The opportunistic fungal pathogen Candida glabrata is a frequent cause of candidiasis, causing infections ranging from superficial to life-threatening disseminated disease. The inherent tolerance of C. glabrata to azole drugs makes this pathogen a serious clinical threat. To identify novel genes implicated in antifungal drug tolerance, we have constructed a large-scale C. glabrata deletion library consisting of 619 unique, individually bar-coded mutant strains, each lacking one specific gene, all together representing almost 12% of the genome. Functional analysis of this library in a series of phenotypic and fitness assays identified numerous genes required for growth of C. glabrata under normal or specific stress conditions, as well as a number of novel genes involved in tolerance to clinically important antifungal drugs such as azoles and echinocandins. We identified 38 deletion strains displaying strongly increased susceptibility to caspofungin, 28 of which encoding proteins that have not previously been linked to echinocandin tolerance. Our results demonstrate the potential of the C. glabrata mutant collection as a valuable resource in functional genomics studies of this important fungal pathogen of humans, and to facilitate the identification of putative novel antifungal drug target and virulence genes.

/pdf/systematic-phenotyping-of-a-large-scale-candida-glabrata-1nntc9h8iu.pdf

Systematic phenotyping of a large-scale Candida glabrata deletion collection reveals novel antifungal tolerance genes.

Candida albicans is a major fungal pathogen of humans, accounting for 15% of nosocomial infections with an estimated attributable mortality of 47%. C. albicans is usually a benign member of the human microbiome in healthy people. Under constant exposure to highly dynamic environmental cues in diverse host niches, C. albicans has successfully evolved to adapt to both commensal and pathogenic lifestyles. The ability of C. albicans to undergo a reversible morphological transition from yeast to filamentous forms is a well-established virulent trait. Over the past few decades, a significant amount of research has been carried out to understand the underlying regulatory mechanisms, signaling pathways, and transcription factors that govern the C. albicans yeast-to-hyphal transition. This review will summarize our current understanding of well-elucidated signal transduction pathways that activate C. albicans hyphal morphogenesis in response to various environmental cues and the cell cycle machinery involved in the subsequent regulation and maintenance of hyphal morphogenesis.

From Jekyll to Hyde: The Yeast-Hyphal Transition of Candida albicans

Fungal virulence is regulated by a tight interplay of transcriptional control and chromatin remodelling. Despite compelling evidence that lysine acetylation modulates virulence of pathogenic fungi such as Candida albicans, the underlying mechanisms have remained largely unexplored. We report here that Gcn5, a paradigm lysyl-acetyl transferase (KAT) modifying both histone and non-histone targets, controls fungal morphogenesis – a key virulence factor of C. albicans. Our data show that genetic removal of GCN5 abrogates fungal virulence in mice, suggesting strongly diminished fungal fitness in vivo. This may at least in part arise from increased susceptibility to killing by macrophages, as well as by other phagocytes such as neutrophils or monocytes. Loss of GCN5 also causes hypersensitivity to the fungicidal drug caspofungin. Caspofungin hypersusceptibility requires the master regulator Efg1, working in concert with Gcn5. Moreover, Gcn5 regulates multiple independent pathways, including adhesion, cell wall-mediated MAP kinase signaling, hypersensitivity to host-derived oxidative stress, and regulation of the Fks1 glucan synthase, all of which play critical roles in virulence and antifungal susceptibility. Hence, Gcn5 regulates fungal virulence through multiple mechanisms, suggesting that specific inhibition of Gcn5 could offer new therapeutic strategies to combat invasive fungal infections.

/pdf/the-fungal-histone-acetyl-transferase-gcn5-controls-4elt2f2c4w.pdf

The Fungal Histone Acetyl Transferase Gcn5 Controls Virulence of the Human Pathogen Candida albicans through Multiple Pathways

Histone acetyltransferase 1 (Hat1) catalyzes the acetylation of newly synthesized histone H4 at lysines 5 and 12 that accompanies replication-coupled chromatin assembly. The acetylation of newly synthesized H4 occurs in the cytoplasm and the function of this acetylation is typically ascribed to roles in either histone nuclear import or deposition. Using cell lines from Hat1+/+ and Hat1-/- mouse embryos, we demonstrate that Hat1 is not required for either histone nuclear import or deposition. We employed quantitative proteomics to characterize Hat1-dependent changes in the composition of nascent chromatin structure. Among the proteins depleted from nascent chromatin isolated from Hat1-/- cells are several bromodomain-containing proteins, including Brg1, Baz1A and Brd3. Analysis of the binding specificity of their bromodomains suggests that Hat1-dependent acetylation of H4 is directly involved in their recruitment. Hat1-/- nascent chromatin is enriched for topoisomerase 2α and 2β. The enrichment of topoisomerase 2 is functionally relevant as Hat1-/- cells are hyper-sensitive to topoisomerase 2 inhibition suggesting that Hat1 is required for proper chromatin topology. In addition, our results indicate that Hat1 is transiently recruited to sites of chromatin assembly, dissociating prior to the maturation of chromatin structure.

