scholarly journals Unraveling How Candida albicans Forms Sexual Biofilms

2020 ◽  
Vol 6 (1) ◽  
pp. 14 ◽  
Author(s):  
Austin M. Perry ◽  
Aaron D. Hernday ◽  
Clarissa J. Nobile
Keyword(s):  
Candida Albicans ◽  
Mating Type ◽  
Fungal Species ◽  
Population Diversity ◽  
Transcriptional Networks ◽  
Host Immune System ◽  
Mating Types ◽  
Growth State ◽  
Primary Focus

Biofilms, structured and densely packed communities of microbial cells attached to surfaces, are considered to be the natural growth state for a vast majority of microorganisms. The ability to form biofilms is an important virulence factor for most pathogens, including the opportunistic human fungal pathogen Candida albicans. C. albicans is one of the most prevalent fungal species of the human microbiota that asymptomatically colonizes healthy individuals. However, C. albicans can also cause severe and life-threatening infections when host conditions permit (e.g., through alterations in the host immune system, pH, and resident microbiota). Like many other pathogens, this ability to cause infections depends, in part, on the ability to form biofilms. Once formed, C. albicans biofilms are often resistant to antifungal agents and the host immune response, and can act as reservoirs to maintain persistent infections as well as to seed new infections in a host. The majority of C. albicans clinical isolates are heterozygous (a/α) at the mating type-like (MTL) locus, which defines Candida mating types, and are capable of forming robust biofilms when cultured in vitro. These “conventional” biofilms, formed by MTL-heterozygous (a/α) cells, have been the primary focus of C. albicans biofilm research to date. Recent work in the field, however, has uncovered novel mechanisms through which biofilms are generated by C. albicans cells that are homozygous or hemizygous (a/a, a/Δ, α/α, or α/Δ) at the MTL locus. In these studies, the addition of pheromones of the opposite mating type can induce the formation of specialized “sexual” biofilms, either through the addition of synthetic peptide pheromones to the culture, or in response to co-culturing of cells of the opposite mating types. Although sexual biofilms are generally less robust than conventional biofilms, they could serve as a protective niche to support genetic exchange between mating-competent cells, and thus may represent an adaptive mechanism to increase population diversity in dynamic environments. Although conventional and sexual biofilms appear functionally distinct, both types of biofilms are structurally similar, containing yeast, pseudohyphal, and hyphal cells surrounded by an extracellular matrix. Despite their structural similarities, conventional and sexual biofilms appear to be governed by distinct transcriptional networks and signaling pathways, suggesting that they may be adapted for, and responsive to, distinct environmental conditions. Here we review sexual biofilms and compare and contrast them to conventional biofilms of C. albicans.

scholarly journals Expression and Immunostaining Analyses Suggest thatPneumocystisPrimary Homothallism Involves Trophic Cells Displaying Both Plus and Minus Pheromone Receptors

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
A. Luraschi ◽  
S. Richard ◽  
J. M. G. C. F. Almeida ◽  
M. Pagni ◽  
M. T. Cushion ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Severe Pneumonia ◽  
Mate Recognition ◽  
Fungal Species ◽  
Sexual Cycle ◽  
Host Immune System ◽  
Type Locus ◽  
Pheromone Receptor ◽  
Human Lungs

