Fecal microbiota transplantation prevents Candida albicans from colonizing the gastrointestinal tract

Gut microbes symbiotically colonize the gastrointestinal (GI) tract, interacting with each other and their host to maintain GI tract homeostasis. Recent reports have shown that gut microbes help protect the gut from colonization by pathogenic microbes. Here, we report that commensal microbes prevent colonization of the GI tract by the pathogenic fungus, Candida albicans. Wild‐type specific pathogen‐free (SPF) mice are resistant to C. albicans colonization of the GI tract. However, administering certain antibiotics to SPF mice enables C. albicans colonization. Quantitative kinetics of commensal bacteria are inversely correlated with the number of C. albicans in the gut. Here, we provide further evidence that transplantation of fecal microbiota is effective in preventing Candida colonization of the GI tract. These data demonstrate the importance of commensal bacteria as a barrier for the GI tract surface and highlight the potential clinical applications of commensal bacteria in preventing pathogenic fungal infections.     

Candida albicans possess a highly versatile and dynamic high‐affinity iron transport system important for its commensal‐pathogenic lifestyle

Iron is an essential nutrient for nearly all organisms, but iron overdose is toxic. The human commensal‐pathogenic fungus Candida albicans traverses host niches with markedly different iron availability. During systemic infection, C. albicans must activate the high‐affinity iron permease Ftr1 to acquire iron sequestered by the host's iron‐withholding defense and suppresses iron uptake while residing in the iron‐rich gut to avoid toxicity. Ftr1 associates with a ferroxidase to form an iron transporter. C. albicans contains four permeases and five ferroxidase homologs, suggesting 20 possible subunit combinations. Here, we investigated the iron‐dependent expression, cellular localization and interacting partners of all permeases and ferroxidases and the significance of each subunit for gastrointestinal colonization and systemic infection in mice. We uncovered three distinct patterns of iron‐dependent expression and highly flexible ferroxidase‐permease partnerships, which underlie a dynamic iron transport system that can be deftly tuned according to iron availability. We found functional differentiation as well as redundancy among the ferroxidases and permeases during both gastrointestinal colonization and bloodstream infection. We propose that C. albicans possesses a sophisticated iron acquisition and utilization system befitting its commensal‐pathogenic lifestyle. Our findings reveal new possibilities for medical intervention of C. albicans infection.     

Cloning and Characterization of PRA1, a Gene Encoding a Novel pH-Regulated Antigen of Candida albicans

Candida albicans is an opportunistic fungal pathogen of humans. The cell wall of the organism defines the interface between the pathogen and host tissues and is likely to play an essential and pivotal role in the host-pathogen interaction. The components of the cell wall critical to this interaction are undefined. Immunoscreening of a lambda expression library with sera raised against mycelial cell walls of C. albicans was used to identify genes encoding cell surface proteins. One of the positive clones represented a candidal gene that was differentially expressed in response to changes in the pH of the culture medium. Maximal expression occurred at neutral pH, with no expression detected below pH 6.0. On the basis of the expression pattern, the corresponding gene was designated PRA1, for pH-regulated antigen. The protein predicted from the nucleotide sequence was 299 amino acids long with motifs characteristic of secreted glycoproteins. The predicted surface localization and N glycosylation of the protein were directly demonstrated by cell fractionation and immunoblot analysis. Deletion of the gene imparted a temperature-dependent defect in hypha formation, indicating a role in morphogenesis. The PRA1 protein was homologous to surface antigens of Aspergillus spp. which react with serum from aspergillosis patients, suggesting that the PRA1 protein may have a role in the host-parasite interaction during candidal infection.     

