highest ability to cause cutaneous infections. the white, opaque and gray phenotypes form a tristable phenotypic switching system. since it is often difficult to differentiate between white, opaque and gray cells phloxine b, a dye, can be added to the medium. a potential regulatory molecule in the white to opaque switching is efg1p, a transcription factor found in the wo-1 strain that regulates dimorphism, and more recently has been suggested to help regulate phenotypic switching. efg1p is expressed only in the white and not in the gray cell-type, and overexpression of efg1p in the gray form causes a rapid conversion to the white form. environmental stress glucose starvation is a likely common environmental stress encountered by c. albicans in its natural habitat. glucose starvation causes an increase in intracellular reactive oxygen. this stress can lead to mating between two individuals of the same mating type, an interaction that may be frequent in nature under stressful conditions. white-gut switch a very special type of phenotypic switch is the white-gut switch (gastrointestinally-induced transition). gut cells are extremely adapted to survival in the digestive tract by metabolic adaptations to available nutrients in the digestive tract. the gut cells live as commensal organisms and outcompete other phenotypes. the transition from white to gut cells is driven by passage through the gut where environmental parameters trigger this transition by increasing the wor1 expression. role in disease main article: candidiasis candida is found worldwide but most commonly compromises immunocompromised individuals diagnosed with serious diseases such as hiv and cancer. candida are ranked as one of the most common groups of organisms that cause hospital-acquired infections. especially high-risk individuals are patients that have recently undergone surgery, a transplant or are in the intensive care units (icu), c. albicans infections is the top source of fungal infections in critically ill or otherwise immunocompromised patients. these patients predominantly develop oropharyngeal or thrush candidiasis, which can lead to malnutrition and interfere with the absorption of medication. methods of transmission include mother to infant through childbirth, people-to-people acquired infections that most commonly occur in hospital settings where immunocompromised patients acquire the yeast from healthcare workers and has a 40% incident rate. people can become infected after having sex with a woman that has an existing vaginal yeast infection. parts of the body that are commonly infected include the skin, genitals, throat, mouth, and blood. distinguishing features of vaginal infection include discharge, and dry and red appearance of vaginal mucosa or skin. candida continues to be the fourth most commonly isolated organism in bloodstream infections. healthy people usually do not suffer (severely) from superficial infections caused by a local alteration in cellular immunity as seen by asthma patients that use oral corticosteroids. superficial and local infections it commonly occurs as a superficial infection on mucous membranes in the mouth or vagina. once in their lives around 75% of women will suffer from vulvovaginal candidiasis (vvc) and about 90% of these infections are caused by c. albicans. it may also affect a number of other regions. for example, higher prevalence of colonization of c. albicans was reported in young individuals with tongue piercing, in comparison to unpierced matched individuals, but not in healthy young individuals who use intraoral orthodontic acrylic appliances. to infect host tissue, the usual unicellular yeast-like form of c. albicans reacts to environmental cues and switches into an invasive, multicellular filamentous form, a phenomenon called dimorphism. in addition, an overgrowth infection is considered a superinfection, the term usually applied when an infection becomes opportunistic and very resistant to antifungals. it then becomes suppressible by antibiotics. the infection is prolonged when the original sensitive strain is replaced by the antibiotic-resistant strain. candidiasis is known to cause gastrointestinal (gi) symptoms particularly in immunocompromised patients or those receiving steroids (e.g. to treat asthma) or antibiotics. recently, there is an emerging literature that an overgrowth of fungus in the small intestine of non-immunocompromised subjects may cause unexplained gi symptoms. small intestinal fungal overgrowth (sifo) is characterized by the presence of an excessive number of fungal organisms in the small intestine associated with gastrointestinal symptoms. the most common symptoms observed in these patients were belching, bloating, indigestion, nausea, diarrhea, and gas. the underlying mechanism(s) that predisposes to sifo is unclear. further studies are needed; both to confirm these observations and to examine the clinical relevance of fungal overgrowth. systemic infections systemic fungal infections (fungemias) including those by c. albicans have emerged as important causes of morbidity and mortality in immunocompromised patients (e.g., aids, cancer chemotherapy, organ or bone marrow transplantation). c. albicans often forms biofilms inside the body. such c. albicans biofilms may form on the surface of implantable medical devices or organs. in these biofilms it is often found together with staphylococcus aureus. such multispecies infections lead to higher mortalities. in addition hospital-acquired infections by c. albicans have become a cause of major health concerns. especially once candida cells are introduced in the bloodstream a high mortality, up to 40–60% can occur. although candida albicans is the most common cause of candidemia, there has been a decrease in the incidence and an increased isolation of non-albicans species of candida in recent years. preventive measures include maintaining a good oral hygiene, keeping a healthy lifestyle including good nutrition, the careful use of antibiotics, treatment of infected areas and keeping skin dry and clean, free from open wounds. role of c. albicans in crohn's disease the link between c. albicans and crohn's disease has been investigated in a large cohort. this study demonstrated that members of families with multiple cases of crohn's disease were more likely to be colonized by c. albicans than members of control families. experimental studies show that chemically induced colitis promotes c. albicans colonization. in turn, c. albicans colonization generates anti-saccharomyces cerevisiae antibodies (asca), increases inflammation, histological scores and pro-inflammatory cytokine expression. treatment there are relatively few drugs that can successfully treat candidiasis. treatment commonly includes: amphotericin b, echinocandin, or fluconazole for systemic