Repurposing Pilocarpine Hydrochloride for Treatment of Candida albicans Infections

Candida albicans is the most common human fungal pathogen with an estimated crude mortality rate of 40%. The ability of the organism to switch from the yeast to hyphal form and produce biofilms are important virulence factors. C. albicans infections are combatted by the host immune system. However, Candida triggers a strong inflammatory response that, if not appropriately regulated, can damage host tissues. Therefore, it is important that the host immune response eliminates the fungus but limits tissue damage. This study provides evidence that targeting cholinergic receptors cannot only curb the virulence of C. albicans by inhibiting filamentous growth and biofilm formation but can also appropriately regulate the host immune response to induce rapid clearance with limited damage to vital tissues. This article provides evidence that repurposing licensed drugs that target cholinergic receptors may offer novel therapeutic solutions for the prevention or treatment of fungal infections.

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Clinical Candida albicans Vaginal Isolates and a Laboratory Strain Show Divergent Behaviors during Macrophage Interactions

mSphere ◽

10.1128/msphere.00393-20 ◽

2020 ◽

Vol 5 (4) ◽

Author(s):

Franziska Gerwien ◽

Christine Dunker ◽

Philipp Brandt ◽

Enrico Garbe ◽

Ilse D. Jacobsen ◽

...

Keyword(s):

Candida Albicans ◽

Fungal Infections ◽

Laboratory Strain ◽

Infection Process ◽

Vulvovaginal Candidiasis ◽

Host Immune System ◽

Host Pathogen Interactions ◽

Content Type ◽

Host Pathogen

ABSTRACT Typically, established lab strains are widely used to study host-pathogen interactions. However, to better reflect the infection process, the experimental use of clinical isolates has come more into focus. Here, we analyzed the interaction of multiple vaginal isolates of the opportunistic fungal pathogen Candida albicans, the most common cause of vulvovaginal candidiasis in women, with key players of the host immune system: macrophages. We tested several strains isolated from asymptomatic or symptomatic women with acute and recurrent infections. While all clinical strains showed a response similar to the commonly used lab strain SC5314 in various in vitro assays, they displayed remarkable differences during interaction with macrophages. This coincided with significantly reduced β-glucan exposure on the cell surface, which appeared to be a shared property among the tested vaginal strains for yeast extract/peptone/dextrose-grown cells, which is partly lost when the isolates faced vaginal niche-like nutrient conditions. However, macrophage damage, survival of phagocytosis, and filamentation capacities were highly strain-specific. These results highlight the high heterogeneity of C. albicans strains in host-pathogen interactions, which have to be taken into account to bridge the gap between laboratory-gained data and disease-related outcomes in an actual patient. IMPORTANCE Vulvovaginal candidiasis is one of the most common fungal infections in humans with Candida albicans as the major causative agent. This study is the first to compare clinical vaginal isolates of defined patient groups in their interaction with macrophages, highlighting the vastly different outcomes in comparison to a laboratory strain using commonly applied virulence-determining assays.

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Candida albicans CUG Mistranslation Is a Mechanism To Create Cell Surface Variation

mBio ◽

10.1128/mbio.00285-13 ◽

2013 ◽

Vol 4 (4) ◽

Cited By ~ 51

Author(s):

Isabel Miranda ◽

Ana Silva-Dias ◽

Rita Rocha ◽

Rita Teixeira-Santos ◽

Carolina Coelho ◽

...

Keyword(s):