Factors Influencing Non-<Emphasis Type="Italic">albicans</Emphasis> Candidemia: A Case–Case–Control Study

The study identified factors predisposing to non-albicans candidemia with special interest to prior antimicrobial treatment. A retrospective, case–case–control study was performed at the University Hospital of Heraklion, Greece, from November 2007 through September 2011 including adult patients. The study had three groups. The first included 58 patients with non-albicans candidemia, the second 48 with C. albicans candidemia, while the third (control) 104 without candidemia. Each of the two candidemia groups was compared with the control using multivariate logistic regression model. The mean (SD) age of the non-albicans, the albicans and the control patients was 67 (12), 67 (18) and 59 (19) years, respectively. The most common non-albicans Candida spp. isolated were C. parapsilosis in 19 patients (33%), C. glabrata in 17 (29%) and C. tropicalis in 15 (26%). Independent risk factors for non-albicans candidemia were prior treatment with quinolones (p < 0.001), b-lactam-b-lactamase inhibitors (p = 0.011) and presence of central venous catheter (p = 0.05), while for C. albicans candidemia were prior treatment with quinolones (p < 0.001), carbapenems (p = 0.003) along with cardiac disease (p < 0.001). Neither duration of hospitalization nor in-hospital mortality [41% for the non-albicans vs 29% for C. albicans group (p = 0.192)] was significantly different between the two candidemia groups. The study reveals the role of antimicrobial exposure as a risk factor for candidemia caused by different species. Prior treatment with b-lactam-b-lactamase inhibitors was associated with non-albicans, while with carbapenems with C. albicans candidemia. Prior use of quinolones was associated with candidemia in general.     

Characterization of Mucosal Candida albicans Biofilms

C. albicans triggers recurrent infections of the alimentary tract mucosa that result from biofilm growth. Although the ability of C. albicans to form a biofilm on abiotic surfaces has been well documented in recent years, no information exists on biofilms that form directly on mucosal surfaces. The objectives of this study were to characterize the structure and composition of Candida biofilms forming on the oral mucosa. We found that oral Candida biofilms consist of yeast, hyphae, and commensal bacteria, with keratin dispersed in the intercellular spaces. Neutrophils migrate through the oral mucosa and form nests within the biofilm mass. The cell wall polysaccharide β-glucan is exposed during mucosal biofilm growth and is more uniformly present on the surface of biofilm organisms invading the oral mucosa. We conclude that C. albicans forms complex mucosal biofilms consisting of both commensal bacterial flora and host components. These discoveries are important since they can prompt a shift of focus for current research in investigating the role of Candida-bacterial interactions in the pathogenesis of mucosal infections as well as the role of β-glucan mediated signaling in the host response.     

Six-Year Trend Analysis of Nosocomial Candidemia and Risk factors in Two Intensive Care Hospitals in Mato Grosso, Midwest Region of Brazil

We conducted this cross-sectional retrospective study using clinical and laboratory data from two tertiary hospitals in Cuiabá, Mato Grosso, Brazil, in order to explore the risk factors and estimate mortality, prevalence and lethality of candidemia between 2006 and 2011. A total of 130 episodes of candidemia were identified. The prevalence of candidemia was 1.8 per 1,000 admissions, the mortality rate was 0.9 per 1,000 admissions, and the lethality was 49.2 %. The main agent in this population was Candida parapsilosis (n = 50), followed by C. albicans (n = 45). Comparison between the numbers of episodes in the two triennia revealed that the non-albicans group grew by 48.2 %. The distribution of yeast species of Candida per hospital unit revealed that C. albicans was more prevalent than C. parapsilosis in the adult ICU and C. parapsilosis was more prevalent than C. albicans in the neonatal ICU. Patients remained hospitalized for an average of 53.5 days. Central venous catheters, parenteral nutrition and age were the variables that proved to be independent in the multivariate analysis and that maintained a statistically significant association with the incidence of death in patients with candidemia. The annual prevalence of candidemia showed a significant increase in the second triennium (2009–2011) compared with the first (2006–2008) probably due to increased exposure to risk factors: central venous catheter, H2 blockers, nutrition parenteral corticosteroids and mean hospital duration.     

