Introduction

Continuous and unforeseen biological and physical perturbations occur in the biosphere and organisms have to cope with them in a rapid and efficient way. These anomalous disturbances are usually known as “stress” and an intensive research effort has been put in by many laboratories in an attempt to mimic the naturally imposed conditions. Nevertheless, this concept is rather ambiguous, since it encompasses risks which might be termed as moderate, to other potentially life-threatening situations. Let us, first, then, clarify what we denote by the word stress. We will briefly discuss some particular examples taking as starting point the definition from a scientific dictionary, where stress is defined as “an unusual environmental condition that causes physiological, emotional, behavioural or cognitive changes in an individual” (or in a population in the case of microorganisms).

A lot of experimental work carried out on stress taking yeast as a biological model has long been performed using just a few species as reference. The best studied is the budding yeast Saccharomyces cerevisiae, the classical baker’s or wine-making yeast, together with other closely related strains employed in brewing. The fission yeast Schizosaccharomyces pombe is also an interesting archetype, since some molecular analyses have pointed to its higher genetic homology with mammals than in the case of budding yeast. In addition, the dimorphic pathogenic yeast Candida albicans holds both scientific and clinical interest. This commentary will mainly be directed at a comparative analysis of the responses developed by S. cerevisiae and C. albicans against oxidative stress and heat-shock challenges. Extensive and detailed analysis on the stress responses in fungi and the putative connection between stress and fungal virulence can be found in the following reviews (Estruch 2000; Ikner and Shiozaki 2005; Román et al. 2007).

Oxidative stress

In aerobic organisms, the generation of toxic reactive oxygen species (ROS), i.e., O2 ·−, H2O2 · or ·OH, is the consequence of internal metabolic oxidations or caused by the supply of external agents, this latter process being common practice in experimental assays (Estruch 2000). ROS are very harmful to essential cellular macromolecules (nucleic acids, lipids and proteins) and, to combat them, yeasts have evolved efficient defensive mechanisms, which involve the synthesis and/or activation of protective enzymes or molecules (Ikner and Shiozaki 2005). However, as regards the damage caused by a given specific oxidative compound, there may be strong differences between the two yeast species taken as a model. For example, in the case of the potential toxic effects of hydrogen peroxide, whereas cellular viability in S. cerevisiae is seriously compromised after low H2O2 exposures (1–5 mM), C. albicans exhibits noticeable resistance and higher non-physiological concentrations are required to cause a significant degree of cell-killing (25–100 mM, Pedreño et al. 2002; Álvarez-Peral et al. 2002, Table 1). In addition to individual features, these sharp contrasts could obey their respective intrinsic metabolisms. Thus, S. cerevisiae is mainly a fermentative yeast with a low respiratory rate (depending on the substrate), while the contribution of oxidative metabolism is more important in C. albicans. The natural habitat might also be relevant in explaining this divergent antioxidant capacity. In the course of an in vivo infection, C. albicans is exposed to the strongly oxidant action of ROS produced by phagocytes, while for the budding yeast the level of oxidant aggression should be theoretically lower (Vazquez-Torres and Balish 1997).

Table 1 Differential sensitivity of S. cerevisiae and C. albican s to oxidative stress triggered by exposure to hydrogen peroxide
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Heat shock

Both mild and acute shifts in the regular growth temperatures of yeasts have been the classical methods followed to study the primary responses to heat stress. There is an ample body of experimental evidence on this topic, which has led to the definition of a family of heat-shock proteins (HSPs, Craig et al. 1993). In this case, variability is lower since, with insignificant exceptions, most of the yeasts are mesophilic microorganisms. Standard growth is compatible in an ample range of temperatures (between 20 and 40°C). Usually, unicellular yeast-like forms are found at around 30°C, and moderate temperature up-shifts (e.g., from 25–30°C to 37–42°C) are often not detrimental, but rather stimulatory of cell growth. Viability is, however, compromised after exposure to higher temperatures (>40–50°C). In fact, proliferating yeast cells are able to withstand a potentially lethal heat shock, provided they are previously submitted to a gentle temperature rise (37 or 42°C). This phenomenon is the well-studied “adaptive thermotolerance”, which, it turns out, can be applied to other types of environmental threat (Argüelles 2000).