Candida Albicans ◽

Cell Surface ◽

Fungal Pathogen ◽

Single Gene ◽

Yeast Cells ◽

Phenotypic Switching ◽

Leucine Incorporation ◽

Host Immune System ◽

Content Type ◽

Human Fungal Pathogen

ABSTRACT In the human fungal pathogen Candida albicans, the CUG codon is translated 97% of the time as serine and 3% of the time as leucine, which potentially originates an array of proteins resulting from the translation of a single gene. Genes encoding cell surface proteins are enriched in CUG codons; thus, CUG mistranslation may influence the interactions of the organism with the host. To investigate this, we compared a C. albicans strain that misincorporates 28% of leucine at CUGs with a wild-type parental strain. The first strain displayed increased adherence to inert and host molecules. In addition, it was less susceptible to phagocytosis by murine macrophages, probably due to reduced exposure of cell surface β-glucans. To prove that these phenotypes occurred due to serine/leucine exchange, the C. albicans adhesin and invasin ALS3 was expressed in Saccharomyces cerevisiae in its two natural isoforms (Als3p-Leu and Als3p-Ser). The cells with heterologous expression of Als3p-Leu showed increased adherence to host substrates and flocculation. We propose that CUG mistranslation has been maintained during the evolution of C. albicans due to its potential to generate cell surface variability, which significantly alters fungus-host interactions. IMPORTANCE The translation of genetic information into proteins is a highly accurate cellular process. In the human fungal pathogen Candida albicans, a unique mistranslation event involving the CUG codon occurs. The CUG codon is mainly translated as serine but can also be translated as leucine. Leucine and serine are two biochemically distinct amino acids, hydrophobic and hydrophilic, respectively. The increased rate of leucine incorporation at CUG decoding triggers C. albicans virulence attributes, such as morphogenesis, phenotypic switching, and adhesion. Here, we show that CUG mistranslation masks the fungal cell wall molecule β-glucan that is normally recognized by the host immune system, delaying its response. Furthermore, we demonstrate that two different proteins of the adhesin Als3 generated by CUG mistranslation confer increased hydrophobicity and adhesion ability on yeast cells. Thus, CUG mistranslation functions as a mechanism to create protein diversity with differential activities, constituting an advantage for a mainly asexual microorganism. This could explain its preservation during evolution.

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Cryptococcus neoformans Rim101 Is Associated with Cell Wall Remodeling and Evasion of the Host Immune Responses

mBio ◽

10.1128/mbio.00522-12 ◽

2013 ◽

Vol 4 (1) ◽

Cited By ~ 55

Author(s):

Teresa R. O'Meara ◽

Stephanie M. Holmer ◽

Kyla Selvig ◽

Fred Dietrich ◽

J. Andrew Alspaugh

Keyword(s):

Immune Response ◽

Cell Wall ◽

Transcription Factor ◽

Immune System ◽

Immune Responses ◽

Cryptococcus Neoformans ◽

Host Immune Response ◽

Host Immune System ◽

Content Type ◽

Host Pathogen

ABSTRACTInfectious microorganisms often play a role in modulating the immune responses of their infected hosts. We demonstrate thatCryptococcus neoformanssignals through the Rim101 transcription factor to regulate cell wall composition and the host-pathogen interface. In the absence of Rim101,C. neoformansexhibits an altered cell surface in response to host signals, generating an excessive and ineffective immune response that results in accelerated host death. This host immune response to therim101Δ mutant strain is characterized by increased neutrophil influx into the infected lungs and an altered pattern of host cytokine expression compared to the response to wild-type cryptococcal infection. To identify genes associated with the observed phenotypes, we performed whole-genome RNA sequencing experiments under capsule-inducing conditions. We defined the downstream regulon of the Rim101 transcription factor and determined potential cell wall processes involved in the capsule attachment defects and altered mechanisms of virulence in therim101Δ mutant. The cell wall generates structural stability for the cell and allows the attachment of surface molecules such as capsule polysaccharides. In turn, the capsule provides an effective mask for the immunogenic cell wall, shielding it from recognition by the host immune system.IMPORTANCECryptococcus neoformansis an opportunistic human pathogen that is a significant cause of death in immunocompromised individuals. There are two major causes of death due to this pathogen: meningitis due to uncontrolled fungal proliferation in the brain in the face of a weakened immune system and immune reconstitution inflammatory syndrome characterized by an overactive immune response to subclinical levels of the pathogen. In this study, we examined howC. neoformansuses the conserved Rim101 transcription factor to specifically remodel the host-pathogen interface, thus regulating the host immune response. These studies explored the complex ways in which successful microbial pathogens induce phenotypes that ensure their own survival while simultaneously controlling the nature and degree of the associated host response.

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Inhibition of Classical and Alternative Modes of Respiration in Candida albicans Leads to Cell Wall Remodeling and Increased Macrophage Recognition

mBio ◽

10.1128/mbio.02535-18 ◽

2019 ◽

Vol 10 (1) ◽

pp. e02535-18 ◽

Cited By ~ 18

Author(s):

Lucian Duvenage ◽

Louise A. Walker ◽

Aleksandra Bojarczuk ◽

Simon A. Johnston ◽

Donna M. MacCallum ◽

...

