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Fungi, such as Candida albicans , are found in the mammalian gut, but we know little about what they are doing there. Tso et al. put C. albicans under evolutionary pressure by serial passage in mice that were treated with antibiotics and were thus lacking gut bacteria (see the Perspective by d'Enfert). Passage accelerated fungal mutation, especially around the FLO8 gene, resulting in low-virulence phenotypes unable to form hyphae. Nevertheless, these phenotypes stimulated proinflammatory cytokines and conferred transient cross-protection against several other gut inhabitants. However, if an intact microbiota was present, only the virulent hyphal forms persisted. Science , this issue p. 589 ; see also p. 523 Virulence is lost after repeated passage of Candida albicans promotes mutation at yeast-to-hypha transformation genes. Gut microbes live in symbiosis with their hosts, but how mutualistic animal-microbe interactions emerge is not understood. By adaptively evolving the opportunistic fungal pathogen Candida albicans in the mouse gastrointestinal tract, we selected strains that not only had lost their main virulence program but also protected their new hosts against a variety of systemic infections. This protection was independent of adaptive immunity, arose as early as a single day postpriming, was dependent on increased innate cytokine responses, and was thus reminiscent of “trained immunity.” Because both the microbe and its new host gain some advantages from their interaction, this experimental system might allow direct study of the evolutionary forces that govern the emergence of mutualism between a mammal and a fungus.

Candida albicans is among the most prevalent fungal species of the human microbiota and asymptomatically colonizes healthy individuals. However, it is also an opportunistic pathogen that can cause severe, and often fatal, bloodstream infections. The medical impact of C. albicans typically depends on its ability to form biofilms, which are closely packed communities of cells that attach to surfaces, such as tissues and implanted medical devices. In this Review, we provide an overview of the processes involved in the formation of C. albicans biofilms and discuss the core transcriptional network that regulates biofilm development. We also consider some of the advantages that biofilms provide to C. albicans in comparison with planktonic growth and explore polymicrobial biofilms that are formed by C. albicans and certain bacterial species.

Key Points Candida albicans is a common cause of mucosal infections. In certain groups of immunocompromised patients it also causes life-threatening bloodstream infections that are disseminated to internal organs. It is a polymorphic fungus, being able to grow in yeast, hyphal and pseudohyphal forms. The hyphal form penetrates epithelia and endothelia, causing tissue damage and allowing access to the bloodstream. C. albicans is exquisitely sensitive to the multiple environments that it encounters in the human host and forms hyphae in response to cues such as 37 °C temperature, serum, CO 2 and O 2 tension, and neutral pH. The morphological switch is also regulated by the presence of not only other C. albicans cells but also bacterial cells, both of which are sensed through quorum sensing compounds. Environmental signals are transduced through multiple pathways that target multiple transcription factors, resulting in the expression of a panel of hypha-specific genes. A key pathway is based on cyclic AMP and targets the transcription factor enhanced filamentous growth protein (Efg1). In this pathway, adenylyl cyclase, which is encoded by CYR1 , integrates multiple cues in Ras-dependent and Ras-independent ways. Negative regulation is exerted by the general transcriptional corepressor Tup1, which is targeted to hypha-specific genes by the DNA-binding proteins Nrg1 and Rox1p-like regulator of filamentous growth (Rfg1). The key outputs of the signal transduction pathway are the expression of three genes, UME6 , EED1 and hyphal G1 cyclin protein 1 ( HGC1 ). Overexpression of the transcription factor Ume6 forces ectopic hyphal growth. The role of Eed1 is currently unclear, but current research suggests that it lies upstream of Ume6. Hgc1 is the C. albicans homologue of the S. cerevisiae Ccn1 and Cln2 G1 cyclin pair, which activate the cyclin-dependent kinase cell division control 28 (Cdc28). Hyphae grow in a highly polarized manner from their tip. This requires the delivery of secretory vesicles along actin cables. These vesicles accumulate in a subapical region called the Spitzenkörper before they fuse with the plasma membrane at the tip after docking with a multiprotein structure called the exocyst. Cell separation after cytokinesis is suppressed in hyphae. This suppression involves phosphorylation of Efg1, which then associates with the promoters of genes encoding septum-degrading enzymes, repressing their Ace2-mediated transcription. A second mechanism suppressing cell separation involves the exclusion of the Cdc14 phosphatase from the septin ring, the subunits of which have different dynamic properties in yeast and hyphae. A key role for kinases is emerging in the cell biology of hyphal growth. Hgc1–Cdc28 targets Rga2, Sec2 and Mob2, as well as Efg1. Rga2 is a GTPase-activating protein (GAP) that negatively regulates the GTPase Cdc42, which has a central role in orchestrating polarized growth. Sec2 is the guanosine exchange factor (GEF) that activates the GTPase Sec4, which is required for polarized exocytosis. Mob2 is the activating partner of the kinase Cbk1, which is absolutely required for hyphal growth. Upon hyphal induction, Cdc28 is partnered by a different cyclin, Ccn1, and cooperates with another kinase, growth-inhibitory protein 4 (Gin4), to phosphorylate the septin Cdc11. In response to certain environmental cues, the unicellular budding yeast Candida albicans can also grow as either a pseudohyphal or a hyphal form. In this Review, Sudbery describes the signal transduction pathways and cellular mechanisms that drive polarized hyphal growth and the role of this growth in disease. The fungus Candida albicans is often a benign member of the mucosal flora; however, it commonly causes mucosal disease with substantial morbidity and in vulnerable patients it causes life-threatening bloodstream infections. A striking feature of its biology is its ability to grow in yeast, pseudohyphal and hyphal forms. The hyphal form has an important role in causing disease by invading epithelial cells and causing tissue damage. This Review describes our current understanding of the network of signal transduction pathways that monitors environmental cues to activate a programme of hypha-specific gene transcription, and the molecular processes that drive the highly polarized growth of hyphae.