The paradigm of trehalose storage

The protective role of the non-reducing disaccharide trehalose is another excellent paradigm of the striking differences existing between S. cerevisiae and C. albicans with respect to the stress response mechanism. In both species, a huge amount of intracellular trehalose is synthesised in resting cells or in exponential cultures subjected to sudden environmental challenge (Argüelles 2000). However, whereas in the opportunistic yeast, trehalose behaves as a specific protector against oxidative agents (Álvarez-Peral et al. 2002), this outcome seems less relevant in budding cells, which rarely encounters high levels of oxidants in their habitat (Fig. 1). Furthermore, S. cerevisiae mutants, whose trehalose-mobilising enzyme (Nth1p) has been disrupted, are extremely sensitive to low H2O2 exposure, while the equivalent mutants in C. albicans show increased resistance even to elevated H2O2 concentrations (Pedreño et al. 2007).

Fig. 1
figure 1

Schematic representation of the hypothetical existence of core stress responses in S. cerevisiae, S. pombe and C. albicans, as well as the specific role played by the non-reducing disaccharide trehalose in cell protection against oxidative stress (ROS) and heat shock (HS) in these three prototypic yeasts. Symbols: plus presence; minus absence; question mark unclear or contradictory evidence

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Do yeasts possess a core stress response mechanism?

A broad experimental body points to the existence of a core stress response (CSR) in S. pombe and S. cerevisiae, which, in part, involves a differential regulation of stress-activated protein kinases pathways (SAPKs). This conserved mechanism ensures cross-protection against different environmental injuries (Smith et al. 2004, Fig. 1). Whereas in fission yeast, the Sty1-SAPK plays a predominant role in the response to a set of stress challenges, in budding yeast the adaptation to stress occurs through a variety of signaling pathways and transcription factors (Smith et al. 2004, Fig. 1). In addition to the zinc finger transcription factors Msn2/Msn4, a good example of SAPK in S. cerevisiae is the Hog1 (homologous to the Sty1), which mainly responds to alterations in osmolarity and regulates the transcription of core stress genes in response to this stress (Smith et al. 2004). In C. albicans, however, Hog1 plays a crucial function in cell protection against oxidative damage, in addition to being activated in response to high external osmotic pressure (Alonso-Monge et al. 2003; see below).

In contrast, a transcript profiling study (using positive stimuli for S. cerevisiae) suggests the absence of a general stress response (Enjalbert et al. 2003) and of stress-cross protection in C. albicans (Fig. 1). However, such an inference is not definitive, since protection against severe oxidative exposure to H2O2 is conferred by previous osmotic stress treatment, in a cross-defense mechanism that is Hog1-dependent (Smith et al. 2004). Moreover, in a recent report, Enjalbert et al. (2006) pointed out that C. albicans can mount a core transcriptional response to stress through the HOG1 pathway. In fact, besides its function in osmotic adaptation and morphogenesis, the Hog1 MAP kinase in C. albicans is essential for resistance to acute oxidative stress (Alonso-Monge et al. 2003), a challenge presumably critical for pathogen survival during host tissue colonization (Vazquez-Torres and Balish 1997). Temperature up-shifts (28–37°C) also increase the capacity to withstand a severe oxidative challenge (Álvarez-Peral et al. 2002)

Final comment

Some general conclusions firmly established in the scientific literature concerning yeast stress responses, the protective role played by certain molecules as well as enzymes and/or signalling pathways, or the putative existence of a general stress core response, should be accepted with caution. They are usually founded on very specific experimental conditions and any finding is not necessarily extrapolable to other yeasts with different biological organizations, activities and habitats. Furthermore, some particular responses, whether at transcriptional or postranslational level, when elicited by a stressing agent may be dose-dependent. First of all, the conditions of a specific cell stress in each specific cell type must be properly defined. Before starting any game, the rules should be correctly established.