Abstract
ABSTRACTThe opportunistic fungal pathogen Candida albicans thrives within diverse niches in the mammalian host. Among the adaptations that underlie this fitness is an ability to utilize a wide array of nutrients, especially sources of carbon that are disfavored by many other fungi; this contributes to its ability to survive interactions with the phagocytes that serve as key barriers against disseminated infections. We have reported that C. albicans generates ammonia as a byproduct of amino acid catabolism to neutralize the acidic phagolysosome and promote hyphal morphogenesis in a manner dependent on the Stp2 transcription factor. Here, we report that this species rapidly neutralizes acidic environments when utilizing carboxylic acids like pyruvate, α-ketoglutarate (αKG), or lactate as the primary carbon source. Unlike in cells growing in amino acid-rich medium, this does not result in ammonia release, does not induce hyphal differentiation, and is genetically distinct. While transcript profiling revealed significant similarities in gene expression in cells grown on either carboxylic or amino acids, genetic screens for mutants that fail to neutralize αKG medium identified a nonoverlapping set of genes, including CWT1, encoding a transcription factor responsive to cell wall and nitrosative stresses. Strains lacking CWT1 exhibit retarded αKG-mediated neutralization in vitro, exist in a more acidic phagolysosome, and are more susceptible to macrophage killing, while double cwt1Δ stp2Δ mutants are more impaired than either single mutant. Together, our observations indicate that C. albicans has evolved multiple ways to modulate the pH of host-relevant environments to promote its fitness as a pathogen.
Highlights
The opportunistic fungal pathogen Candida albicans thrives within diverse niches in the mammalian host
We have proposed a model in which C. albicans cells growing with amino acids as the sole carbon source excrete the amine groups as ammonia, leading to an increase in extracellular pH [14, 24]
We grew wild-type C. albicans cells on minimal medium adjusted to an initial pH of 4.0 in which the sole carbon sources were glucose, Casamino Acids (CAA), the amino acid glutamate, or the deaminated form of glutamate, ␣KG, in which the amino nitrogen is replaced by a carbonyl group
Summary
The opportunistic fungal pathogen Candida albicans thrives within diverse niches in the mammalian host. We show here that the metabolism of certain organic acids enables C. albicans to neutralize acidic environments, such as those within macrophages This phenomenon is distinct in several significant ways from previous reports of similar processes, indicating that C. albicans has evolved multiple mechanisms to combat the harmful acidity of phagocytic cells. Risk factors include hematological malignancies, chemotherapy, and organ transplantation; even mild iatrogenic interventions, such as the use of venous catheters, can increase the incidence of candidiasis [4, 5] Dysfunctions of both the phagocytic and nonphagocytic barriers of the innate immune system predispose a patient to disseminated disease, and there has been significant interest in elucidating the mechanisms by which Candida species interact with relevant host cell types, such as macrophages, neutrophils, endothelial cells, and epithelial cells. We and others have shown that the catabolic pathways for a variety of nonsugar compounds are induced by phagocytosis and are required for fungal survival in macrophages and/or virulence in a mouse model of disseminated candidiasis [18,19,20,21,22,23], suggesting that certain host niches are carbon-limited environments
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