N-Acetylglucosamine Induces White to Opaque Switching, a Mating Prerequisite in Candida albicans

To mate, the fungal pathogen Candida albicans must undergo homozygosis at the mating-type locus and then switch from the white to opaque phenotype. Paradoxically, opaque cells were found to be unstable at physiological temperature, suggesting that mating had little chance of occurring in the host, the main niche of C. albicans. Recently, however, it was demonstrated that high levels of CO2, equivalent to those found in the host gastrointestinal tract and select tissues, induced the white to opaque switch at physiological temperature, providing a possible resolution to the paradox. Here, we demonstrate that a second signal, N-acetylglucosamine (GlcNAc), a monosaccharide produced primarily by gastrointestinal tract bacteria, also serves as a potent inducer of white to opaque switching and functions primarily through the Ras1/cAMP pathway and phosphorylated Wor1, the gene product of the master switch locus. Our results therefore suggest that signals produced by bacterial co-members of the gastrointestinal tract microbiota regulate switching and therefore mating of C. albicans

The Set3/Hos2 Histone Deacetylase Complex Attenuates cAMP/PKA Signaling to Regulate Morphogenesis and Virulence of Candida albicans

Candida albicans, like other pleiomorphic fungal pathogens, is able to undergo a reversible transition between single yeast-like cells and multicellular filaments. This morphogenetic process has long been considered as a key fungal virulence factor. Here, we identify the evolutionarily conserved Set3/Hos2 histone deacetylase complex (Set3C) as a crucial repressor of the yeast-to-filament transition. Cells lacking core components of the Set3C are able to maintain all developmental phases, but are hypersusceptible to filamentation-inducing signals, because of a hyperactive cAMP/Protein Kinase A signaling pathway. Strikingly, Set3C-mediated control of filamentation is required for virulence in vivo, since set3Δ/Δ cells display strongly attenuated virulence in a mouse model of systemic infection. Importantly, the inhibition of histone deacetylase activity by trichostatin A exclusively phenocopies the absence of a functional Set3C, but not of any other histone deacetylase gene. Hence, our work supports a paradigm for manipulating morphogenesis in C. albicans through alternative antifungal therapeutic strategies

Genes Selectively Up-Regulated by Pheromone in White Cells Are Involved in Biofilm Formation in Candida albicans

To mate, MTL-homozygous strains of the yeast pathogen Candida albicans must switch from the white to opaque phase. Mating-competent opaque cells then release pheromone that induces polarization, a G1 block and conjugation tube formation in opaque cells of opposite mating type. Pheromone also induces mating-incompetent white cells to become adhesive and cohesive, and form thicker biofilms that facilitate mating. The pheromone response pathway of white cells shares the upstream components of that of opaque cells, but targets a different transcription factor. Here we demonstrate that the genes up-regulated by the pheromone in white cells are activated through a common cis-acting sequence, WPRE, which is distinct from the cis-acting sequence, OPRE, responsible for up-regulation in opaque cells. Furthermore, we find that these white-specific genes play roles in white cell biofilm formation, and are essential for biofilm formation in the absence of an added source of pheromone, suggesting either an autocrine or pheromone-independent mechanism. These results suggest an intimate, complex and unique relationship between switching, mating and MTL-homozygous white cell biofilm formation, the latter a presumed virulence factor in C. albicans

The accessibility and acceptability of self-management support interventions for men with long term conditions: a systematic review and meta-synthesis of qualitative studies

Background: Self-management support interventions can improve health outcomes, but their impact is limited by the numbers of people able or willing to access them. Men’s attendance at existing self-management support services appears suboptimal despite their increased risk of developing many of the most serious long term conditions. The aim of this review was to determine whether current self-management support interventions are acceptable and accessible to men with long term conditions, and explore what may act as facilitators and barriers to access of interventions and support activities. Methods: A systematic search for qualitative research was undertaken on CINAHL, EMBASE, MEDLINE, PsycINFO and Social Science Citation Index, in July 2013. Reference lists of relevant articles were also examined. Studies that used a qualitative design to explore men’s experiences of, or perceptions towards, self-management support for one or more long term condition were included. Studies which focused on experiences of living with a long term condition without consideration of self-management support were excluded. Thirty-eight studies met the inclusion criteria. A meta-ethnography approach was employed to synthesise the findings. Results: Four constructs associated with men’s experience of, and perceptions towards, self management support were identified: 1) need for purpose; 2) trusted environments; 3) value of peers; and 4) becoming an expert. The synthesis showed that men may feel less comfortable participating in self-management support if it is viewed as incongruous with valued aspects of their identity, particularly when activities are perceived to challenge masculine ideals associated with independence, stoicism, and control. Men may find self-management support more attractive when it is perceived as action-oriented, having a clear purpose, and offering personally meaningful information and practical strategies that can be integrated into daily life. Conclusions: Self-management support is most likely to be successful in engaging men when it is congruent with key aspects of their masculine identity. In order to overcome barriers to access and fully engage with interventions, some men may need self-management support interventions to be delivered in an environment that offers a sense of shared understanding, connectedness, and normality, and involves and/or is facilitated by men with a shared illness experience