ABSTRACTThe genusPneumocystisencompasses fungal species that colonize mammals’ lungs with host specificity. Should the host immune system weaken, the fungal species can cause severe pneumonia. The life cycle of these pathogens is poorly known, mainly because anin vitroculture method has not been established. Both asexual and sexual cycles would occur. Trophic cells, the predominant forms during infection, could multiply asexually but also enter into a sexual cycle. Comparative genomics revealed a single mating type locus, including plus and minus genes, suggesting that primary homothallism involving self-fertility of each strain is the mode of reproduction ofPneumocystisspecies. We identified and analyzed the expression of themam2andmap3genes encoding the receptors for plus and minus pheromones using reverse transcriptase PCR, in both infected mice and bronchoalveolar lavage fluid samples from patients withPneumocystispneumonia. Both receptors were most often concomitantly expressed during infection, revealing that both pheromone-receptor systems are involved in the sexual cycle. Themap3transcripts were subject to alternative splicing. Using immunostaining, we investigated the presence of the pheromone receptors at the surfaces ofPneumocystiscells from a patient. The staining tools were first assessed inSaccharomyces cerevisiaedisplaying thePneumocystisreceptors at their cellular surface. Both receptors were present at the surfaces of the vast majority of the cells that were likely trophic forms. The receptors might have a role in mate recognition and/or postfertilization events. Their presence at the cell surface might facilitate outbreeding versus inbreeding of self-fertile strains.IMPORTANCEThe fungi belonging to the genusPneumocystismay cause severe pneumonia in immunocompromised humans, a disease that can be fatal if not treated. This disease is nowadays one of the most frequent invasive fungal infections worldwide. Whole-genome sequencing revealed that the sexuality of these fungi involves a single partner that can self-fertilize. Here, we report that two receptors recognizing specifically excreted pheromones are involved in this self-fertility within infected human lungs. Using fluorescent antibodies binding specifically to these receptors, we observed that most often, the fungal cells display both receptors at their surface. These pheromone-receptor systems might play a role in mate recognition and/or postfertilization events. They constitute an integral part of thePneumocystisobligate sexuality within human lungs, a cycle that is necessary for the dissemination of the fungus to new individuals.

scholarly journals Candida albicans Secreted Aspartyl Proteinases in Virulence and Pathogenesis

2003 ◽  
Vol 67 (3) ◽  
pp. 400-428 ◽  
Author(s):  
Julian R. Naglik ◽  
Stephen J. Challacombe ◽  
Bernhard Hube
Keyword(s):  
Candida Albicans ◽  
Proteinase Inhibitors ◽  
Host Immune System ◽  
Human Proteins ◽  
Candida Infections ◽  
Human Infections ◽  
Host Cell Membranes ◽  
Aspartyl Proteinases

SUMMARY 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.

scholarly journals Deletion of a Yci1 Domain Protein ofCandida albicansAllows Homothallic Mating inMTLHeterozygous Cells

mBio ◽  
2016 ◽  
Vol 7 (2) ◽  
Author(s):  
Yuan Sun ◽  
Christine Gadoury ◽  
Matthew P. Hirakawa ◽  
Richard J. Bennett ◽  
Doreen Harcus ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mating Type ◽  
Transcriptional Profiling ◽  
Mammalian Host ◽  
Epigenetic Switch ◽  
Type Locus ◽  
Human Fungal Pathogen ◽  
Mating Type Locus ◽  
New Gene

ABSTRACTIt has been proposed that the ancestral fungus was mating competent and homothallic. However, many mating-competent fungi were initially classified as asexual because their mating capacity was hidden behind layers of regulation. For efficientin vitromating, the essentially obligate diploid ascomycete pathogenCandida albicanshas to change its mating type locus from heterozygousMTLa/α to homozygousMTLa/aorMTLα/α and then undergo an environmentally controlled epigenetic switch to the mating-competent opaque form. These requirements greatly reduce the potential forC. albicansmating. Deletion of the Yci1 domain geneOFR1bypasses the need forC. albicanscells to change the mating type locus from heterozygous to homozygous prior to switching to the opaque form and mating and allows homothallic mating ofMTLheterozygous strains. This bypass is carbon source dependent and does not occur when cells are grown on glucose. Transcriptional profiling ofofr1mutant cells shows that in addition to regulating cell type and mating circuitry, Ofr1 is needed for proper regulation of histone and chitin biosynthesis gene expression. It appears thatOFR1is a key regulator inC. albicansand functions in part to maintain the cryptic mating phenotype of the pathogen.IMPORTANCECandida albicansis a human fungal pathogen with a recently discovered, highly cryptic mating ability. For efficient mating, it has to lose heterozygosity at its mating type locus. Then,MTLhomozygous strains can undergo an epigenetic switch to an elongated yeast state, termed the opaque form, and become mating competent. This infrequent two-step process greatly reduces the potential for mating; few strains areMTLhomozygous, and the opaque state is unstable at the temperature of the mammalian host.C. albicanshas a complex mechanism for mating that appears designed to ensure that mating is infrequent. Here, we have characterized a new gene, opaque-formation regulator 1 (OFR1). Deleting theOFR1gene allowsMTLa/α strains to mate efficiently with either mating type or even mate homothallically. It is possible that downregulatingOFR1in the host environment could allow mating inC. albicansby a route that does not involveMTLhomozygosis.