The fungus Candida albicans frequently colonizes the human gastrointestinal tract, from which it can disseminate to cause systemic disease. This polymorphic species can transition between growing as single-celled yeast and as multicellular hyphae to adapt to its environment. The current dogma of C. albicans commensalism is that the yeast form is optimal for gut colonization, whereas hyphal cells are detrimental to colonization but critical for virulence 1 – 3 . Here, we reveal that this paradigm does not apply to multi-kingdom communities in which a complex interplay between fungal morphology and bacteria dictates C. albicans fitness. Thus, whereas yeast-locked cells outcompete wild-type cells when gut bacteria are absent or depleted by antibiotics, hyphae-competent wild-type cells outcompete yeast-locked cells in hosts with replete bacterial populations. This increased fitness of wild-type cells involves the production of hyphal-specific factors including the toxin candidalysin 4 , 5 , which promotes the establishment of colonization. At later time points, adaptive immunity is engaged, and intestinal immunoglobulin A preferentially selects against hyphal cells 1 , 6 . Hyphal morphotypes are thus under both positive and negative selective pressures in the gut. Our study further shows that candidalysin has a direct inhibitory effect on bacterial species, including limiting their metabolic output. We therefore propose that C. albicans has evolved hyphal-specific factors, including candidalysin, to better compete with bacterial species in the intestinal niche. Both the yeast and hyphal forms of Candida albicans enable colonization of the mammalian gut, with hyphal cells secreting the toxin candidalysin to inihibit bacteria and support fungal commensalism.

Cytolytic proteins and peptide toxins are classical virulence factors of several bacterial pathogens which disrupt epithelial barrier function, damage cells and activate or modulate host immune responses. Such toxins have not been identified previously in human pathogenic fungi. Here we identify the first, to our knowledge, fungal cytolytic peptide toxin in the opportunistic pathogen Candida albicans . This secreted toxin directly damages epithelial membranes, triggers a danger response signalling pathway and activates epithelial immunity. Membrane permeabilization is enhanced by a positive charge at the carboxy terminus of the peptide, which triggers an inward current concomitant with calcium influx. C. albicans strains lacking this toxin do not activate or damage epithelial cells and are avirulent in animal models of mucosal infection. We propose the name ‘Candidalysin’ for this cytolytic peptide toxin; a newly identified, critical molecular determinant of epithelial damage and host recognition of the clinically important fungus, C. albicans . This study identifies a cytolytic peptide toxin in the opportunistic human fungal pathogen Candida albicans —the peptide is both a crucial virulence factor that permeabilizes the host cell plasma membrane and a key signal that triggers a host danger response pathway. A toxin identified in a human fungal pathogen This study identifies and characterizes a cytolytic peptide toxin in the opportunistic human fungal pathogen Candida albicans . The peptide, termed Candidalysin, acts both as a crucial virulence factor that permeabilizes the host cell plasma membrane and as a key signal that triggers a host danger-response pathway.

New strategies are needed to counter the escalating threat posed by drug-resistant fungi. The molecular chaperone Hsp90 affords a promising target because it supports survival, virulence and drug-resistance across diverse pathogens. Inhibitors of human Hsp90 under development as anticancer therapeutics, however, exert host toxicities that preclude their use as antifungals. Seeking a route to species-selectivity, we investigate the nucleotide-binding domain (NBD) of Hsp90 from the most common human fungal pathogen, Candida albicans . Here we report structures for this NBD alone, in complex with ADP or in complex with known Hsp90 inhibitors. Encouraged by the conformational flexibility revealed by these structures, we synthesize an inhibitor with >25-fold binding-selectivity for fungal Hsp90 NBD. Comparing co-crystals occupied by this probe vs. anticancer Hsp90 inhibitors revealed major, previously unreported conformational rearrangements. These insights and our probe’s species-selectivity in culture support the feasibility of targeting Hsp90 as a promising antifungal strategy. The chaperone Hsp90 is a potential target for the development of drugs against fungal pathogens. Here the authors determine the structure of the Hsp90 nucleotide-binding domain from Candida albicans , which they use to design an inhibitor and demonstrate its selectivity for the fungal enzyme, both biochemically and in cells.