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Electron Transport ◽

Fungal Pathogen ◽

Fungal Infections ◽

Nitric Oxide Donor ◽

Mammalian Host ◽

Content Type ◽

Human Fungal Pathogen ◽

Cell Wall Remodeling

ABSTRACT The human fungal pathogen Candida albicans requires respiratory function for normal growth, morphogenesis, and virulence. Mitochondria therefore represent an enticing target for the development of new antifungal strategies. This possibility is bolstered by the presence of characteristics specific to fungi. However, respiration in C. albicans, as in many fungal organisms, is facilitated by redundant electron transport mechanisms, making direct inhibition a challenge. In addition, many chemicals known to target the electron transport chain are highly toxic. Here we made use of chemicals with low toxicity to efficiently inhibit respiration in C. albicans. We found that use of the nitric oxide donor sodium nitroprusside (SNP) and of the alternative oxidase inhibitor salicylhydroxamic acid (SHAM) prevents respiration and leads to a loss of viability and to cell wall rearrangements that increase the rate of uptake by macrophages in vitro and in vivo. We propose that treatment with SNP plus SHAM (SNP+SHAM) leads to transcriptional changes that drive cell wall rearrangement but which also prime cells to activate the transition to hyphal growth. In line with this, we found that pretreatment of C. albicans with SNP+SHAM led to an increase in virulence. Our data reveal strong links between respiration, cell wall remodeling, and activation of virulence factors. Our findings demonstrate that respiration in C. albicans can be efficiently inhibited with chemicals that are not damaging to the mammalian host but that we need to develop a deeper understanding of the roles of mitochondria in cellular signaling if they are to be developed successfully as a target for new antifungals. IMPORTANCE Current approaches to tackling fungal infections are limited, and new targets must be identified to protect against the emergence of resistant strains. We investigated the potential of targeting mitochondria, which are organelles required for energy production, growth, and virulence, in the human fungal pathogen Candida albicans. Our findings suggest that mitochondria can be targeted using drugs that can be tolerated by humans and that this treatment enhances their recognition by immune cells. However, release of C. albicans cells from respiratory inhibition appears to activate a stress response that increases the levels of traits associated with virulence. Our results make it clear that mitochondria represent a valid target for the development of antifungal strategies but that we must determine the mechanisms by which they regulate stress signaling and virulence ahead of successful therapeutic advance.

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Failure To Recruit Anti-Inflammatory CD103+Dendritic Cells and a Diminished CD4+Foxp3+Regulatory T Cell Pool in Mice That Display Excessive Lung Inflammation and Increased Susceptibility to Mycobacterium tuberculosis

Infection and Immunity ◽

10.1128/iai.05552-11 ◽

2012 ◽

Vol 80 (3) ◽

pp. 1128-1139 ◽

Cited By ~ 46

Author(s):

Chaniya Leepiyasakulchai ◽

Lech Ignatowicz ◽

Andrzej Pawlowski ◽

Gunilla Källenius ◽

Markus Sköld

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Mycobacterium Tuberculosis ◽

T Cell ◽

Bacterial Growth ◽

Lung Inflammation ◽

Chronic Infection ◽

Host Immune Response ◽

Content Type ◽

Tnf Α

Susceptibility toMycobacterium tuberculosisis characterized by excessive lung inflammation, tissue damage, and failure to control bacterial growth. To increase our understanding of mechanisms that may regulate the host immune response in the lungs, we characterized dendritic cells expressing CD103 (αEintegrin) (αE-DCs) and CD4+Foxp3+regulatory T (Treg) cells duringM. tuberculosisinfection. In resistant C57BL/6 and BALB/c mice, the number of lung αE-DCs increased dramatically duringM. tuberculosisinfection. In contrast, highly susceptible DBA/2 mice failed to recruit αE-DCs even during chronic infection. Even though tumor necrosis factor alpha (TNF-α) is produced by multiple DCs and macrophage subsets and is required for control of bacterial growth, αE-DCs remained TNF-α negative. Instead, αE-DCs contained a high number of transforming growth factor beta-producing cells in infected mice. Further, we show that Tregcells in C57BL/6 and DBA/2 mice induce gamma interferon during pulmonary tuberculosis. In contrast to resistant mice, the Tregcell population was diminished in the lungs, but not in the draining pulmonary lymph nodes (PLN), of highly susceptible mice during chronic infection. Tregcells have been reported to inhibitM. tuberculosis-specific T cell immunity, leading to increased bacterial growth. Still, despite the reduced number of lung Tregcells in DBA/2 mice, the bacterial load in the lungs was increased compared to resistant animals. Our results show that αE-DCs and Tregcells that may regulate the host immune response are increased inM. tuberculosis-infected lungs of resistant mice but diminished in infected lungs of susceptible mice.