scholarly journals BAR Domain Proteins Rvs161 and Rvs167 Contribute to Candida albicans Endocytosis, Morphogenesis, and Virulence

2009 ◽  
Vol 77 (9) ◽  
pp. 4150-4160 ◽  
Author(s):  
Lois M. Douglas ◽  
Stephen W. Martin ◽  
James B. Konopka
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Plasma Membrane ◽  
Antifungal Drugs ◽  
Host Immune System ◽  
Membrane Function ◽  
Histatin 5 ◽  
Essentially Normal ◽  
Altered Cell

ABSTRACT The Candida albicans plasma membrane plays critical roles in growth and virulence and as a target for antifungal drugs. Three C. albicans genes that encode Bin-Amphiphysin-Rvs homology domain proteins were mutated to define their roles in plasma membrane function. The deletion of RVS161 and RVS167, but not RVS162, caused strong defects. The rvs161Δ mutant was more defective in endocytosis and morphogenesis than rvs167Δ, but both were strongly defective in polarizing actin patches. Other plasma membrane constituents were still properly localized, including a filipin-stained domain at the hyphal tips. An analysis of growth under different in vitro conditions showed that the rvs161Δ and rvs167Δ mutants grew less invasively in agar and also suggested that they have defects in cell wall synthesis and Rim101 pathway signaling. These mutants were also more resistant to the antimicrobial peptide histatin 5 but showed essentially normal responses to the drugs caspofungin and amphotericin. Surprisingly, the rvs161Δ mutant was more sensitive to fluconazole, whereas the rvs167Δ mutant was more resistant, indicating that these mutations cause overlapping but distinct effects on cells. The rvs161Δ and rvs167Δ mutants both showed greatly reduced virulence in mice. However, the mutants were capable of growing to high levels in kidneys. Histological analyses of infected kidneys revealed that these rvsΔ mutants grew in a large fungal mass that was walled off by leukocytes, rather than forming disseminated microabscesses as seen for the wild type. The diminished virulence is likely due to a combination of the morphogenesis defects that reduce invasive growth and altered cell wall construction that exposes proinflammatory components to the host immune system.

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

mSphere ◽  
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.

scholarly journals Mating-Type Gene Structure and Spatial Distribution of Didymella tanaceti in Pyrethrum Fields

2016 ◽  
Vol 106 (12) ◽  
pp. 1521-1529 ◽  
Author(s):  
Tamieka L. Pearce ◽  
Jason B. Scott ◽  
Frank S. Hay ◽  
Sarah J. Pethybridge
Keyword(s):  
Spatial Distribution ◽  
Mating Type ◽  
Tan Spot ◽  
Mating Types ◽  
Tanacetum Cinerariifolium ◽  
Polymerase Chain ◽  
Type Gene ◽  
Mat Genes

