...hypha development is coupled to multiple invasion-associated properties, but if invasion per se does not directly damage host cells, how does this process occur? ...when encountering yeast cells, ...our mucosal tissues tolerate these as benign colonisers but when encountering damage-inducing hyphae, Candidalysin induces the danger response pathway.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Candidalysin is the first peptide toxin identified in any human fungal pathogen.•Candidalysin is critical for Candida albicans mucosal and systemic infections.•Candidalysin activates danger-response ...and damage-protection pathways in host cells.•Candidalysin activates the epidermal growth factor receptor in epithelial cells and the NLRP3 inflammasome in macrophages.•Candidalysin drives neutrophil recruitment and Type 17 immunity.
Candidalysin is a cytolytic peptide toxin secreted by the invasive form of the human pathogenic fungus, Candida albicans. Candidalysin is critical for mucosal and systemic infections and is a key driver of host cell activation, neutrophil recruitment and Type 17 immunity. Candidalysin is regarded as the first true classical virulence factor of C. albicans but also triggers protective immune responses. This review will discuss how candidalysin was discovered, the mechanisms by which this peptide toxin contributes to C. albicans infections, and how its discovery has advanced our understanding of fungal pathogenesis and disease.
•Candidalysin is the first peptide toxin identified in any human fungal pathogen.•Epithelial cells identify invasive C. albicans by detecting Candidalysin activity.•Neutrophils are critical for ...protection against mucosal C. albicans infection.•IL-17 signaling is essential for immunity to mucosal C. albicans infections.•Candidalysin induces innate Type 17 production via IL-1 receptor signaling.
Candida albicans is a human fungal pathogen that causes millions of mucosal and life-threatening infections annually. C. albicans initially interacts with epithelial cells, resulting in fungal recognition and the formation of hyphae. Hypha formation is critical for host cell damage and immune activation, which are both driven by the secretion of Candidalysin, a recently discovered peptide toxin. Epithelial activation leads to the production of inflammatory mediators that recruit innate immune cells including neutrophils, macrophages and innate Type 17 cells, which together work with epithelial cells to clear the fungal infection. This review will focus on the recent discoveries that have advanced our understanding of C. albicans-epithelial interactions and the induction of mucosal innate immunity.
Candida albicans is a common fungus of the human microbiota. While generally a harmless commensal in healthy individuals, several factors can lead to its overgrowth and cause a range of complications ...within the host, from localized superficial infections to systemic life-threatening disseminated candidiasis. A major virulence factor of C. albicans is its ability to form biofilms, a closely packed community of cells that can grow on both abiotic and biotic substrates, including implanted medical devices and mucosal surfaces. These biofilms are extremely hard to eradicate, are resistant to conventional antifungal treatment and are associated with high morbidity and mortality rates, making biofilm-associated infections a major clinical challenge. Here, we review the current knowledge of the processes involved in C. albicans biofilm formation and development, including the central processes of adhesion, extracellular matrix production and the transcriptional network that regulates biofilm development. We also consider the advantages of the biofilm lifestyle and explore polymicrobial interactions within multispecies biofilms that are formed by C. albicans and selected microbial species.
Clearance of invading microbes requires phagocytes of the innate immune system. However, successful pathogens have evolved sophisticated strategies to evade immune killing. The opportunistic human ...fungal pathogen Candida albicans is efficiently phagocytosed by macrophages, but causes inflammasome activation, host cytolysis, and escapes after hypha formation. Previous studies suggest that macrophage lysis by C. albicans results from early inflammasome-dependent cell death (pyroptosis), late damage due to glucose depletion and membrane piercing by growing hyphae. Here we show that Candidalysin, a cytolytic peptide toxin encoded by the hypha-associated gene ECE1, is both a central trigger for NLRP3 inflammasome-dependent caspase-1 activation via potassium efflux and a key driver of inflammasome-independent cytolysis of macrophages and dendritic cells upon infection with C. albicans. This suggests that Candidalysin-induced cell damage is a third mechanism of C. albicans-mediated mononuclear phagocyte cell death in addition to damage caused by pyroptosis and the growth of glucose-consuming hyphae.