The HOG Pathway Is Critical for the Colonization of the Mouse Gastrointestinal Tract by Candida albicans

The opportunistic pathogen Candida albicans is a frequent inhabitant of the human gastrointestinal tract where it usually behaves as a harmless commensal. In this particular niche, it needs to adapt to the different micro environments that challenge its survival within the host. In order to determine those factors involved in gut adaptation, we have used a gastrointestinal model of colonization in mouse to trace the behaviour of fungal cells. We have developed a genetic labelling system based on the complementary spectral properties of the fluorescent proteins GFP and a new C. albicans codon-adapted RFP (dTOM2) that allow a precise quantification of the fungal population in the gut via standard in vitro cultures or flow cytometry. This methodology has allowed us to determine the role of the three MAP kinase pathways of C. albicans (mediated by the MAPK Mkc1, Cek1 or Hog1) in mouse gut colonization via competitive assays with MAPK pathway mutants and their isogenic wild type strain. This approach reveals the signalling through HOG pathway as a critical factor influencing the establishment of C. albicans in the mouse gut. Less pronounced effects for mkc1 or cek1 mutants were found, only evident after 2–3 weeks of colonization. We have also seen that hog1 mutants is defective in adhesion to the gut mucosa and sensitive to bile salts. Finally, we have developed a genetic strategy for the in vivo excision (tetracycline-dependent) of any specific gene during the course of colonization in this particular niche, allowing the analysis of its role during gut colonization.     

Phosphoglycerate kinase and fructose bisphosphate aldolase of Candida albicans as new antigens recognized by human salivary IgA

BackgroundCandida albicans is an opportunistic dimorphic fungus commonly present in the human oral cavity that causes infections in immunocompromised patients. The antigen variability, influenced by growth conditions, is a pathogenicity factor.AimsTo determine the effect of nutritional and heat stress on the antigen expression of C. albicans, and to identify major antigens recognized by human salivary secretory immunoglobulin A (sIgA).MethodsUnder various different nutritional conditions, heat shock was induced in C. albicans cells in stationary and exponential growth phases. The expression of protein determinants of C. albicans was assessed by Western blot analysis against human saliva. The antigens were purified and characterized by two-dimensional electrophoresis and identified by protein microsequencing.ResultsFive antigens recognized by salivary IgA were characterized as mannoproteins due to their reactivity with concanavalin A. They did not show reactivity with anti-heat shock protein monoclonal antibodies. Two of them (42 and 36 kDa) were found to be regulated by heat shock and by nutritional stress and they were identified as phosphoglycerate kinase and fructose bisphosphate aldolase, respectively.ConclusionsThese glycolytic enzymes are major antigens of C. albicans, and their differential expression and recognition by the mucosal immune response system could be involved in protection against oral infection.     

Disruption of the intestinal mucosal barrier in Candida albicans infections

Candida albicans is a common microorganism in the intestine. However, invasive C. albicans infection has emerged as a life-threatening disease in recent years. The mortality rate of invasive candidiasis is high in critically ill hosts. C. albicans can switch from the yeast to the hyphal morphology, and take advantage of the impaired intestinal mucosal barrier and insufficient immunity of the host to facilitate its colonization and penetration. Despite the availability of potent new antifungal drugs in recent years, the treatment of severe candidiasis, especially candidaemia, has not been substantially improved. In this review, the virulence factors of C. albicans, as well as the antagonistic role of the intestinal mucosal barrier will be discussed to illuminate the mechanisms of C. albicans enterogenic infections.     

Comprehensive genetic analysis of adhesin proteins and their role in virulence of Candida albicans