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Phagocytes from Mice Lacking the Sts Phosphatases Have an Enhanced Antifungal Response to Candida albicans

mBio ◽

10.1128/mbio.00782-18 ◽

2018 ◽

Vol 9 (4) ◽

Cited By ~ 8

Author(s):

David Frank ◽

Shamoon Naseem ◽

Gian Luigi Russo ◽

Cindy Li ◽

Kaustubh Parashar ◽

...

Keyword(s):

Bone Marrow ◽

Immune Response ◽

Candida Albicans ◽

Tyrosine Kinase ◽

Critical Role ◽

Inflammasome Activation ◽

Wild Type ◽

Content Type ◽

Enhanced Production ◽

Immunological Mechanisms

ABSTRACT Mice lacking expression of the homologous phosphatases Sts-1 and Sts-2 (Sts−/− mice) are resistant to disseminated candidiasis caused by the fungal pathogen Candida albicans. To better understand the immunological mechanisms underlying the enhanced resistance of Sts−/− mice, we examined the kinetics of fungal clearance at early time points. In contrast to the rapid C. albicans growth seen in normal kidneys during the first 24 h postinfection, we observed a reduction in kidney fungal CFU within Sts−/− mice beginning at 12 to 18 h postinfection. This corresponds to the time period when large numbers of innate leukocytes enter the renal environment to counter the infection. Because phagocytes of the innate immune system are important for host protection against pathogenic fungi, we evaluated responses of bone marrow leukocytes. Relative to wild-type cells, Sts−/− marrow monocytes and bone marrow-derived dendritic cells (BMDCs) displayed a heightened ability to inhibit C. albicans growth ex vivo. This correlated with significantly enhanced production of reactive oxygen species (ROS) by Sts−/− BMDCs downstream of Dectin-1, a C-type lectin receptor that plays a critical role in stimulating host responses to fungi. We observed no visible differences in the responses of other antifungal effector pathways, including cytokine production and inflammasome activation, despite enhanced activation of the Syk tyrosine kinase downstream of Dectin-1 in Sts−/− cells. Our results highlight a novel mechanism regulating the immune response to fungal infections. Further understanding of this regulatory pathway could aid the development of therapeutic approaches to enhance protection against invasive candidiasis. IMPORTANCE Systemic candidiasis caused by fungal Candida species is becoming an increasingly serious medical problem for which current treatment is inadequate. Recently, the Sts phosphatases were established as key regulators of the host antifungal immune response. In particular, genetic inactivation of Sts significantly enhanced survival of mice infected intravenously with Candida albicans. The Sts−/− in vivo resistance phenotype is associated with reduced fungal burden and an absence of inflammatory lesions. To understand the underlying mechanisms, we studied phagocyte responses. Here, we demonstrate that Sts−/− phagocytes have heightened responsiveness to C. albicans challenge relative to wild-type cells. Our data indicate the Sts proteins negatively regulate phagocyte activation via regulating selective elements of the Dectin-1–Syk tyrosine kinase signaling axis. These results suggest that phagocytes lacking Sts respond to fungal challenge more effectively and that this enhanced responsiveness partially underlies the profound resistance of Sts−/− mice to systemic fungal challenge.

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Leishmania donovani Secretory Mevalonate Kinase Regulates Host Immune Response and Facilitates Phagocytosis

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.641985 ◽

2021 ◽

Vol 11 ◽

Author(s):

Tanvir Bamra ◽

Taj Shafi ◽

Sushmita Das ◽

Manjay Kumar ◽

Manas Ranjan Dikhit ◽

...

