Candidalysin Is Required for Neutrophil Recruitment and Virulence During Systemic Candida albicans Infection

Swidergall, Marc; Khalaji, Mina; Solis, Norma V.; Moyes, David L.; Drummond, Rebecca A.; Hube, Bernhard; Lionakis, Michail S.; Murdoch, Craig; Filler, Scott G.; Naglik, Julian R.

doi:10.1093/infdis/jiz322

Cited by 78 publications

(75 citation statements)

References 45 publications

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“…Disruption of the ECE1 locus or the region specifically encoding for candidalysin results in severe attenuation of pathogenicity in multiple infection models, including murine invasive and oral candidiasis, zebrafish swim bladder infection, and a variety of cell culture systems [77,[80][81][82][83]. Similarly, deletion of ECE1 or candidalysin significantly reduces immunopathologic markers of infection (neutrophils, pro-inflammatory cytokines, alarmins) and tissue damage during experimental VVC (Figure 1) [81].…”

Section: An Indispensable Role For Candidalysinmentioning

confidence: 99%

Vulvovaginal Candidiasis: A Current Understanding and Burning Questions

Willems

Ahmed

Liu

et al. 2020

JoF

213

197

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Candida albicans, along with other closely related Candida species, are the primary causative agents of vulvovaginal candidiasis (VVC)-a multifactorial infectious disease of the lower female reproductive tract resulting in pathologic inflammation. Unlike other forms of candidiasis, VVC is a disease of immunocompetent and otherwise healthy women, most predominant during their child-bearing years. While VVC is non-lethal, its high global incidence and profound negative impact on quality-of-life necessitates further understanding of the host and fungal factors that drive disease pathogenesis. In this review, we cover the current state of our understanding of the epidemiology, host response, fungal pathogenicity mechanisms, impact of the microbiome, and novel approaches to treatment of this most prevalent human candidal infection. We also offer insight into the latest advancements in the VVC field and identify important questions that still remain.

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Section: An Indispensable Role For Candidalysinmentioning

confidence: 99%

Vulvovaginal Candidiasis: A Current Understanding and Burning Questions

Willems

Ahmed

Liu

et al. 2020

JoF

213

197

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“…Interestingly, recently it was discovered that hyphae-induced epithelial damage was mainly mediated through the secretion of a cytolytic peptide toxin called candidalysin, encoded by the hyphal-specific gene ECE1. The importance of this newly identified virulence factor was clearly established when C. albicans mutants were found to be incapable of inducing tissue damage, and were highly attenuated in a mouse model of oropharyngeal candidiasis [35,48,49].…”

Section: Candida Albicans: An Opportunistic Pathogenmentioning

confidence: 99%

Oral Candidiasis: A Disease of Opportunity

Vila

Sultan

Montelongo-Jauregui

et al. 2020

JoF

307

241

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Oral candidiasis, commonly referred to as “thrush,” is an opportunistic fungal infection that commonly affects the oral mucosa. The main causative agent, Candida albicans, is a highly versatile commensal organism that is well adapted to its human host; however, changes in the host microenvironment can promote the transition from one of commensalism to pathogen. This transition is heavily reliant on an impressive repertoire of virulence factors, most notably cell surface adhesins, proteolytic enzymes, morphologic switching, and the development of drug resistance. In the oral cavity, the co-adhesion of C. albicans with bacteria is crucial for its persistence, and a wide range of synergistic interactions with various oral species were described to enhance colonization in the host. As a frequent colonizer of the oral mucosa, the host immune response in the oral cavity is oriented toward a more tolerogenic state and, therefore, local innate immune defenses play a central role in maintaining Candida in its commensal state. Specifically, in addition to preventing Candida adherence to epithelial cells, saliva is enriched with anti-candidal peptides, considered to be part of the host innate immunity. The T helper 17 (Th17)-type adaptive immune response is mainly involved in mucosal host defenses, controlling initial growth of Candida and inhibiting subsequent tissue invasion. Animal models, most notably the mouse model of oropharyngeal candidiasis and the rat model of denture stomatitis, are instrumental in our understanding of Candida virulence factors and the factors leading to host susceptibility to infections. Given the continuing rise in development of resistance to the limited number of traditional antifungal agents, novel therapeutic strategies are directed toward identifying bioactive compounds that target pathogenic mechanisms to prevent C. albicans transition from harmless commensal to pathogen.

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“…This peptide acted as a cytolytic toxin, damaging epithelial host membranes, leading to the release of damage associated cytokines. Further, ece1 mutants were avirulent in the animal model of mucosal infection [30] as well as zebrafish and murine models of systemic fungal infections [31]. The upregulation of ECE1 reported previously [15], together with other genes that were implicated in virulence, may explain the restoration of virulence in the hog1 sko1 double mutant.…”

Section: Discussionmentioning

confidence: 75%

Deletion of the SKO1 Gene in a hog1 Mutant Reverts Virulence in Candida albicans

Urrialde

Prieto

Hidalgo-Vico

et al. 2019

JoF

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Candida albicans displays the ability to adapt to a wide variety of environmental conditions, triggering signaling pathways and transcriptional regulation. Sko1 is a transcription factor that was previously involved in early hypoxic response, cell wall remodeling, and stress response. In the present work, the role of sko1 mutant in in vivo and ex vivo studies was explored. The sko1 mutant behaved as its parental wild type strain regarding the ability to colonize murine intestinal tract, ex vivo adhesion to murine gut epithelium, or systemic virulence. These observations suggest that Sko1 is expendable during commensalism or pathogenesis. Nevertheless, the study of the hog1 sko1 double mutant showed unexpected phenotypes. Previous researches reported that the deletion of the HOG1 gene led to avirulent C. albicans mutant cell, which was, therefore, unable to establish as a commensal in a gastrointestinal murine model. Here, we show that the deletion of sko1 in a hog1 background reverted the virulence of the hog1 mutant in a systemic infection model in Galleria mellonella larvae and slightly improved the ability to colonize the murine gut in a commensalism animal model compared to the hog1 mutant. These results indicate that Sko1 acts as a repressor of virulence related genes, concluding that Sko1 plays a relevant role during commensalism and systemic infection.

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Candidalysin Is Required for Neutrophil Recruitment and Virulence During Systemic Candida albicans Infection

Cited by 78 publications

References 45 publications

Vulvovaginal Candidiasis: A Current Understanding and Burning Questions

Vulvovaginal Candidiasis: A Current Understanding and Burning Questions

Oral Candidiasis: A Disease of Opportunity

Deletion of the SKO1 Gene in a hog1 Mutant Reverts Virulence in Candida albicans

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