Tan spot of pyrethrum (Tanacetum cinerariifolium) is caused by the ascomycete Didymella tanaceti. To assess the evolutionary role of ascospores in the assumed asexual species, the structure and arrangement of mating-type (MAT) genes were examined. A single MAT1-1 or MAT1-2 idiomorph was identified in all isolates examined, indicating that the species is heterothallic. The idiomorphs were flanked upstream and downstream by regions encoding pyridoxamine phosphate oxidase-like and DNA lyase-like proteins, respectively. A multiplex MAT-specific polymerase chain reaction assay was developed and used to genotype 325 isolates collected within two transects in each of four fields in Tasmania, Australia. The ratio of isolates of each mating-type in each transect was consistent with a 1:1 ratio. The spatial distribution of the isolates of the two mating-types within each transect was random for all except one transect for MAT1-1 isolates, indicating that clonal patterns of each mating-type were absent. However, evidence of a reduced selection pressure on MAT1-1 isolates was observed, with a second haplotype of the MAT1-1-1 gene identified in 4.4% of MAT1-1 isolates. In vitro crosses between isolates with opposite mating-types failed to produce ascospores. Although the sexual morph could not be induced, the occurrence of both mating-types in equal frequencies suggested that a cryptic sexual mode of reproduction may occur within field populations.

scholarly journals Impact of Mating Type, Serotype, and Ploidy on the Virulence of Cryptococcus neoformans

2008 ◽  
Vol 76 (7) ◽  
pp. 2923-2938 ◽  
Author(s):  
Xiaorong Lin ◽  
Kirsten Nielsen ◽  
Sweta Patel ◽  
Joseph Heitman
Keyword(s):  
Cryptococcus Neoformans ◽  
Mating Type ◽  
Pathogenic Fungi ◽  
Mating Types ◽  
Type Locus ◽  
Virulence Potential ◽  
The Impact ◽  
Ad Hybrids

ABSTRACT Hybridization with polyploidization is a significant biological force driving evolution. The effect of combining two distinct genomes in one organism on the virulence potential of pathogenic fungi is not clear. Cryptococcus neoformans, the most common cause of fungal infection of the central nervous system, has a bipolar mating system with a and α mating types and occurs as A (haploid), D (haploid), and AD hybrid (mostly diploid) serotypes. Diploid AD hybrids are derived either from a-α mating or from unisexual mating between haploid cells. The precise contributions of increased ploidy, the effect of hybridization between serotypes A and D, and the combination of mating types to the virulence potential of AD hybrids have remained elusive. By using in vitro and in vivo characterization of laboratory-constructed isogenic diploids and AD hybrids with all possible mating type combinations in defined genetic backgrounds, we found that higher ploidy has a minor negative effect on virulence in a murine inhalation model of cryptococcosis. The presence of both mating types a and α in AD hybrids did not affect the virulence potential, irrespective of the serotype origin. Interestingly, AD hybrids with only one mating type behaved differently, with the virulence of αADα strains similar to that of other hybrids, while aADa hybrids displayed significantly lower virulence due to negative epistatic interactions between the Aa and Da alleles of the mating type locus. This study provides insights into the impact of ploidy, mating type, and serotype on virulence and the impact of hybridization on the fitness and virulence of a eukaryotic microbial pathogen.

scholarly journals In Vivo and In Vitro Anaerobic Mating in Candida albicans

2007 ◽  
Vol 6 (3) ◽  
pp. 465-472 ◽  
Author(s):  
Raluca Dumitru ◽  
Dhammika H. M. L. P. Navarathna ◽  
Camile P. Semighini ◽  
Christian G. Elowsky ◽  
Razvan V. Dumitru ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mating Types ◽  
Direct Test ◽  
Body Temperatures ◽  
Gi Tract ◽  
Anaerobic Conditions

