Fig 1.
Candida biogeography and the different host-imposed constraints during human colonization.
The most frequently isolated Candida species are listed according to their principal habitat in the human body (oral cavity, lungs, gastrointestinal tract, bloodstream, urogenital tract, and skin). The different host-imposed constraints are highlighted for several microenvironments where Candida thrives in the human body, including inside phagocytic cells or biofilms. Key references: C. albicans [2,3], C. glabrata [3], C. parapsilosis [2], C. tropicalis [2], C. lusitaniae [13], and C. krusei [6]. ECM, extracellular matrix; NOS, nitric oxide species; ROS, reactive oxygen species; UG, urogenital.
Fig 2.
Schematic representation of the main sensing, transport, and transduction systems for the utilization of different host nutrients in Candida species.
(a) In C. albicans, glucose is sensed by Hgt4, generating an intracellular signal that induces the expression of HGTs and other metabolic genes. (b) In C. albicans and C. tropicalis, the uptake of GlcNAc occurs through the Ngt1 transporter. (c) The uptake of carboxylic acids is facilitated by the Jen (in C. albicans) and Ato transporters (in C. albicans and C. glabrata). In C. albicans, Gpr1 is reported to be a lactate and methionine sensor. In the presence of lactate, Gpr1 is thought to activate Crz1 in a calcineurin-independent manner and, together with Ace2, regulates a polygenic response that leads to β-glucan masking. (d) Peptides and amino acids are sensed by the SPS complex, which induces the expression of Opts, Aaps, and Ato transporters, as well as SAPs and amino acid catabolic genes. Intracellular ammonia resulting from the catabolism of GlcNAc or amino acids is exported via Ato transporters. In the presence of methionine, and in low glucose conditions, the methionine-induced morphogenesis is activated via Gpr1 sensor and Mup1 transporter. AA, amino acid; Aap, amino acid permease; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; DcSAM, decarboxylated S-adenosylmethionine; GlcNAc, N-acetylglucosamine; GPI, glycosylphosphatidylinositol; HGT, hexose transporter; Opt, oligopeptide transporter; SAM, S-adenosylmethionine; SAP, secretory aspartyl proteinase; SPS, Ssy1-Ptr3-SSy5; Sp2DC, Sp2 decarboxylase; TCA, tricarboxylic acid cycle; UDP, uridine diphosphate.
Fig 3.
Candida adaptation to pH fluctuations.
In Candida species, pH adaptation is mediated by the Rim pathway. Under acidic pH, the exposure of both chitin and β-glucan is enhanced and facilitates their recognition by the host innate immune system. Chitin exposure is promoted by the repression of both Rim101 and Bcr1, resulting in reduced expression of CHT2. β-glucan exposure is regulated by a noncanonical signaling pathway. Under alkaline pH, Rim8 is hyperphosphorylated, a signal that induces the endocytosis of the Rim complex and the recruitment of Rim13. The C-terminal proteolysis of Rim101 by Rim13 activates it and promotes the expression of target genes, including CHT2.
Fig 4.
Candida adaptation to hypoxic host niches.
During C. albicans infections, the recruitment of PMNs creates an hypoxic environment [88]. In the fungus, this oxygen limitation triggers increased formation of ROS, such as superoxide (O2•−), from the electron transport chain [98,99]. Superoxide is then converted into diffusible hydrogen peroxide (H2O2) by the action of Sod1. H2O2 has been proposed to activate adenylyl cyclase (Cyr1) and cAMP-PKA (Tpk1/2) signaling, which in turn triggers cell-wall remodeling and β-glucan masking [97]. This β-glucan masking allows the fungus to evade phagocytosis by the PMNs [88]. cAMP, cyclic Adenosine Monophosphate; NET, neutrophil extracellular trap; PKA, Protein Kinase A; PMN, polymorphonuclear leukocyte; ROS, reactive oxygen species; Sod1, superoxide dismutase 1.
Fig 5.
Molecular circuits required for thermal adaptation in C. albicans.
(a) HSPs rescue proteins from unfolding or target damaged proteins for degradation. (b) In response to temperature upshifts, Hsf1 becomes phosphorylated, inducing the expression of HSP genes. After thermal adaptation, Hsf1 returns to basal levels through a negative feedback loop dependent on Hsp90. Long-term adaptation is controlled by Hsp90 through Hog1, Mkc1, and Cek1. HSE, heat shock element; Hsf1, heat shock transcription factor 1; HSP, heat shock protein; MAPK, mitogen-activated protein kinase; MAPKK/MAPKKK, MAPK kinase/ MAPKK kinase.
Fig 6.
Host immune defenses and adaptation mechanisms displayed by C. albicans and C. glabrata.
(a) Cap1 plays a key role in the activation of responses to ROS generated by phagocytic cells, leading to the induction of oxidative stress genes (XS genes), including catalase, superoxide dismutases, glutathione peroxidases, and thioredoxins, among others. However, cations inhibit catalase and Cap1, thereby delaying the induction of the oxidative stress response and leading to the death of C. albicans cells. (b) Host-enforced micronutrient restriction results in reduced iron, copper, and zinc availability, but C. albicans responds by up-regulating efficient metal-scavenging strategies. Host phagocytes also exploit the toxicity of copper and zinc by pumping these metals in excess into phagosomes to intoxicate internalized pathogens. NOS, nitric oxide species; PM, plasma membrane; ROS, reactive oxygen species; Sod, superoxide dismutase; XS, oxidative stress.