Intestinal-colonizing Candida albicans is a primary source of systemic infection where it translocates across intestinal barriers into the bloodstream leading to disseminated candidiasis. To persist in the gastrointestinal tract, C. albicans must adapt to complex environments, including extreme hypoxic conditions (EHC). Here, we performed a functional genomic screen to identify genes important for C. albicans fitness under EHC. We discovered that one of the two C. albicans sterol C4-methyl oxidases, Erg251, is specifically required for producing ergosterol, an essential component for fungal membrane, in low oxygen conditions. Deleting Erg251 or mutating key amino acid residues for its function under EHC impaired C. albicans virulence and colonization in mouse models of systemic infection and commensalism, respectively. Selective inhibitors of fungal sterol C4-methyl oxidases, inhibit C. albicans growth in vitro and in a nematode infection model, showing therapeutic potential. Candida albicans must adapt to hypoxia. Here, the authors discover the sterol C4-methyl oxidase (SMO) Erg251 is essential for extreme hypoxic growth, as well as virulence and colonization, and that SMO inhibitors have therapeutic potential.

ABSTRACT Candida albicans is a major fungal pathogen of humans. It exists as a commensal in the oral cavity, gut or genital tract of most individuals, constrained by the local microbiota, epithelial barriers and immune defences. Their perturbation can lead to fungal outgrowth and the development of mucosal infections such as oropharyngeal or vulvovaginal candidiasis, and patients with compromised immunity are susceptible to life-threatening systemic infections. The importance of the interplay between fungus, host and microbiota in driving the transition from C. albicans commensalism to pathogenicity is widely appreciated. However, the complexity of these interactions, and the significant impact of fungal, host and microbiota variability upon disease severity and outcome, are less well understood. Therefore, we summarise the features of the fungus that promote infection, and how genetic variation between clinical isolates influences pathogenicity. We discuss antifungal immunity, how this differs between mucosae, and how individual variation influences a person's susceptibility to infection. Also, we describe factors that influence the composition of gut, oral and vaginal microbiotas, and how these affect fungal colonisation and antifungal immunity. We argue that a detailed understanding of these variables, which underlie fungal-host-microbiota interactions, will present opportunities for directed antifungal therapies that benefit vulnerable patients. The complexity and variability of FunHoMic interactions between the fungal pathogen, its human host and the Microbiota strongly influence the development and outcomes of the superficial and systemic Candida albicans infections that plague human health worldwide.

Candida albicans , the most prevalent human fungal pathogen, is considered to be an obligate diploid that carries recessive lethal mutations throughout the genome. Here we demonstrate that C. albicans has a viable haploid state that can be derived from diploid cells under in vitro and in vivo conditions, and that seems to arise through a concerted chromosome loss mechanism. Haploids undergo morphogenetic changes like those of diploids, including the yeast–hyphal transition, chlamydospore formation and a white-opaque switch that facilitates mating. Haploid opaque cells of opposite mating type mate efficiently to regenerate the diploid form, restoring heterozygosity and fitness. Homozygous diploids arise spontaneously by auto-diploidization, and both haploids and auto-diploids show a similar reduction in fitness, in vitro and in vivo , relative to heterozygous diploids, indicating that homozygous cell types are transient in mixed populations. Finally, we constructed stable haploid strains with multiple auxotrophies that will facilitate molecular and genetic analyses of this important pathogen. Candida albicans is a prominent human fungal pathogen that until now was thought to be an obligate diploid; here it is shown that C. albicans can form viable haploids, that these haploids are able to mate to form heterozygous diploids, and that haploids and their auto-diploids are significantly less fit in vitro and in vivo than heterozygous progenitors or diploids formed by haploid mating pairs. Candida albicans goes halves The common human fungal pathogen Candida albicans has long been considered an obligate diploid organism, with a rare, parasexual tetraploid stage and no meiosis. This has hindered classical genetic studies and made molecular manipulations more difficult than in model yeasts like Saccharomyces cerevisiae . Now Judith Berman and colleagues have identified a viable haploid C. albicans state derived from diploid cells. These cells can be isolated from in vitro stress conditions or following in vivo passage through a mammalian host. Haploids and their auto-diploids are significantly less fit in vivo when compared to heterozygous diploids. The authors have constructed a number of stable haploid strains to facilitate molecular and genetic analyses of C. albicans biology and virulence.

Elucidating population structure and levels of genetic diversity and recombination is necessary to understand the evolution and adaptation of species. $Candida\\ albicans$ is the second most frequent agent of human fungal infections worldwide, causing high-mortality rates. Here we present the genomic sequences of 182 C. $albicans$ isolates collected worldwide, including commensal isolates, as well as ones responsible for superficial and invasive infections, constituting the largest dataset to date for this major fungal pathogen. Although, C. $albicans$ shows a predominantly clonal population structure, we find evidence of gene flow between previously known and newly identified genetic clusters, supporting the occurrence of (para)sexuality in nature. A highly clonal lineage, which experimentally shows reduced fitness, has undergone pseudogenization in genes required for virulence and morphogenesis, which may explain its niche restriction. $Candida\\ albicans$ thus takes advantage of both clonality and gene flow to diversify.