Abstract
Host innate immunity is fundamental to the resistance against Candida albicans and Candida glabrata infection, two of the most important agents contributing to human fungal infections. Phagocytic cells, such as neutrophils, constitute the first line of host defense mechanisms, and the release of neutrophil extracellular traps (NETs) represent an important strategy to immobilize and to kill invading microorganisms, arresting the establishment of infection. The purinergic system operates an important role in the homeostasis of immunity and inflammation, and ectophosphatase and ectonucleotidase activities are recognized as essential for survival strategies and infectious potential of several pathogens. The expression and unique activity of a 3′-nucleotidase/nuclease (3′NT/NU), able to hydrolyze not only AMP but also nucleic acids, has been considered as part of a possible mechanism of microbes to escape from NETs. The aim of the present study was to evaluate if yeasts escape from the NET-mediated killing through their 3′NT/NU enzymatic activity contributing to NET-hydrolysis. After demonstrating the presence of 3′NT/NU activity in C. albicans, C. glabrata, and Saccharomyces cerevisiae, we show that, during neutrophils-Candida interaction, when NETs formation and release are triggered, NETs digestion occurs and this process of NETs disruption promoted by yeast cells was prevented by ammonium tetrathiomolybdate (TTM), a 3′NT/NU inhibitor. In conclusion, although the exact nature and specificity of yeasts ectonucleotidases are not completely unraveled, we highlight the importance of these enzymes in the context of infection, helping yeasts to overcome host defenses, whereby C. albicans and C. glabrata can escape NET-mediate killing through their 3′NT/NU activity.
Highlights
Fungi are ubiquitous microorganisms able to interact with humans in multiple ways (Baxi et al, 2016; Firacative, 2020)
Further studies were performed under the optimal pH 4 and, after 1 h incubation period, intact C. albicans, C. glabrata, and S. cerevisiae cells were able to hydrolyse both 5′ AMP and 3′AMP substrates (Figure 2A)
The TTM concentration used, 100 mM, was selected based on inhibitory concentration curves obtained with C. albicans, the most pathogenic yeast used in this study (Supplementary Figure 1)
Summary
Fungi are ubiquitous microorganisms able to interact with humans in multiple ways (Baxi et al, 2016; Firacative, 2020). The interactions between host cells and microbes will define whether the microbe can evolve into pathogenicity, or colonize passively the human host or will be eradicated by the immune system (Hube, 2009). The dynamics of this interaction may vary among different fungal species and morphologies and may be intrinsically influenced by the host’s defense mechanisms and the associated immune responses (Romani, 2011; Sparber and Leibundgut-Landmann, 2017). Innate immunity is fundamental in the resistance against pathogenic microorganisms, with phagocytic cells playing important roles during host infection, killing or damaging the fungal pathogens (Shoham and Levitz, 2005; Erwig and Gow, 2016). Two types of NETosis are described, lytic and non-lytic (Yang et al, 2016; Papayannopoulos, 2018), representing an important strategy to immobilize and kill invading microorganisms, preventing the establishment of infection (Brinkmann et al, 2004; Kaplan and Radic, 2012; Branzk et al, 2014; Dainichi et al, 2020)
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