Keyword(s):

Immune Response ◽

Immune System ◽

Leishmania Donovani ◽

Indian Subcontinent ◽

Parasite Burden ◽

Host Immune Response ◽

Host Cells ◽

Interleukin 4 ◽

Host Immune System ◽

Mevalonate Kinase

Summary StatementLeishmania secretes over 151 proteins during in vitro cultivation. Cellular functions of one such novel protein: mevalonate kinase is discussed here; signifying its importance in Leishmania infection.Visceral Leishmaniasis is a persistent infection, caused by Leishmania donovani in Indian subcontinent. This persistence is partly due to phagocytosis and evasion of host immune response. The underlying mechanism involves secretory proteins of Leishmania parasite; however, related studies are meagre. We have identified a novel secretory Leishmania donovani glycoprotein, Mevalonate kinase (MVK), and shown its importance in parasite internalization and immuno-modulation. In our studies, MVK was found to be secreted maximum after 1 h temperature stress at 37°C. Its secretion was increased by 6.5-fold in phagolysosome-like condition (pH ~5.5, 37°C) than at pH ~7.4 and 25°C. Treatment with MVK modulated host immune system by inducing interleukin-10 and interleukin-4 secretion, suppressing host’s ability to kill the parasite. Peripheral blood mononuclear cell (PBMC)-derived macrophages infected with mevalonate kinase-overexpressing parasites showed an increase in intracellular parasite burden in comparison to infection with vector control parasites. Mechanism behind the increase in phagocytosis and immunosuppression was found to be phosphorylation of mitogen-activated protein (MAP) kinase pathway protein, Extracellular signal-regulated kinases-1/2, and actin scaffold protein, cortactin. Thus, we conclude that Leishmania donovani Mevalonate kinase aids in parasite engulfment and subvert the immune system by interfering with signal transduction pathways in host cells, which causes suppression of the protective response and facilitates their persistence in the host. Our work elucidates the involvement of Leishmania in the process of phagocytosis which is thought to be dependent largely on macrophages and contributes towards better understanding of host pathogen interactions.

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Spitzenkörper, Exocyst, and Polarisome Components in Candida albicans Hyphae Show Different Patterns of Localization and Have Distinct Dynamic Properties

Eukaryotic Cell ◽

10.1128/ec.00109-10 ◽

2010 ◽

Vol 9 (10) ◽

pp. 1455-1465 ◽

Cited By ~ 65

Author(s):

Laura A. Jones ◽

Peter E. Sudbery

Keyword(s):

Candida Albicans ◽

Cell Surface ◽

Fluorescence Recovery After Photobleaching ◽

Dynamic Properties ◽

Secretory Vesicles ◽

Content Type ◽

Human Fungal Pathogen ◽

Actin Cables ◽

Cytochalasin A ◽

Subapical Region

ABSTRACT During the extreme polarized growth of fungal hyphae, secretory vesicles are thought to accumulate in a subapical region called the Spitzenkörper. The human fungal pathogen Candida albicans can grow in a budding yeast or hyphal form. When it grows as hyphae, Mlc1 accumulates in a subapical spot suggestive of a Spitzenkörper-like structure, while the polarisome components Spa2 and Bud6 localize to a surface crescent. Here we show that the vesicle-associated protein Sec4 also localizes to a spot, confirming that secretory vesicles accumulate in the putative C. albicans Spitzenkörper. In contrast, exocyst components localize to a surface crescent. Using a combination of fluorescence recovery after photobleaching (FRAP) and fluorescence loss in photobleaching (FLIP) experiments and cytochalasin A to disrupt actin cables, we showed that Spitzenkörper-located proteins are highly dynamic. In contrast, exocyst and polarisome components are stably located at the cell surface. It is thought that in Saccharomyces cerevisiae exocyst components are transported to the cell surface on secretory vesicles along actin cables. If each vesicle carried its own complement of exocyst components, then it would be expected that exocyst components would be as dynamic as Sec4 and would have the same pattern of localization. This is not what we observe in C. albicans. We propose a model in which a stream of vesicles arrives at the tip and accumulates in the Spitzenkörper before onward delivery to the plasma membrane mediated by exocyst and polarisome components that are more stable residents of the cell surface.

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A Biofilm Matrix-Associated Protease Inhibitor ProtectsPseudomonas aeruginosafrom Proteolytic Attack

mBio ◽

10.1128/mbio.00543-18 ◽

2018 ◽

Vol 9 (2) ◽

Cited By ~ 26

Author(s):

Boo Shan Tseng ◽

Courtney Reichhardt ◽

Gennifer E. Merrihew ◽

Sophia A. Araujo-Hernandez ◽

Joe J. Harrison ◽

...

