that indicates that resident bacteria play a role; some commensal species can eradicateS. aureusfrom the nasal cavity. Among these,Corynebacterium pseudodiphtheriticumcan eliminateS. aureusfrom the human nose. We sought to understand this phenomenon at a molecular level and found thatC. pseudodiphtheriticumproduces a factor(s) that specifically killsS. aureus. While resistantS. aureusisolates were recovered at a low frequency, resistance came at the cost of attenuated virulence in these strains. Molecular dissection of the specific strategies used byC. pseudodiphtheriticumto killS. aureuscould lead to the development of novel treatments or therapies. Furthermore, commensal competition that requires virulence components of the competitor may represent an exciting and unexplored possibility for development of novel antimicrobial compounds.

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Anal abscess – a trivial disease or a serious one?

Nowa Medycyna ◽

10.25121/nm.2019.26.1.20 ◽

2019 ◽

Vol 26 (1) ◽

Author(s):

Małgorzata Kołodziejczak ◽

Przemysław Ciesielski

Keyword(s):

Inflammatory Diseases ◽

Postoperative Management ◽

Immunocompromised Patients ◽

Anal Abscess ◽

Septic Complications ◽

Inappropriate Treatment ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

The One ◽

Seriously Ill

A patient who reports to the hospital due to anal abscess is often treated as not seriously ill, although in about 40% of cases, abscess may initiate anal fistula development, and the one that is not or insufficiently emptied, may also cause septic complications that directly threaten patient’s life. The majority of inflammatory diseases in the rectum, including abscesses and anal fistulae, are a growing infection in the anal crypts. In recent years, a large group of patients with rectal abscesses have been patients with inflammatory bowel diseases, as well as immunocompromised patients, e.g. in the course of HIV infection. The anal abscess in any case should be urgently treated by its opening and drainage. The majority of patients with rectal abscesses should be admitted to the hospital and operated in the operating block, in adequate anesthesia (regional or general). The article discusses recommendations for the opening of low and high abscesses, postoperative management and possible complications associated with this disease and its inappropriate treatment. An abscess of the anus, generally considered a trivial disease, treated inappropriately, can cause serious complications.

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Antimicrobial Peptides Human Beta-Defensin-2 and -3 Protect the Gut During Candida albicans Infections Enhancing the Intestinal Barrier Integrity: In Vitro Study

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.666900 ◽

2021 ◽

Vol 11 ◽

Author(s):

Alessandra Fusco ◽

Vittoria Savio ◽

Maria Donniacuo ◽

Brunella Perfetto ◽

Giovanna Donnarumma

Keyword(s):

Candida Albicans ◽

Epithelial Cells ◽

Antimicrobial Peptides ◽

Intestinal Barrier ◽

In Vitro Study ◽

Opportunistic Pathogen ◽

Mucosal Barrier ◽

Apoptotic Pathway ◽

Intestinal Pathogens

The intestinal mucosa is composed of a monolayer of epithelial cells, which is highly polarized and firmly united to each other thanks to the presence of proteins complexes, called Tight junctions (TJs). Alteration of the mucus layer and TJs causes an increase in intestinal permeability, which can lead to a microbial translocation and systemic disorders. Candida albicans, in addition to its role of commensal, is an opportunistic pathogen responsible for disseminated candidiasis, especially in immunocompromised subjects where the dysbiosis leads to damage of the intestinal mucosal barrier . In this work, we used a line of intestinal epithelial cells able to stably express the genes that encodes human beta defensin-2 (HBD-2) and -3 (HBD-3) to monitor the invasion of C. albicans in vitro. Defensins are a group of antimicrobial peptides (AMPs) found in different living organisms, and are involved in the first line of defense in the innate immune response against pathogens. The results obtained show that the presence of antimicrobial peptides improves the expression of TJs and increases the Trans Epithelial Electrical Resistence value. In addition, the invasive ability of C. albicans in transfected cells is significantly reduced, as well as the expression levels of genes involved in the apoptotic pathway. Through the study of interaction between antimicrobial peptides and microbiota we will be able in the future to better understand the mechanisms by which they exert the host defense function against intestinal pathogens.

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EFG1 Mutations, Phenotypic Switching, and Colonization by Clinical a/α Strains of Candida albicans

mSphere ◽

10.1128/msphere.00795-19 ◽

2020 ◽

Vol 5 (1) ◽

Cited By ~ 3

Author(s):

Yang-Nim Park ◽

Kayla Conway ◽

Claude Pujol ◽

Karla J. Daniels ◽

David R. Soll

Keyword(s):

Candida Albicans ◽

Microscopic Analysis ◽

Great Majority ◽

Phenotypic Switching ◽

Live Cells ◽

Content Type ◽

Dominant Phenotype ◽

Colonization Model ◽

The One ◽

Model Support

ABSTRACT The transcription factor EFG1 functions as a suppressor of white-to-opaque and white-to-gray switching in a/α strains of Candida albicans. In a collection of 27 clinical isolates, 4 of the 17 EFG1/EFG1 strains, 1 of the 2 EFG1/efg1 strains, and all 8 of the efg1/efg1 strains underwent white-to-opaque switching. The four EFG1/EFG1 strains, the one EFG1/efg1 strain, and one of the eight efg1/efg1 strains that underwent switching to opaque did not switch to gray and could not be complemented with a copy of EFG1. Competition experiments in a mouse model for gastrointestinal (GI) colonization confirmed that efg1/efg1 cells rapidly outcompete EFG1/EFG1 cells, and in plating experiments, formed colonies containing both gray and opaque cells. Direct microscopic analysis of live cells in the feces, however, revealed that the great majority of cells were opaque, suggesting opaque, not gray, may be the dominant phenotype at the site of colonization. IMPORTANCE Close to half of a collection of 27 clinical a/α isolates of Candida albicans underwent white-to-opaque switching. Complementation experiments revealed that while approximately half of the a/α switchers were due to EFG1 mutations, the remaining half were due to mutations in other genes. In addition, the results of competition experiments in a mouse GI tract colonization model support previous observations that efg1/efg1 cells rapidly outcompete EFG1/EFG1 strains, but direct microscopic analysis reveals that the major colonizing cells were opaque, not gray.

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