2. The Role of Yeast-to-Hyphae Transition and Other Phenotypic Changes for C. albicans Survival
2.1. Morphogenesis and the Road to Infection
Candida albicans is a polymorphic fungus which can grow in diverse morphological forms, such as round budding yeast cells, pseudohyphae which are ellipsoid cells that are constricted at their septa, or parallel-walled cells with no visible constrictions, so-called true hyphae (
Berman & Sudbery, 2002;
Odds, 1988;
Sudbery, Gow, & Berman, 2004). It was long believed that the formation of filamentous growth forms, morphogenesis, was essential for
C. albicans virulence, since
C. albicans mutant strains that are locked in either morphological form were attenuated in their virulence in murine infection models (
Braun, Head, Wang, & Johnson, 2000;
Braun, Kadosh, & Johnson, 2001;
Lo et al., 1997;
Murad et al., 2001). However, recent research suggests that this hypothesis is oversimplified as some strains that are defective for morphogenesis are still virulent in a systemic mouse model (
Banerjee et al., 2008;
Noble, French, Kohn, Chen, & Johnson, 2010;
Saville, Lazzell, Chaturvedi, Monteagudo, & Lopez-Ribot, 2008;
Spiering et al., 2010); furthermore, hypha formation is coregulated with several virulence-associated factors, rendering it difficult to determine to which extend the formation of hyphae per se contributes to virulence (
Kumamoto & Vinces, 2005b). Therefore, the current model integrates both, yeast and hyphae, as important players during
C. albicans infection with distinct roles of the different morphologies during different steps of infection (
Gow, Brown, & Odds, 2002;
Kumamoto & Vinces, 2005b;
Saville, Lazzell, Monteagudo, & Lopez-Ribot, 2003). Both growth forms can be found during systemic infections; yeast forms have been proposed to be important for dissemination via the bloodstream while hyphae formation appears to be associated with invasion of tissue (
Jacobsen et al., 2012;
Martin, Wachtler, Schaller, Wilson, & Hube, 2011;
Zhu & Filler, 2010). The morphology might furthermore reflect niche-specific fungal responses (
Jacobsen et al., 2012).
Figure 2 Candida albicans survival strategies. (1) morphological flexibility; (2) white-to-opaque switching and mating; (3) contact-induced filamentation; (4) hypha-associated expression of adhesins; invasion into host cells by induced endocytosis (5) or active penetration (6); (7) release of hydrolytic enzymes (e.g., secreted aspartic proteases (Saps)) that support penetration and the breakdown of tissue material; (8) acquisition of nutrients and micronutrients from host cells, e.g., zinc and iron uptake systems; (9) stress response pathways facilitating resistance to adverse environmental conditions, e.g., reactive oxygen species (ROS), reactive nitrogen species (RNS), low pH, and starvation; (10) active modification of the phagosome to promote hyphal growth, facilitating macrophage damage and escape.
While the role of filamentation for virulence has been studied in detail, comparatively little is known about morphology during commensal growth. In contrast to infection, where invasive growth and host damage are intrinsically linked, commensalism is a balanced state that allows fungal growth without inflicting host damage (
Gow & Hube, 2012). Although yeast cells are thought to be the dominant morphology during GI tract colonization, genetic analysis revealed that colonization is associated with high levels of hypha-associated gene (HAG) expression, such as upregulation of
EFH1,
ECE1,
RBT4, and
RBT1 in yeast cells (
Doedt et al., 2004;
d'Enfert, 2009;
Rosenbach, Dignard, Pierce, Whiteway, & Kumamoto, 2010;
White et al., 2007). This might promote the maintenance of the yeast cells in the GI tract and is independent of morphogenesis. Efg1, a major regulator of filamentation, was also shown to be important for the regulation of GI tract colonization (
d'Enfert, 2009;
Kumamoto & Vinces, 2005b;
Pierce, Dignard, Whiteway, & Kumamoto, 2013;
Pierce & Kumamoto, 2012;
Stoldt, Sonneborn, Leuker, & Ernst, 1997).
EFG1 expression in the GI tract can either be high, promoting immune evasion, or rather low, supporting commensal growth. Based on these observations, Pierce et al. hypothesized that variations in Efg1 levels in the GI tract lead to subpopulations of cells with different characteristics, enabling host-dependent shaping and diversity of the colonizing population (
Pierce et al., 2013).
