Role of Cellular Metabolism during Candida-Host Interactions

Abstract

Microscopic fungi are widely present in the environment and, more importantly, are also an essential part of the human healthy mycobiota. However, many species can become pathogenic under certain circumstances, with Candida spp. being the most clinically relevant fungi. In recent years, the importance of metabolism and nutrient availability for fungi-host interactions have been highlighted. Upon activation, immune and other host cells reshape their metabolism to fulfil the energy-demanding process of generating an immune response. This includes macrophage upregulation of glucose uptake and processing via aerobic glycolysis. On the other side, Candida modulates its metabolic pathways to adapt to the usually hostile environment in the host, such as the lumen of phagolysosomes. Further understanding on metabolic interactions between host and fungal cells would potentially lead to novel/enhanced antifungal therapies to fight these infections. Therefore, this review paper focuses on how cellular metabolism, of both host cells and Candida, and the nutritional environment impact on the interplay between host and fungal cells.

Keywords: Candida albicans; epithelial cells; glucose; glycolysis; immunometabolism; macrophages; metabolism; moonlighting proteins.

Figure 1

Immunometabolism in innate immune cells. (A) Challenging innate immune cells with either exogenous (LPS, β-glucan) or endogenous (IL-4) stimuli leads to metabolic reprogramming, which involves changes in pathways as glycolysis, FAO/FAS, OxPhos, etc. These shifts in metabolism provide cells with energy and building blocks to develop their functions. (B) Metabolic enzymes regulate immune responses at many levels, including their moonlighting functions. They can act as transcription/translation facilitators (ENO1, PKM2, GAPDH, LDH), immune receptors or activators (HK) or facilitators of immune cell migration (ENO1). bNAG, bacterial N-acetylglucosamine; ECM, extracellular matrix; ENO1, enolase 1; FAO, fatty acid oxidation; FAS, fatty acid synthesis; GAPDH, glyceraldehyde dehydrogenase; HK, hexokinase; LDH, lactate dehydrogenase; OxPhos, oxidative phosphorylation; PKM2, pyruvate kinase M2; PLG, plasminogen; PLIN, plasmin; PPP, pentose phosphate pathway; TCA, tricarboxylic acid. Created with BioRender.com (last accessed 12 January 2022).

Figure 2

Metabolic plasticity in Candida. (A) Candida species are able to grow on a wide range of compounds, giving them the chance to thrive in very different environments. This metabolic plasticity is tightly regulated by a network of transcription factors that are activated depending on the nutritional requirements of the fungus. (B) Growing on different compounds leads to changes in Candida, for example cell wall structure or composition. This is of special importance when physiologically relevant nutrients, such as lactate, are present. Utilization of these metabolites by C. albicans remodel its cells wall increasing antifungal drug resistance. Moreover, like host cells metabolic enzymes in Candida display moonlighting functions associated with, for instance, cell adhesion to the ECM (GAPDH, Eno1) or host cells (Ssa1). ECM, extracellular matrix; Eno1, enolase 1; GAPDH, glyceraldehyde dehydrogenase; FIB, fibronectin; LAM, laminin; PLG, plasminogen. Created with BioRender.com (last accessed 12 January 2022).

Figure 3

Interplay between Candida and host cells lead to metabolic reprogramming in both organisms. (A) Recognition of C. albicans by macrophages/monocytes drive changes in metabolism towards aerobic glycolysis, leading to the production of lactate that can be used by the fungus to enhance its β-glucan masking to evade immune responses. In turn, phagocytosed fungal cells use their metabolic plasticity to adapt to the nutrient-poor environment inside phagolysosomes. After piercing cell membranes using hyphae, C. albicans switches to glycolysis and depletes glucose from the medium, leading to macrophage cell death. (B) Oral epithelial cells activate HIF-1α when challenged with C. parapsilosis, whilst C. albicans adapts its metabolism upon interaction with these cells. (C) Variable responses are observed in different Candida species after interacting with vaginal epithelial cells. However, host cells exert a common early response to all of them mediated by changes in mitochondrial activity and morphology, with higher release of mitochondrial reactive oxygen species (mtROS) and DNA (mtDNA). Created with BioRender.com (last accessed 12 January 2022).