Abstract
Candida glabrata is an emerging fungal pathogen whose success depends on its ability to resist antifungal drugs but also to thrive against host defenses. In this study, the predicted multidrug transporter CgTpo4 (encoded by ORF CAGL0L10912g) is described as a new determinant of virulence in C. glabrata, using the infection model Galleria mellonella. The CgTPO4 gene was found to be required for the C. glabrata ability to kill G. mellonella. The transporter encoded by this gene is also necessary for antimicrobial peptide (AMP) resistance, specifically against histatin-5. Interestingly, G. mellonella’s AMP expression was found to be strongly activated in response to C. glabrata infection, suggesting AMPs are a key antifungal defense. CgTpo4 was also found to be a plasma membrane exporter of polyamines, especially spermidine, suggesting that CgTpo4 is able to export polyamines and AMPs, thus conferring resistance to both stress agents. Altogether, this study presents the polyamine exporter CgTpo4 as a determinant of C. glabrata virulence, which acts by protecting the yeast cells from the overexpression of AMPs, deployed as a host defense mechanism.
Highlights
Candida species are among the top 10 most frequently isolated nosocomial bloodstream pathogens, with an annual incidence rate of up to 4.8 cases in Europe and 13.3 cases in the US per 100,000 inhabitants [1]
Using G. mellonella larvae as an infection model, the possible effect of CgTpo4 transporter in C. glabrata ability to exert its virulence was assessed, resorting to the overexpression of its encoding gene in the wild type of C. glabrata, and to its deletion in the parental strain, followed by its complementation
The results show that deleting the CgTPO4 gene in the wild-type background reduces its virulence in this infection model
Summary
Candida species are among the top 10 most frequently isolated nosocomial bloodstream pathogens, with an annual incidence rate of up to 4.8 cases in Europe and 13.3 cases in the US per 100,000 inhabitants [1]. Candida glabrata has risen as the most frequently non-albicans pathogenic Candida species isolated from candidemia patients, accounting for 20% of the diagnosed cases of candidiasis in both Europe and North America [3,4]. The frequency and relative high mortality levels (up to 45% for C. glabrata) of these infections [5] are generally attributed to the capacity of these pathogenic yeasts to efficiently develop multidrug resistance (MDR), tolerate host defense mechanisms, maintain high proliferative and repopulation capacity through biofilm formation, and to display the ability to withstand prolonged harmful conditions such as nutrient starvation and oxidative stress [6,7]. Since the host defense mechanisms are multifaceted, a number of different evasion strategies have evolved [8] These include avoidance of contact with macrophages, rapid escape from host immune cells, ability to withstand macrophage antimicrobial activities and, most importantly, use of macrophages as an intracellular niche for protection and replication processes [8]. Antimicrobial peptides, small positively charged amphipathic molecules, work directly against microbes, mainly through a mechanism that involves membrane disruption and pore formation, meaning that being able to resist them can be highly positive for the yeast to complete its infection cycle [10]
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