2.1.1. Regulation of Morphogenesis
Many virulence-associated traits of pathogenic
Candida species have possibly evolved to facilitate survival as a commensal, e.g., in the fluctuating environment of the gut and in competition with commensal bacteria. Mechanisms acquired by the fungus to deal with adverse conditions as a commensal can also promote virulence, since they provide the fungus with the necessary weaponry to overcome host barriers (
Hube, 2009;
Pierce et al., 2013). Indeed, hypha formation is triggered by environmental signals that resemble unfavorable growth conditions or indicate a putatively hostile environment. Such factors include the presence of serum, elevated temperature, neutral pH, presence of certain nutrients, starvation signals, matrix embedding, CO2 and O2 levels, cell density, and contact to physical surfaces (
Inglis & Sherlock, 2013;
Sudbery, 2011). It is intriguing how many of these factors resemble growth conditions the fungus might encounter in the human host (
Cottier & Muhlschlegel, 2009;
Sudbery, 2011). In each niche or microniche,
C. albicans will be affected by a unique combination of biological and chemical factors, which either promote or inhibit morphogenesis (
Cottier & Muhlschlegel, 2009). It has recently been proposed that a distinct combination of these environmental conditions might be necessary for the shift from a commensal to pathogenic lifestyle in
C. albicans (
Kadosh & Lopez-Ribot, 2013;
Lu, Su, Solis, Filler, & Liu, 2013).
Morphogenesis generally requires two steps, hyphal initiation and hyphal maintenance (
Lu, Su, Wang, & Liu, 2011;
Martin, Moran, et al., 2011;
Sudbery, 2011). Hyphal initiation in response to elevated temperature requires the removal of the filamentation repressor Nrg1 from the promoter regions of HAGs (
Lu et al., 2011). In the second step, the absence of Nrg1 allows binding of Brg1, a GATA-transcription factor, to the HAG promoter that recruits the histone deacetylase Hda1. Hda1 in turn leads to chromatin remodeling and the establishment of a filamentous chromatin state promoting hyphal maintenance and the expression of HAGs (
Lu et al., 2011;
Lu, Su, & Liu, 2012;
Su, Lu, & Liu, 2013). However, combinatorial environmental signals have been shown to bypass the requirement for Brg1 and Hda1 by a newly identified O2 sensor and an uncharacterized CO2 sensor (
Lu et al., 2013).
The yeast-to-hyphae induction is furthermore influenced by a range of small molecules, e.g., cell cycle inhibitors, quorum sensing molecules (QSMs; e.g., farnesol, tyrosol, homoserine lactone (HSL)), fatty acids (e.g., butyric, capric, palmitoleic, linoleic, and arachidonic acid), eicosanoids, peptides and proteins, rapamycin, geldanamycin, and histone deacetylase inhibitors (
Shareck & Belhumeur, 2011). Some of these molecules are produced by the fungus itself in order to autoregulate hyphal formation in the presence of environmental stimuli (e.g., QSM, eicosanoids), others may be produced by the host or the host microbiome to manipulate
C. albicans morphogenesis (e.g., QSM, fatty acids, peptides, proteins) (
Albuquerque & Casadevall, 2012;
Hogan, 2006;
Nickerson, Atkin, & Hornby, 2006;
Shareck & Belhumeur, 2011;
Sudbery, 2011). Only recently it was described that a glucanase, secreted by
C. albicans, has the ability to induce filamentation, which may be an adaptive response to cell wall damaging enzymes (
Xu, Nobile, & Dongari-Bagtzoglou, 2013). A range of additional signaling pathways, activated by various environmental signals, stimulate morphogenesis and expression of HAGs. These pathways include the inhibition of heat shock protein 90 (Hsp90) by elevated temperatures and subsequent activation of Ras1, the cAMP/PKA-signaling pathway via direct or indirect activation of the adenylyl cyclase Cyr1, mitogen activated protein kinase (MAPK) signaling via Ras1/Hst7 and Cek1, activation of the Rim101 pathway by neutral to alkaline pH, Czf1 activation under embedded conditions via Rac1, hypoxia-induced Efg1/Efh1 activation, and reactive oxygen species (ROS) signaling induced by genotoxic stress (
Gow, van de Veerdonk, Brown, & Netea, 2012;
Huang, 2012;
Inglis & Sherlock, 2013;
Shapiro & Cowen, 2012;
Shapiro, Robbins, & Cowen, 2011;
Sudbery, 2011). Nrg1, Tup1, and Rfg1, as well as the stress-activated Hog1 pathway are important negative regulators of morphogenesis (
Inglis & Sherlock, 2013;
Shapiro et al., 2011;
Sudbery, 2011). Especially Ras1 and Cyr1 play a crucial role since they integrate a wide range of environmental signals, and in case of Ras1 may even activate a variety of cell signaling cascades (
Hogan & Muhlschlegel, 2011;...
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