The relevance of heat shock regulation in fungal pathogens of humans

Brown, Alistair J. P.; Leach, Michelle; Nicholls, Susan M.

doi:10.4161/viru.1.4.12364

Cited by 28 publications

(20 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Synthesized as an adaptive response to noxious conditions, these proteins contribute to the survival of pathogenic microorganisms in the host (Jacob et al, 2015). Hsp90 has been related to fungal pathogenicity, phase transition in dimorphic fungi and antifungal drug resistance, making it a potential target for antifungal therapy (Burnie et al, 2006; Brown et al, 2010; Jacob et al, 2015). Jacob et al (2015) examined the transcription profiles of Trichophyton rubrum under different stress conditions, such as interaction with nail and skin cells and molecules, nutrients and treatment with antifungal drugs.…”

Section: Antifungal Mechanism Of Action: Old and New Targets Of Antifmentioning

confidence: 99%

Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis

et al. 2017

View full text Add to dashboard Cite

The high rates of morbidity and mortality caused by fungal infections are associated with the current limited antifungal arsenal and the high toxicity of the compounds. Additionally, identifying novel drug targets is challenging because there are many similarities between fungal and human cells. The most common antifungal targets include fungal RNA synthesis and cell wall and membrane components, though new antifungal targets are being investigated. Nonetheless, fungi have developed resistance mechanisms, such as overexpression of eﬄux pump proteins and biofilm formation, emphasizing the importance of understanding these mechanisms. To address these problems, different approaches to preventing and treating fungal diseases are described in this review, with a focus on the resistance mechanisms of fungi, with the goal of developing efficient strategies to overcoming and preventing resistance as well as new advances in antifungal therapy. Due to the limited antifungal arsenal, researchers have sought to improve treatment via different approaches, and the synergistic effect obtained by the combination of antifungals contributes to reducing toxicity and could be an alternative for treatment. Another important issue is the development of new formulations for antifungal agents, and interest in nanoparticles as new types of carriers of antifungal drugs has increased. In addition, modifications to the chemical structures of traditional antifungals have improved their activity and pharmacokinetic parameters. Moreover, a different approach to preventing and treating fungal diseases is immunotherapy, which involves different mechanisms, such as vaccines, activation of the immune response and inducing the production of host antimicrobial molecules. Finally, the use of a mini-host has been encouraging for in vivo testing because these animal models demonstrate a good correlation with the mammalian model; they also increase the speediness of as well as facilitate the preliminary testing of new antifungal agents. In general, many years are required from discovery of a new antifungal to clinical use. However, the development of new antifungal strategies will reduce the therapeutic time and/or increase the quality of life of patients.

show abstract

Section: Antifungal Mechanism Of Action: Old and New Targets Of Antifmentioning

confidence: 99%

Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The roles of Hsp90 in supporting morphogenesis and drug resistance were recently shown to be relevant to biofilm formation in pathogenic fungi, providing a pharmacological foothold into this clinically intransigent mode of infection (367,415). The heat shock response has also been found to be highly relevant to pathogenesis, likely in an HSF-dependent context (39,318,319). Our understanding of HSPs and the HSR in pathogenic fungi lags far behind that of S. cerevisiae and is clearly at an early stage.…”

Section: The Hsr In Pathogenic Fungimentioning

confidence: 99%

“…For example, a novel compound capable of activating human HSF1 was recently uncovered by using the complementation of yeast Hsf1 as a phenotype in high-throughput screens (312). C. albicans and Plasmodium falciparum Hsp70s have both been expressed in S. cerevisiae to generate safe and tractable experimental systems to utilize for the development of anti-infectives (20,39). We predict that investigations of the HSR and molecular chaperones in yeast will proceed for some time and will continue to lead the way in discovery and impact.…”

Section: Perspectivesmentioning

confidence: 99%

Biology of the Heat Shock Response and Protein Chaperones: Budding Yeast (Saccharomyces cerevisiae) as a Model System

Verghese

Abrams

Wang

et al. 2012

Microbiol Mol Biol Rev

504

410

View full text Add to dashboard Cite

SUMMARY The eukaryotic heat shock response is an ancient and highly conserved transcriptional program that results in the immediate synthesis of a battery of cytoprotective genes in the presence of thermal and other environmental stresses. Many of these genes encode molecular chaperones, powerful protein remodelers with the capacity to shield, fold, or unfold substrates in a context-dependent manner. The budding yeast Saccharomyces cerevisiae continues to be an invaluable model for driving the discovery of regulatory features of this fundamental stress response. In addition, budding yeast has been an outstanding model system to elucidate the cell biology of protein chaperones and their organization into functional networks. In this review, we evaluate our understanding of the multifaceted response to heat shock. In addition, the chaperone complement of the cytosol is compared to those of mitochondria and the endoplasmic reticulum, organelles with their own unique protein homeostasis milieus. Finally, we examine recent advances in the understanding of the roles of protein chaperones and the heat shock response in pathogenic fungi, which is being accelerated by the wealth of information gained for budding yeast.

show abstract

“…In line with this, the heat shock regulon of an organism obligately associated with warm-blooded animals, such as C. albicans, has been proposed to modulate growth of the fungus in response to minor temperature perturbations occurring in its host (3). Fine-tuning the expression of several molecular chaperones, among which is Hsp104, appears to be accomplished by the transcription factor Hsf1 in C. albicans (18).…”

Section: Discussionmentioning

confidence: 95%

The Heat-Induced Molecular Disaggregase Hsp104 of Candida albicans Plays a Role in Biofilm Formation and Pathogenicity in a Worm Infection Model

Fiori¹,

Kucharíková²,

Govaert

et al. 2012

Eukaryot Cell

View full text Add to dashboard Cite

The consequences of deprivation of the molecular chaperone Hsp104 in the fungal pathogen Candida albicans were investigated. Mutants lacking HSP104 became hypersusceptible to lethally high temperatures, similarly to the corresponding mutants of Saccharomyces cerevisiae, whereas normal susceptibility was restored upon reintroduction of the gene. By use of a strain whose only copy of HSP104 is an ectopic gene under the control of a tetracycline-regulated promoter, expression of Hsp104 prior to the administration of heat shock could be demonstrated to be sufficient to confer protection from the subsequent temperature increase. This result points to a key role for Hsp104 in orchestrating the cell response to elevated temperatures. Despite their not showing evident growth or morphological defects, biofilm formation by cells lacking HSP104 proved to be defective in two established in vitro models that use polystyrene and polyurethane as the substrates. Biofilms formed by the wild-type and HSP104-reconstituted strains showed patterns of intertwined hyphae in the extracellular matrix. In contrast, biofilm formed by the hsp104⌬/hsp104⌬ mutant showed structural defects and appeared patchy and loose. Decreased virulence of the hsp104⌬/ hsp104⌬ mutant was observed in the Caenorhabditis elegans infection model, in which high in vivo temperature does not play a role. In agreement with the view that stress responses in fungal pathogens may have evolved to provide niche-specific adaptation to environmental conditions, these results provide an indication of a temperature-independent role for Hsp104 in support of Candida albicans virulence, in addition to its key role in governing thermotolerance.

show abstract

The relevance of heat shock regulation in fungal pathogens of humans

Cited by 28 publications

References 33 publications

Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis

Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis

Biology of the Heat Shock Response and Protein Chaperones: Budding Yeast (Saccharomyces cerevisiae) as a Model System

The Heat-Induced Molecular Disaggregase Hsp104 of Candida albicans Plays a Role in Biofilm Formation and Pathogenicity in a Worm Infection Model

Contact Info

Product

Resources

About