The mechanism of action in producing oxidative stress resistance

The mechanism of action in producing oxidative stress resistance and morphogenetic transitions appears to be closely related, as strains lacking Ras1 and Cyr1 cease to demonstrate the same resistance as wild

type when exposed to hydrogen peroxide when preincubated with farnesol. The mechanism of action probably does not depend on the Hog1 pathway, as hog1 mutants fared no differently from the wild type when farnesol-mediated oxidative stress resistance was measured (Menon et al., 2006). The fact that farnesol induces such resistance indicates that it plays a role during infections, as ROS has been shown to play a central role in host defense against fungal pathogenesis (Jain et al., 2009). Furthermore, the induction of oxidative stress by macrophages PD-1/PD-L1 cancer is part of the defense repertoire against pathogens (Lorenz & Fink, 2001, 2002) and resisting such stresses is critical for survival of PLX3397 nmr Candida within macrophages. Thus, it is hypothesized that C. albicans, via farnesol-mediated resistance, may survive action by macrophages and neutrophils (Fan et al., 2007). If Candida survives the host ROS, it can differentiate into a hyphal form (which farnesol inhibits) and subsequently invade and lyse the host cell to escape. Inhibition of farnesol, and therefore the oxidative resistance it produces, promises new development strategies for antifungal drugs. Opposing the

action of farnesol is the aromatic alcohol tyrosol, a catabolic product of the amino acid tyrosine. In diluted cultures, tyrosol concentration is reduced and C. albicans experiences an exceptionally long lag phase before re-entering exponential growth (Chen et al., 2004). This long lag phase is abolished by the

addition of tyrosol to the culture medium. The dilution of exponential-phase culture may destabilize transcripts necessary for cell division; therefore, it is hypothesized that tyrosol stabilizes them, enabling exponential growth to proceed. Because tyrosol is released into the culture medium by C. albicans and has 3-mercaptopyruvate sulfurtransferase a concentration-dependent behavior, it is an autostimulatory small molecule; however, unlike those observed in bacteria, it does not appear to explicitly upregulate its own production (Chen et al., 2004). Although Saccharomyces cerevisiae is not a threatening pathogen, it has been used as a model for fungal pathogenesis (McCusker, 2006). Saccharomyces cerevisiae uses at least two aromatic alcohols, phenylethanol and tryptophol (Chen & Fink, 2006), as environmental cues, whose effect is also dependent on population density. The ambient concentration of these aromatic alcohols, in turn, regulates morphogenesis by encouraging a transition from the unicellular morphotype to a ‘multicellular’ filamentous one. The biosynthetic pathway for the two alcohols is activated upon nitrogen starvation and repressed in rich medium.

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