Keyword(s):

Immune Response ◽

Immune System ◽

Protease Inhibitor ◽

Neutrophil Elastase ◽

Matrix Protein ◽

Lipid Vesicles ◽

Matrix Proteins ◽

Host Immune System ◽

Content Type ◽

Biofilm Matrix

ABSTRACTPseudomonas aeruginosaproduces an extracellular biofilm matrix that consists of nucleic acids, exopolysaccharides, lipid vesicles, and proteins. In general, the protein component of the biofilm matrix is poorly defined and understudied relative to the other major matrix constituents. While matrix proteins have been suggested to provide many functions to the biofilm, only proteins that play a structural role have been characterized thus far. Here we identify proteins enriched in the matrix ofP. aeruginosabiofilms. We then focused on a candidate matrix protein, the serine protease inhibitor ecotin (PA2755). This protein is able to inhibit neutrophil elastase, a bactericidal enzyme produced by the host immune system duringP. aeruginosabiofilm infections. We show that ecotin binds to the key biofilm matrix exopolysaccharide Psl and that it can inhibit neutrophil elastase when associated with Psl. Finally, we show that ecotin protects both planktonic and biofilmP. aeruginosacells from neutrophil elastase-mediated killing. This may represent a novel mechanism of protection for biofilms to increase their tolerance against the innate immune response.IMPORTANCEProteins associated with the extracellular matrix of bacterial aggregates called biofilms have long been suggested to provide many important functions to the community. To date, however, only proteins that provide structural roles have been described, and few matrix-associated proteins have been identified. We developed a method to identify matrix proteins and characterized one. We show that this protein, when associated with the biofilm matrix, can inhibit a bactericidal enzyme produced by the immune system during infection and protect biofilm cells from death induced by the enzyme. This may represent a novel mechanism of protection for biofilms, further increasing their tolerance against the immune response. Together, our results are the first to show a nonstructural function for a confirmed matrix-interacting protein.

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MIG1Regulates Resistance of Candida albicans against the Fungistatic Effect of Weak Organic Acids

Eukaryotic Cell ◽

10.1128/ec.00129-15 ◽

2015 ◽

Vol 14 (10) ◽

pp. 1054-1061 ◽

Cited By ~ 19

Author(s):

Fabien Cottier ◽

Alrina Shin Min Tan ◽

Xiaoli Xu ◽

Yue Wang ◽

Norman Pavelka

Keyword(s):

Candida Albicans ◽

Organic Acids ◽

Fungal Infections ◽

Glucose Repression ◽

Single Gene ◽

Human Microbiome ◽

Fungal Resistance ◽

Content Type ◽

Weak Organic Acids ◽

Fungistatic Effect

ABSTRACTCandida albicansis the leading cause of fungal infections; but it is also a member of the human microbiome, an ecosystem of thousands of microbial species potentially influencing the outcome of host-fungal interactions. Accordingly, antibacterial therapy raises the risk of candidiasis, yet the underlying mechanism is currently not fully understood. We hypothesize the existence of bacterial metabolites that normally controlC. albicansgrowth and of fungal resistance mechanisms against these metabolites. Among the most abundant microbiota-derived metabolites found on human mucosal surfaces are weak organic acids (WOAs), such as acetic, propionic, butyric, and lactic acid. Here, we used quantitative growth assays to investigate the dose-dependent fungistatic properties of WOAs onC. albicansgrowth and found inhibition of growth to occur at physiologically relevant concentrations and pH values. This effect was conserved across distantly related fungal species both inside and outside the CTG clade. We next screened a library of transcription factor mutants and identified several genes required for the resistance ofC. albicansto one or more WOAs. A single gene,MIG1, previously known for its role in glucose repression, conferred resistance against all four acids tested. Consistent with glucose being an upstream activator of Mig1p, the presence of this carbon source was required for WOA resistance in wild-typeC. albicans. Conversely, aMIG1-complemented strain completely restored the glucose-dependent resistance against WOAs. We conclude that Mig1p plays a central role in orchestrating a transcriptional program to fight against the fungistatic effect of this class of highly abundant metabolites produced by the gastrointestinal tract microbiota.

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