Abstract
Candida albicans is the main causative agent of candidiasis and one of the most frequent causes of nosocomial infections worldwide. In order to establish an infection, this pathogen supports effective stress responses to counter host defenses and adapts to changes in the availability of important nutrients, such as alternative carbon sources. These stress responses have clear implications on the composition and structure of Candida cell wall. Therefore, we studied the impact of lactate, a physiologically relevant carbon source, on the activity of C. albicans RLM1 transcriptional factor. RLM1 is involved in the cell wall integrity pathway and plays an important role in regulating the flow of carbohydrates into cell wall biosynthesis pathways. The role of C. albicans RLM1 in response to lactate adaptation was assessed in respect to several virulence factors, such as the ability to grow under cell wall damaging agents, filament, adhere or form biofilm, as well as to immune recognition. The data showed that growth of C. albicans cells in the presence of lactate induces the secretion of tartaric acid, which has the potential to modulate the TCA cycle on both the yeast and the host cells. In addition, we found that adaptation of C. albicans cells to lactate reduces their internalization by immune cells and consequent % of killing, which could be correlated with a lower exposure of the cell wall β-glucans. In addition, absence of RLM1 has a minor impact on internalization, compared with the wild-type and complemented strains, but it reduces the higher efficiency of lactate grown cells at damaging phagocytic cells and induces a high amount of IL-10, rendering these cells more tolerable to the immune system. The data suggests that RLM1 mediates cell wall remodeling during carbon adaptation, impacting their interaction with immune cells.
Highlights
Candida albicans is an opportunistic pathogenic fungus responsible for a wide spectrum of infections in immunocompromised individuals, ranging from superficial mycosis to systemic and disseminated candidiasis (Pfaller and Diekema, 2007; Brown et al, 2012)
We have proposed that the major role of C. albicans RLM1 is in the biogenesis of the cell wall, in regulating the flow of carbohydrates into cell wall biosynthesis pathways (DelgadoSilva et al, 2014)
We have used a set of RLM1 null mutants previously constructed from the prototrophic wildtype model strain SC5314 (Delgado-Silva et al, 2014) to evaluate phenotype and impact on immune recognition when cells are exposed to different carbon sources: glucose or lactate
Summary
Candida albicans is an opportunistic pathogenic fungus responsible for a wide spectrum of infections in immunocompromised individuals, ranging from superficial mycosis to systemic and disseminated candidiasis (Pfaller and Diekema, 2007; Brown et al, 2012). This pathogen thrives within distinct niches in the human host, including the skin, the oral cavity, the gut, and the genitourinary tracts (Southern et al, 2008) These niches differ considerably in terms of nutrients, pH, and local microbiota and, in order to survive and proliferate, C. albicans must adapt to the changing host environment. C. albicans possesses a dynamic cell wall that responds efficiently to host-imposed stresses, including changes in carbon sources (Ene et al, 2012a, 2013; Ballou et al, 2016) or exposure to antifungal drugs (Wheeler et al, 2008) This protection is conferred by a carbohydrate-based matrix containing chitin, β-glucans, and mannoproteins, each of which has an important role in innate immune recognition (Netea et al, 2008). Any change in the structure of cell wall will impact innate immune recognition and virulence (Hall, 2017)
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