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.
Unlike other forms of candidiasis, vulvovaginal candidiasis, caused primarily by the fungal pathogen
, is a disease of immunocompetent and otherwise healthy women. Despite its prevalence, the fungal ...factors responsible for initiating symptomatic infection remain poorly understood. One of the hallmarks of vaginal candidiasis is the robust recruitment of neutrophils to the site of infection, which seemingly do not clear the fungus, but rather exacerbate disease symptomatology. Candidalysin, a newly discovered peptide toxin secreted by
hyphae during invasion, drives epithelial damage, immune activation, and phagocyte attraction. Therefore, we hypothesized that Candidalysin is crucial for vulvovaginal candidiasis immunopathology. Anti-
immune responses are anatomical-site specific, as effective gastrointestinal, oral, and vaginal immunities are uniquely compartmentalized. Thus, we aimed to identify the immunopathologic role of Candidalysin and downstream signaling events at the vaginal mucosa. Microarray analysis of
-infected human vaginal epithelium
revealed signaling pathways involved in epithelial damage responses, barrier repair, and leukocyte activation. Moreover, treatment of A431 vaginal epithelial cells with Candidalysin induced dose-dependent proinflammatory cytokine responses (including interleukin 1α IL-1α, IL-1β, and IL-8), damage, and activation of c-Fos and mitogen-activated protein kinase (MAPK) signaling, consistent with fungal challenge. Mice intravaginally challenged with
strains deficient in Candidalysin exhibited no differences in colonization compared to isogenic controls. However, significant decreases in neutrophil recruitment, damage, and proinflammatory cytokine expression were observed with these strains. Our findings demonstrate that Candidalysin is a key hypha-associated virulence determinant responsible for the immunopathogenesis of
vaginitis.
Fungi are ubiquitous organisms that thrive in diverse natural environments including soils, plants, animals, and the human body. In response to warmth, humidity, and moisture, certain fungi which ...grow on crops and harvested foodstuffs can produce mycotoxins; secondary metabolites which when ingested have a deleterious impact on health. Ongoing research indicates that some mycotoxins and, more recently, peptide toxins are also produced during active fungal infection in humans and experimental models. A combination of innate and adaptive immune recognition allows the host to eliminate invading pathogens from the body. However, imbalances in immune homeostasis often facilitate microbial infection. Despite the wide-ranging effects of fungal toxins on health, our understanding of toxin-mediated modulation of immune responses is incomplete. This review will explore the current understanding of fungal toxins and how they contribute to the modulation of host immunity.
We previously reported that a bi-phasic innate immune MAPK response, constituting activation of the mitogen-activated protein kinase (MAPK) phosphatase MKP1 and c-Fos transcription factor, ...discriminates between the yeast and hyphal forms of Candida albicans in oral epithelial cells (ECs). Since the vast majority of mucosal Candida infections are vaginal, we sought to determine whether a similar bi-phasic MAPK-based immune response was activated by C. albicans in vaginal ECs. Here, we demonstrate that vaginal ECs orchestrate an innate response to C. albicans via NF-κB and MAPK signaling pathways. However, unlike in oral ECs, the first MAPK response, defined by c-Jun transcription factor activation, is delayed until 2 h in vaginal ECs but is still independent of hypha formation. The 'second' or 'late' MAPK response, constituting MKP1 and c-Fos transcription factor activation, is identical to oral ECs and is dependent upon both hypha formation and fungal burdens. NF-κB activation is immediate but independent of morphology. Furthermore, the proinflammatory response in vaginal ECs is different to oral ECs, with an absence of G-CSF and CCL20 and low level IL-6 production. Therefore, differences exist in how C. albicans activates signaling mechanisms in oral and vaginal ECs; however, the activation of MAPK-based pathways that discriminate between yeast and hyphal forms is retained between these mucosal sites. We conclude that this MAPK-based signaling pathway is a common mechanism enabling different human epithelial tissues to orchestrate innate immune responses specifically against C. albicans hyphae.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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