Candida albicans is a microbial fungus that exists as a commensal member of the human microbiome and an opportunistic pathogen. Cell surface-associated adhesin proteins play a crucial role in C. albicans’ ability to undergo cellular morphogenesis, develop robust biofilms, colonize, and cause infection in a host. However, a comprehensive analysis of the role and relationships between these adhesins has not been explored. We previously established a CRISPR-based platform for efficient generation of single- and double-gene deletions in C. albicans, which was used to construct a library of 144 mutants, comprising 12 unique adhesin genes deleted singly, and every possible combination of double deletions. Here, we exploit this adhesin mutant library to explore the role of adhesin proteins in C. albicans virulence. We perform a comprehensive, high-throughput screen of this library, using Caenorhabditis elegans as a simplified model host system, which identified mutants critical for virulence and significant genetic interactions. We perform follow-up analysis to assess the ability of high- and low-virulence strains to undergo cellular morphogenesis and form biofilms in vitro, as well as to colonize the C. elegans host. We further perform genetic interaction analysis to identify novel significant negative genetic interactions between adhesin mutants, whereby combinatorial perturbation of these genes significantly impairs virulence, more than expected based on virulence of the single mutant constituent strains. Together, this study yields important new insight into the role of adhesins, singly and in combinations, in mediating diverse facets of virulence of this critical fungal pathogen.     

Heterologous Expression of Candida albicans Cell Wall-Associated Adhesins in Saccharomyces cerevisiae Reveals Differential Specificities in Adherence and Biofilm Formation and in Binding Oral Streptococcus gordonii

Colonization and infection of the human host by opportunistic pathogen Candida albicans derive from an ability of this fungus to colonize mucosal tissues and prosthetic devices within the polymicrobial communities present. To determine the functions of C. albicans cell wall proteins in interactions with host or bacterial molecules, Saccharomyces cerevisiae was utilized as a surrogate host to express C. albicans cell wall proteins Als3p, Eap1p, Hwp1p, and Rbt1p. Salivary pellicle and fibrinogen were identified as novel substrata for Als3p and Hwp1p, while only Als3p mediated adherence of S. cerevisiae to basement membrane collagen type IV. Parental S. cerevisiae cells failed to form biofilms on salivary pellicle, polystyrene, or silicone, but cells expressing Als3p or Hwp1p exhibited significant attachment to each surface. Virulence factor Rbt1p also conferred lower-level binding to salivary pellicle and polystyrene. S. cerevisiae cells expressing Eap1p formed robust biofilms upon polystyrene surfaces but not salivary pellicle. Proteins Als3p and Eap1p, and to a lesser degree Hwp1p, conferred upon S. cerevisiae the ability to bind cells of the oral primary colonizing bacterium Streptococcus gordonii. These interactions, which occurred independently of amyloid aggregate formation, provide the first examples of specific C. albicans surface proteins serving as receptors for bacterial adhesins. Streptococcus gordonii did not bind parental S. cerevisiae or cells expressing Rbt1p. Taken collectively, these data suggest that a network of cell wall proteins comprising Als3p, Hwp1p, and Eap1p, with complementary adhesive functions, promotes interactions of C. albicans with host and bacterial molecules, thus leading to effective colonization within polymicrobial communities.Candida albicans is a pleiomorphic fungus found on mucosal surfaces of the gastrointestinal and genitourinary tracts, skin, and oral cavity (2). As an opportunistic pathogen, C. albicans can form potentially lethal fungal masses in the kidney, heart, and brain upon gaining access to the bloodstream (4), and invasive fungal infections are becoming increasingly problematic in the clinical setting (34). Candida species are now the third most common cause of nosocomial bloodstream infections. In the United States alone there are an estimated 70,000 cases per year of disseminated candidiasis (34), with an associated health care cost of $2 billion to $4 billion/year (44, 45). C. albicans is also responsible for >90% of oral fungal diseases derived from polymicrobial biofilms, and ≤90% of HIV-infected individuals suffer from oral candidiasis, which may progress to advanced esophageal candidiasis (10).C. albicans can colonize a wide variety of sites within the host in addition to mucosal tissues, such as catheters, stents, surgical implants, and dentures. This ability can be attributed, at least in part, to the large number of proteins expressed on the candidal cell surface, which mediate adhesion to a range of substrata. Cell wall proteins (CWPs) in C. albicans also play a critical role in biofilm formation. Within the host, Candida species are frequently found as part of polymicrobial biofilms, in which antagonistic, synergistic, and mutualistic interactions among microbes significantly influence composition of the community microflora (17). This is particularly pertinent for colonization of the oral cavity, where up to 100 different microbial species may be isolated from a single site at any given time. To successfully colonize the host and cause disease, C. albicans must therefore not only attach directly to host tissues or medical devices but also navigate interactions with a diverse microflora to ensure the availability of suitable binding sites, nutrients, and growth conditions.It has been shown that C. albicans coaggregates (coadheres) strongly with Streptococcus bacteria indigenous to the human oral cavity such as Streptococcus gordonii and Streptococcus sanguinis (13, 18). These bacteria are pioneer colonizers of oral cavity surfaces, and it is hypothesized that interactions with these streptococci may promote oral carriage and persistence of C. albicans, thereby supporting candidal reservoirs for opportunistic infections following disruption of the oral ecology. Previous work by Holmes et al. (13, 14) identified Streptococcus gordonii cell wall-associated polypeptides SspA, SspB, and CshA, together with linear cell wall phosphopolysaccharides, as potential targets for C. albicans binding streptococcal cells. However, the reciprocal receptors on the surface of C. albicans recognized by streptococci have yet to be identified.This work utilizes Saccharomyces cerevisiae, which does not bind streptococci, as a heterologous host for expression and identification of candidal surface proteins targeted by Streptococcus gordonii. Four surface proteins were selected that had been previously implicated in C. albicans colonization and pathogenesis: Als3p, Eap1p, Hwp1p, and Rbt1p. Als3p (comprehensively reviewed by Hoyer et al. [15]), Hwp1p (29, 40), and Eap1p (20, 22) are associated with mediating interactions of C. albicans with host epithelial cells and with biofilm formation in catheter models. Expression of Als3p or Hwp1p has been shown to be hypha specific, while Eap1p is expressed by each morphological form (16, 20, 41). Rbt1p shares 43% sequence identity with Hwp1p and has been associated with virulence in mouse and rabbit models of C. albicans infection (6). Using a recombinase-based Gateway cloning system (Invitrogen), each of the C. albicans proteins was expressed on the surface of S. cerevisiae. Their functional properties in adherence and biofilm formation were determined, and proteins Als3p and Eap1p were identified as potential Streptococcus gordonii receptors on the surface of C. albicans.     