ABSTRACT Candida albicans cells of opposite mating types are thought to conjugate during infection in mammalian hosts, but paradoxically, the mating-competent opaque state is not stable at mammalian body temperatures. We found that anaerobic conditions stabilize the opaque state at 37°C, block production of farnesol, and permit in vitro mating at 37°C at efficiencies of up to 84%. Aerobically, farnesol prevents mating because it kills the opaque cells necessary for mating, and as a corollary, farnesol production is turned off in opaque cells. These in vitro observations suggest that naturally anaerobic sites, such as the efficiently colonized gastrointestinal (GI) tract, could serve as niches for C. albicans mating. In a direct test of mating in the mouse GI tract, prototrophic cells were obtained from auxotrophic parent cells, confirming that mating will occur in this organ. These cells were true mating products because they were tetraploid, mononuclear, and prototrophic, and they contained the heterologous hisG marker from one of the parental strains.

scholarly journals Candida albicans Zinc Cluster Protein Upc2p Confers Resistance to Antifungal Drugs and Is an Activator of Ergosterol Biosynthetic Genes

2005 ◽  
Vol 49 (5) ◽  
pp. 1745-1752 ◽  
Author(s):  
Sarah MacPherson ◽  
Bassel Akache ◽  
Sandra Weber ◽  
Xavier De Deken ◽  
Martine Raymond ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Biosynthetic Pathway ◽  
Fungal Species ◽  
Antifungal Drugs ◽  
Zinc Cluster ◽  
Expression Of Genes ◽  
Ergosterol Synthesis ◽  
Resistant Strains ◽  
Drug Resistant Strains

ABSTRACT The human pathogen Candida albicans is responsible for a large proportion of infections in immunocompromised individuals, and the emergence of drug-resistant strains is of medical concern. Resistance to antifungal azole compounds is often due to an increase in drug efflux or an alteration of the pathway for synthesis of ergosterol, an important plasma membrane component in fungi. However, little is known about the transcription factors that mediate drug resistance. In Saccharomyces cerevisiae, two highly related transcriptional activators, Upc2p and Ecm22p, positively regulate the expression of genes involved in ergosterol synthesis (ERG genes). We have identified a homologue in C. albicans of the S. cerevisiae UPC2/ECM22 genes and named it UPC2. Deletion of this gene impaired growth under anaerobic conditions and rendered cells highly susceptible to the antifungal drugs ketoconazole and fluconazole. Conversely, overexpression of Upc2p increased resistance to ketoconazole, fluconazole, and fluphenazine. Azole-induced expression of the ERG genes was abolished in a Δupc2 strain, while basal levels of these mRNAs remained unchanged. Importantly, the purified DNA binding domain of Upc2p bound in vitro to putative sterol response elements in the ERG2 promoter, suggesting that Upc2p increases the expression of the ERG genes by directly binding to their promoters. These results provide an important link between changes in the ergosterol biosynthetic pathway and azole resistance in this opportunistic fungal species.

Evaluation of the in-vitro Antifungal Activity of Selected Fungal Species Tested Against Opportunistic Human Pathogen Candida albicans

2020 ◽  
Vol 8 (01) ◽  
pp. 01-08
Author(s):  
Aakriti Shukla ◽  
Apoorva Pathak
Keyword(s):  
Candida Albicans ◽  
Fungal Infections ◽  
Bloodstream Infections ◽  
Fungal Species ◽  
Fungal Metabolites ◽  
Antifungal Antibiotics ◽  
Opportunistic Human Pathogen ◽  
Hospital Acquired ◽  
In Vitro Antifungal Activity

Candida albicans is currently the fourth-leading cause of hospital-acquired bloodstream infections, reaching a mortality rate of up to 35–40% for systemic or disseminated infections. Systemic mycoses can occur in patients with severely impaired immune systems (AIDS), with organ or bone marrow transplants, cancer patients undergoing chemotherapy, and patients in ICU (neonates and elderly). It is, therefore, obvious that there is a substantial need for fast, effective antifungal antibiotics to combat fungal infections. The present investigation has been proposed to screen effective fungal metabolites for the control of Candida albicans by evaluating the potential of fungal bioactive compounds, its purification and characterization

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