Growth of Candida albicans Cells on the Physiologically Relevant Carbon Source Lactate Affects Their Recognition and Phagocytosis by Immune Cells

Abstract

bCandida albicans is a normal resident of the human gastrointestinal and urogenital tracts and also a prevalent fungal pathogen. During both commensalism and infection, it must match the immunological defenses of its host while adapting to environmental cues and the local nutrient status. C. albicans regularly colonizes glucose-poor niches, thereby depending upon alternative carbon sources for growth. However, most studies of host immune responses to C. albicans have been performed on fungal cells grown on glucose, and the extent to which alternative physiologically relevant carbon sources impact innate immune responses has not been studied. The fungal cell wall is decorated with multifarious pathogen-associated molecular patterns and is the main target for recognition by host innate immune cells. Cell wall architecture is both robust and dynamic, and it is dramatically influenced by growth conditions. We found that growth of C. albicans cells on lactate, a nonfermentative carbon source available in numerous anatomical niches, modulates their interactions with immune cells and the resultant cytokine profile. Notably, lactate-grown C. albicans stimulated interleukin-10 (IL-10) production while decreasing IL-17 levels, rendering these cells less visible to the immune system than were glucose-grown cells. This trend was observed in clinical C. albicans isolates from different host niches and from different epidemiological clades. In addition, lactate-grown C. albicans cells were taken up by macrophages less efficiently, but they were more efficient at killing and escaping these phagocytic cells. Our data indicate that carbon source has a major impact upon the C. albicans interaction with the innate immune system.

The vaginal mycobiome: A contemporary perspective on fungi in women's health and diseases

“…116 Recently, however, one group has posited that their findings are more consistent with Lactobacillus being associated with greater risk for vulvovaginal candidiasis. 117 By elucidating the mechanism by which lactic acid suppresses immune responses to C. albicans, Ene et al 46 have supplied evidence for this claim.…”

“…Recent in vitro work has shown that in the presence of lactic acid (as the sole carbon source) C. albicans is taken up by macrophages less efficiently and can alter immune cell cytokine profiles, specifically by increasing IL-10 and decreasing IL-17 production. 46,47 Interestingly, cells grown in a mixed lactate-glucose media behave more like lactate-grown cells. This has particular relevance in the vaginal context because of the abundance of both glycogen (and its breakdown sugar products) and lactic acid, which could effectively promote anti-inflammatory responses to Candida.…”

Vulvovaginal Candida albicans infections: pathogenesis, immunity and vaccine prospects

“…Lactate-grown fungal cells induce production of the inhibitory cytokine IL-10 and decrease the production of the pro-inflammatory cytokine IL-17, and are more virulent than glucose-grown cells in an experimental vaginal infection model. 70 Overall, there still is no clear evidence to suggest that women with VVC or RVVC have a vaginal microbiota definitely different from that of normal women. Studies at genomic or sub-genomic level are requested to identify fine, possibly strain or type-related differences in the microbiota that could affect the vaginal pathology.…”

The Candida albicans ATO Gene Family Promotes Neutralization of the Macrophage Phagolysosome

“…The importance of metabolic adaptation is underscored by the decreased virulence in animal models of C. albicans strains that are defective in the glyoxylate cycle and in ␤-oxidation (18-21). Furthermore, carbon source utilization plays a significant role in cell wall composition, stress susceptibility, and phagocyte recognition (22,23).Our laboratory has demonstrated that C. albicans grown in vitro in medium that mimics the nutrients predicted to be available after phagocytosis rapidly alkalinizes the extracellular environment (24). This process depends upon the utilization of amino acids as a carbon source and leads to the extrusion of ammonia from the cell, which is derived from amino acid catabolism.…”

“…The importance of metabolic adaptation is underscored by the decreased virulence in animal models of C. albicans strains that are defective in the glyoxylate cycle and in ␤-oxidation (18-21). Furthermore, carbon source utilization plays a significant role in cell wall composition, stress susceptibility, and phagocyte recognition (22,23).…”