Rheumatoid arthritis patients exhibit impaired Candida albicans-specific Th17 responses

Introduction

Accumulating data implicate the CD4+ T cell subset (Th17 cells) in rheumatoid arthritis (RA). IL-17 is an inflammatory cytokine that induces tumor necrosis factor (TNF)α, IL-1β and IL-6, all of which are targets of biologic therapies used to treat RA. RA patients are well documented to experience more infections than age-matched controls, and biologic therapies further increase the risk of infection. The Th17/IL-17 axis is vital for immunity to fungi, especially the commensal fungus Candida albicans. Therefore, we were prompted to examine the relationship between RA and susceptibility to C. albicans because of the increasing interest in Th17 cells and IL-17 in driving autoimmunity, and the advent of new biologics that target this pathway.

Methods

We analyzed peripheral blood and saliva from 48 RA and 33 healthy control subjects. To assess C. albicans-specific Th17 responses, PBMCs were co-cultured with heat-killed C. albicans extract, and IL-17A levels in conditioned supernatants were measured by ELISA. The frequency of Th17 and Th1 cells was determined by flow cytometry. As a measure of IL-17A-mediated effector responses, we evaluated C. albicans colonization rates in the oral cavity, salivary fungicidal activity and levels of the antimicrobial peptide β-defensin 2 (BD2) in saliva.

Results

Compared to controls, PBMCs from RA subjects exhibited elevated baseline production of IL-17A (P = 0.004), although they had similar capacity to produce IL-17A in response to Th17 cell differentiating cytokines (P = 0.91). However RA PBMCs secreted less IL-17A in response to C. albicans antigens (P = 0.006). Significantly more RA patients were colonized with C. albicans in the oral cavity than healthy subjects (P = 0.02). Concomitantly, RA saliva had reduced concentrations of salivary BD2 (P = 0.02). Nonetheless, salivary fungicidal activity was preserved in RA subjects (P = 0.70).