/pdf/identification-of-multiple-roles-for-histone-th5f27q05y.pdf

Identification of multiple roles for histone acetyltransferase 1 in replication-coupled chromatin assembly

According to the World Health Organization, infectious diseases stand out as the major cause of death worldwide. Although bacterial, viral, and parasitic infections appear to constitute the major threat, the clinical relevance of fungal infections has not been adequately recognized. In fact, invasive fungal infections constitute a biomedical problem of epic proportions, because a handful of human fungal pathogens claim an estimated 1.5 million lives per year [1]. Importantly, invasive fungal diseases represent leading causes of morbidity and mortality in immunocompromised individuals, particularly in patients with hematological malignancies, bonemarrow and organ transplant recipients, intensive care unit patients, preterm neonates, and patients with inborn or acquired immune deficiencies such as AIDS [2]. The vast majority of fungal infections are caused primarily by Candida albicans, Aspergillus fumigatus, and Cryptococcus spp. [2]. The overall mortality rate of 35%–40% for candidemia alone exceeds all gram-negative acute bacterial septicemia [3]. Importantly, pronounced inherent clinical antifungal drug resistance, especially in species like Candida glabrata [4], promotes a dramatic increase of infections [5, 6]. The unsolved challenge of getting fast, reliable, and accurate pathogen-specific clinical diagnosis of fungi has remained as another major impediment to successful and efficient antifungal therapy [7]. A mere four chemical entities (polyenes, azoles, echinocandins, and flucytosine) constitute the armory of clinically relevant drugs [1]. A few variant azoles and echinocandins received recent United States Food and Drug Administration (FDA) approval, but new chemical entities are either missing or mainly experimental in nature [8]. Of note, vaccination against fungal infections is currently unavailable and heavily debated, although recent clinical trials may hold new promises as well as challenges ahead [9–11]. Interestingly enough, compelling evidence indicates that chromatin tightly controls fungal virulence and/or pathogen fitness in the host. Nucleosome remodeling and assembly pathways impact the dynamic interplay with host immune surveillance, facilitate immune evasion, as well as drive antifungal drug resistance [12]. For example, several lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) control fungal virulence [13]. This suggests that KATs/KDACs modifying both histones and non-histone targets could aid in antifungal drug discovery [13, 14]. Here, we provide a comprehensive overview of chromatin modifications in human fungal pathogens, particularly those altering virulence (Table 1, Fig 1). However, owing to space constraints, we will focus our discussion on KDACs/KATs in Candida spp. In addition, we discuss how the modulation of KATs/KDACs in Candida spp. could pave the way for novel therapeutic strategies to combat fungal infections [13].

/pdf/fungal-kats-kdacs-a-new-highway-to-better-antifungal-drugs-ti6c46xbo3.pdf

Fungal KATs/KDACs: A New Highway to Better Antifungal Drugs?

Summary


Chromatin assembly and remodelling is an important process during the repair of DNA damage in eukaryotic cells. Although newly synthesized histone H4 is acetylated prior to nuclear import and incorporation into chromatin during DNA damage repair, the precise role of acetylation in this process is poorly understood. Here, we identify the histone acetyltransferase 1 (Hat1) catalysing the conserved acetylation pattern of histone H4 preceding its chromatin deposition in the fungal pathogen Candida albicans. Surprisingly, Hat1 is required for efficient repair of not just exogenous but also endogenous DNA damage. Cells lacking Hat1 rapidly accumulate DNA damages and switch from yeast-like to pseudohyphal growth. In addition, reduction of histone H4 mimics lack of Hat1, suggesting that inefficient H4 supply for deposition into chromatin is the key functional consequence of Hat1 deficiency. Thus, remarkably, we demonstrate that C. albicans is the first organism known to require histone H4 processing for endogenous DNA damage repair and morphogenesis. Strikingly, we also discover that hat1Δ/Δ cells are hypersusceptible to caspofungin due to intracellular reactive oxygen species induced by this drug. Hence, we propose that targeting this class of histone acetyltransferases in fungal pathogens may have potential in antifungal therapy.

The histone acetyltransferase Hat1 facilitates DNA damage repair and morphogenesis in Candida albicans

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The histone acetyltransferase Hat1 facilitates DNA damage repair and morphogenesis in Candida albicans