infections nystatin for oral and esophageal infections clotrimazole for skin and genital yeast infections similarly to antibiotic resistance, resistance to many anti-fungals is becoming a problem. new anti-fungals have to be developed to cope with this problem since only a limited number of anti-fungals are available. a general problem is that in contrast to bacteria, fungi are often overlooked as a potential health problem. economic implications given the fact that candidiasis is the fourth- (to third-) most frequent hospital acquired infection worldwide it leads to immense financial implications. approximately 60,000 cases of systemic candidiasis each year in the usa alone lead up to a cost to be between $2–4 billion. the total costs for candidiasis are among the highest compared to other fungal infections due to the high prevalence. the immense costs are partly explained by a longer stay in the intensive care unit or hospital in general. an extended stay for up to 21 more days compared to non-infected patients is not uncommon. role of gsdmd in c.albicans infection gasdermin d (gsdmd) is a protein that in humans is encoded by the gsdmd gene and is a known target of the inflammasome and acts as an effector molecule of programmed cell death known as pyroptosis. this protein determines cell lysis to prevent pathogen replication and results in the release of the inflammatory cytokine interleukin-1β (il-1β) into the extracellular space to recruit and activate immune cells at the site of infection. inflammasome activation due to c.albicans infection triggers the release of a cytokine storm necessary to fight the pathogen. excessive release of these pro-inflammatory mediators has been shown to exaggerate systemic inflammation leading to vascular injury and damage to vital organs. unfortunately, candida albicans therapy is often ineffective despite the availability of many antifungal drugs, mainly because of resistance phenomena. during conventional pyroptosis controlled by the inflammasome-gsdmd axis is hijacked by c. albicans to facilitate escape from macrophages through unfolding of hyphae and candidalysin, a fungal toxin released from hyphae. it has been shown that disruption of gsdmd in macrophages infected with candida albicans reduces the fungal load. in addition, the presence of hyphae and candidalysin are key factors in the activation of gsdmd and the release of candida from macrophages. also using candida-infected mice, inhibition of gsdmd has been shown to paradoxically improve prognosis and survival, indicating that this protein may be a potential therapeutic target in c. albicans-induced sepsis. biofilm development biofilm formation steps the biofilm of c. albicans is formed in four steps. first, there is the initial adherence step, where the yeast-form cells adhere to the substrate. the second step is called intermediate step, where the cells propagate to form microcolonies, and germ tubes form to yield hyphae. in the maturation step, the biofilm biomass expands, the extracellular matrix accumulates and drug resistance increases. in the last step of biofilm formation, the yeast-form cells are released to colonize the surrounding environment (dispersion). yeast cells released from a biofilm have novel properties, including increased virulence and drug tolerance. zap1 zap1, also known as csr1 and sur1 (zinc-responsive activator protein), is a transcription factor which is required for the hypha formation in c. albicans biofilms. zap1 controls the equilibrium of yeast and hyphal cells, the zinc transporters and zinc regulated genes in biofilms of c. albicans. zinc zinc (zn2+) is important for cell function of c. albicans and zap1 controls the zinc levels in the cells through the zinc transporters zrt1 and zrt2. the regulation of zinc concentration in the cells is important for the cell viability and if the zinc levels get too high, it is toxic for the cells. the zrt1 is transporting the zinc ions with high affinity and the zrt2 is transporting the zinc ions with low affinity. mechanisms and proteins important for pathogenesis filamentation the ability to switch between yeast cells and hyphal cells is an important virulence factor. many proteins play a role in this process. filamentation in c. albicans is a very complex process. the formation of hyphae can for example help candida albicans to escape from macrophages in the human body. moreover, c. albicans undergo yeast-to-hyphal transition within the acidic macrophage phagosome. this initially causes phagosome membrane distension which eventually leads to phagosomal alkalinization by physical rupture, followed by escape. hwp1 hwp1 stands for hyphal wall protein 1. hwp1 is a mannoprotein located on the surface of the hyphae in the hyphal form of c. albicans. hwp1 is a mammalian transglutaminase substrate. this host enzyme allows candida albicans to attach stably to host epithelial cells. adhesion of c. albicans to host cells is an essential first step in the infection process for colonization and subsequent induction of mucosal infection. slr1 the rna-binding protein slr1 plays a role in instigating hyphal formation and virulence in c. albicans. candidalysin candidalysin is a cytolytic 31-amino acid α-helical peptide toxin that is released by c. albicans during hyphal formation. it contributes to virulence during mucosal infections. genetic and genomic tools due to its nature as a model organism, being an important human pathogen and the alternative codon usage (cug translated into serine rather than leucine), several specific projects and tools have been created to study c. albicans. the diploid nature and the absence of a sexual cycle, however, makes it a hard to study organism. in the last 20 years, however, many systems have been developed to study c. albicans in a more in depth genetic level. selection markers the most used selection markers in c. albicans are the canat1 resistance marker (confers resistance against nourseothricin) and mpar or imh3r (confers resistance to mycophenolic acid). next to the above-mentioned selection makers a few auxotrophic strains were generated to work with auxotrophic makers. the ura3 marker (ura3 blaster method) is an often-used strategy in uridine auxotrophic strains; however, studies have shown that differences in ura3 position in the genome can be involved in the pathogeny of c. albicans. besides the ura3 selection one can also use the histidine, leucine and arginine autotrophy. the advantage of using those autotrophies lies in the fact that they exhibit wild-type or nearly wild-type virulence in a mouse model compared to the ura3 system. one application of the leucine, arginine and histidine autotrophy is for example the candida two-hybrid system. full sequence genome the full genome of c. albicans has been sequenced and made publicly available in