Conclusions

RA subjects exhibit detectable impairments in oral immune responses to C. albicans, a strongly Th17-dependent opportunistic pathogen, despite an overall elevated baseline production of IL-17A.     

Intestinal Colonization by Candida albicans Alters Inflammatory Responses in Bruton's Tyrosine Kinase-Deficient Mice

The commensal yeast Candida albicans is part of the human intestinal microflora and is considered a “pathobiont”, a resident microbe with pathogenic potential yet harmless under normal conditions. The aim of this study was to investigate the effect of C. albicans on inflammation of the intestinal tract and the role of Bruton''s tyrosine kinase (Btk). Btk is an enzyme that modulates downstream signaling of multiple receptors involved in innate and adaptive immunity, including the major anti-fungal receptor Dectin-1. Colitis was induced in wild type and Btk-/- mice by treatment with dextran sodium sulfate (DSS) and the gastrointestinal tract of selected treatment groups were then colonized with C. albicans. Colonization by C. albicans neither dampened nor exacerbated inflammation in wild type mice, but colon length and spleen weight were improved in Btk-deficient mice colonized with C. albicans. Neutrophil infiltration was comparable between wild type and Btk-/- mice, but the knockout mice displayed severely reduced numbers of macrophages in the colon during both DSS and DSS/Candida treatment. Smaller numbers and reduced responsiveness of Btk-/- macrophages might partially explain the improved colon length of Btk-/- mice as a result of Candida colonization. Surprisingly, DSS/Candida-treated Btk-/- animals had higher levels of certain pro-inflammatory cytokines and levels of the anti-inflammatory cytokine TGF-β were reduced compared to wild type. A clustering and correlation analysis showed that for wild type animals, spleen TGF-β and colon IL-10 and for Btk-/- spleen and colon levels of IL-17A best correlated with the inflammatory parameters. We conclude that in Btk-/- immunocompromised animals, colonization of the gastrointestinal tract by the commensal yeast C. albicans alters inflammatory symptoms associated with colitis.     

Detection of anti-<Emphasis Type="Italic">Candida</Emphasis> antibodies in neonates from a neonatal intensive care unit

Anti-Candida antibodies were determined in a group of preterm neonates from a neonatal intensive care unit with serious diseases including candidemia. Antibodies toC. albicans blastospores,i.e. antibodies toC. albicans surface mannan and toC. albicans germ tubes were detected. Higher titers of antibodies to blastospores (1:320) occurred in all patients examined while antibodies toC. albicans germ tubes (with the highest titer of 1:160) were present in 32 out of 66 neonates examined. The highest titers of both anti-C. albicans blastospore antibodies and anti-C. albicans germ tube antibodies were detected in neonates with candidemia and disorders of saccharide metabolism.     

SSD1 is integral to host defense peptide resistance in Candida albicans

Candida albicans is usually a harmless human commensal. Because inflammatory responses are not normally induced by colonization, antimicrobial peptides are likely integral to first-line host defense against invasive candidiasis. Thus, C. albicans must have mechanisms to tolerate or circumvent molecular effectors of innate immunity and thereby colonize human tissues. Prior studies demonstrated that an antimicrobial peptide-resistant strain of C. albicans, 36082^R, is hypervirulent in animal models versus its susceptible counterpart (36082^S). The current study aimed to identify a genetic basis for antimicrobial peptide resistance in C. albicans. Screening of a C. albicans genomic library identified SSD1 as capable of conferring peptide resistance to a susceptible surrogate, Saccharomyces cerevisiae. Sequencing confirmed that the predicted translation products of 36082^S and 36082^R SSD1 genes were identical. However, Northern analyses corroborated that SSD1 is expressed at higher levels in 36082^R than in 36082^S. In isogenic backgrounds, ssd1Δ/ssd1Δ null mutants were significantly more susceptible to antimicrobial peptides than parental strains but had equivalent susceptibilities to nonpeptide stressors. Moreover, SSD1 complementation of ssd1Δ/ssd1Δ mutants restored parental antimicrobial peptide resistance phenotypes, and overexpression of SSD1 conferred enhanced peptide resistance. Consistent with these in vitro findings, ssd1 null mutants were significantly less virulent in a murine model of disseminated candidiasis than were their parental or complemented strains. Collectively, these results indicate that SSD1 is integral to C. albicans resistance to host defense peptides, a phenotype that appears to enhance the virulence of this organism in vivo.     

