New Insights in Candida albicans Innate Immunity at the Mucosa: Toxins, Epithelium, Metabolism, and Beyond

Pellón, Aize; Nasab, Shervin Dokht Sadeghi; Moyes, David L.

doi:10.3389/fcimb.2020.00081

Cited by 69 publications

(57 citation statements)

References 185 publications

(232 reference statements)

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“…It thereby elicits a pro-inflammatory response that contributes to the recruitment of immune cells like macrophages, Th17 cells, and neutrophils to the site of infections. It mediates a protective crosstalk via the latter [ 19 , 104 , 105 , 106 , 107 ]. This danger response is also activated by candidalysin in endothelial cells and vaginal cells [ 30 , 102 ].…”

Section: Dual Function Of Candidalysin During Infectionmentioning

confidence: 99%

The Dual Function of the Fungal Toxin Candidalysin during Candida albicans—Macrophage Interaction and Virulence

König

Hube

Kasper

2020

Toxins

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The dimorphic fungus Candida albicans is both a harmless commensal organism on mucosal surfaces and an opportunistic pathogen. Under certain predisposing conditions, the fungus can overgrow the mucosal microbiome and cause both superficial and life-threatening systemic infections after gaining access to the bloodstream. As the first line of defense of the innate immune response, infecting C. albicans cells face macrophages, which mediate the clearance of invading fungi by intracellular killing. However, the fungus has evolved sophisticated strategies to counteract macrophage antimicrobial activities and thus evade immune surveillance. The cytolytic peptide toxin, candidalysin, contributes to this fungal defense machinery by damaging immune cell membranes, providing an escape route from the hostile phagosome environment. Nevertheless, candidalysin also induces NLRP3 inflammasome activation, leading to an increased host-protective pro-inflammatory response in mononuclear phagocytes. Therefore, candidalysin facilitates immune evasion by acting as a classical virulence factor but also contributes to an antifungal immune response, serving as an avirulence factor. In this review, we discuss the role of candidalysin during C. albicans infections, focusing on its implications during C. albicans-macrophage interactions.

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Section: Dual Function Of Candidalysin During Infectionmentioning

confidence: 99%

The Dual Function of the Fungal Toxin Candidalysin during Candida albicans—Macrophage Interaction and Virulence

König

Hube

Kasper

2020

Toxins

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“… Candida albicans is an opportunistic fungal pathogen and a normal colonizer of mucosa of the gut, the oral cavity, and the vulvovaginal tract. When the balance of the microbial flora is disrupted or the immune defenses are compromised, it can become pathogenic, often causing recurrent disease in susceptible individuals ( 1 ). Symptomatic infections in the female reproductive tract, termed vulvovaginal candidiasis (VVC), typically occur in otherwise healthy women.…”

Section: Observationmentioning

confidence: 99%

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

Gerwien

Dunker

Brandt

et al. 2020

mSphere

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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.

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“…Thus, cells obtained the required energy required to boost antimicrobial mechanisms and cytokine production. This behavior resembles the so-called Warburg effect observed in cancer cells, in which aerobic glycolysis is the main source of energy (Pearce and Pearce, 2013;Pellon et al, 2020). When macrophages are challenged with C. albicans, C. albicans rapidly consumes glucose, causing macrophage death (Tucey et al, 2018).…”

Section: Discussionmentioning

confidence: 62%

SWL-1 Reverses Fluconazole Resistance in Candida albicans by Regulating the Glycolytic Pathway

Zhang

Wang

et al. 2020

Front. Microbiol.

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Candida albicans is a ubiquitous clinical fungal pathogen. Prolonged use of the first-line antifungal agent fluconazole (FLC) has intensified fungal resistance and limited its effectiveness for the treatment of fungal infections. The combined administration of drugs has been extensively studied and applied. SWL-1 is a lignin compound derived from the Traditional Chinese Medicine Schisandra chinensis. In this study, we show that SWL-1 reverses resistance to fluconazole in C. albicans when delivered in combination, with a sharp decrease in the IC 50 of fluconazole from >200 to 3.74 ± 0.25 μg/ml, and also reverses the fluconazole resistance of C. albicans in vitro, with IC 50 from >200 to 5.3 ± 0.3 μg/ml. Moreover, killing kinetics curves confirmed the synergistic effects of fluconazole and SWL-1. Intriguingly, when SWL-1 was administered in combination with fluconazole in a mouse model of systemic infection, the mortality of mice was markedly decreased and fungal colonization of the kidney and lung was reduced. Further mechanistic studies showed that SWL-1 significantly decreased intracellular adenosine 5'-triphosphate (ATP) levels and inhibited the function of the efflux pump responsible for fluconazole resistance of C. albicans. Proteomic analysis of the effects of SWL-1 on C. albicans showed that several enzymes were downregulated in the glycolytic pathway. We speculate that SWL-1 significantly decreased intracellular ATP levels by hindering the glycolysis, and the function of the efflux pump responsible for fluconazole resistance of C. albicans was inhibited, resulting in restoration of fluconazole sensitivity in FLC-resistant C. albicans. This study clarified the effects and mechanism of SWL-1 on C. albicans in vitro and in vivo, providing a novel approach to overcoming fungal resistance.

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New Insights in Candida albicans Innate Immunity at the Mucosa: Toxins, Epithelium, Metabolism, and Beyond

Cited by 69 publications

References 185 publications

The Dual Function of the Fungal Toxin Candidalysin during Candida albicans—Macrophage Interaction and Virulence

The Dual Function of the Fungal Toxin Candidalysin during Candida albicans—Macrophage Interaction and Virulence

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

SWL-1 Reverses Fluconazole Resistance in Candida albicans by Regulating the Glycolytic Pathway

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