Particular Candida albicans strains in the digestive tract of dyspeptic patients, identified by multilocus sequence typing

Background

Candida albicans is a human commensal that is also responsible for chronic gastritis and peptic ulcerous disease. Little is known about the genetic profiles of the C. albicans strains in the digestive tract of dyspeptic patients. The aim of this study was to evaluate the prevalence, diversity, and genetic profiles among C. albicans isolates recovered from natural colonization of the digestive tract in the dyspeptic patients.

Methods and Findings

Oral swab samples (n = 111) and gastric mucosa samples (n = 102) were obtained from a group of patients who presented dyspeptic symptoms or ulcer complaints. Oral swab samples (n = 162) were also obtained from healthy volunteers. C. albicans isolates were characterized and analyzed by multilocus sequence typing. The prevalence of Candida spp. in the oral samples was not significantly different between the dyspeptic group and the healthy group (36.0%, 40/111 vs. 29.6%, 48/162; P > 0.05). However, there were significant differences between the groups in the distribution of species isolated and the genotypes of the C. albicans isolates. C. albicans was isolated from 97.8% of the Candida-positive subjects in the dyspeptic group, but from only 56.3% in the healthy group (P < 0.001). DST1593 was the dominant C. albicans genotype from the digestive tract of the dyspeptic group (60%, 27/45), but not the healthy group (14.8%, 4/27) (P < 0.001).

Conclusions

Our data suggest a possible link between particular C. albicans strain genotypes and the host microenvironment. Positivity for particular C. albicans genotypes could signify susceptibility to dyspepsia.     

Calcium-Activated-Calcineurin Reduces the In Vitro and In Vivo Sensitivity of Fluconazole to Candida albicans via Rta2p

Due to the emergence of drug-resistance, first-line therapy with fluconazole (FLC) increasingly resulted in clinical failure for the treatment of candidemia. Our previous studies found that in vitro RTA2 was involved in the calcineurin-mediated resistance to FLC in C. albicans. In this study, we found that calcium-activated-calcineurin significantly reduced the in vitro sensitivity of C. albicans to FLC by blocking the impairment of FLC to the plasma membrane via Rta2p. Furthermore, we found that RTA2 itself was not involved in C. albicans virulence, but the disruption of RTA2 dramatically increased the therapeutic efficacy of FLC in a murine model of systemic candidiasis. Conversely, both re-introduction of one RTA2 allele and ectopic expression of RTA2 significantly reduced FLC efficacy in a mammalian host. Finally, we found that calcium-activated-calcineurin, through its target Rta2p, dramatically reduced the efficacy of FLC against candidemia. Given the critical roles of Rta2p in controlling the efficacy of FLC, Rta2p can be a potential drug target for antifungal therapies.     

Enemies and brothers in arms: Candida albicans and gram‐positive bacteria

Candida albicans is an important human opportunistic fungal pathogen which is frequently found as part of the normal human microbiota. It is well accepted that the fungus interacts with other components of the resident microbiota and that this impacts the commensal or pathogenic outcome of C. albicans colonization. Different types of interactions, including synergism or antagonism, contribute to a complex balance between the multitude of different species. Mixed biofilms of C. albicans and streptococci are a well‐studied example of a mutualistic interaction often potentiating the virulence of the individual members. In contrast, other bacteria like lactobacilli are known to antagonize C. albicans, and research has just started elucidating the mechanisms behind these interactions. This scenario is even more complicated by a third player, the host. This review focuses on interactions between C. albicans and gram‐positive bacteria whose investigation will without doubt ultimately help understanding C. albicans infections.