Fungi cause >300 million cases of serious diseases worldwide each year and can lead to 1.6 million deaths. Additionally, fungi cause several common, superficial infections such as thrush and athlete’s foot. Few treatment options exist for fungal infections; those available have limited efficacy and, worryingly, resistance to drugs is growing. A key regulator of virulence in many pathogenic fungi is the chaperone heat shock protein 90 (Hsp90). The article “Hsp90 interaction networks in fungi – tools and techniques” published in FEMS Yeast Research explores available approaches to uncover Hsp90’s role in fungal infections. Dr Julia Crunden explains for the #FEMSmicroBlog how this knowledge could help find new ways to treat deadly fungal infections. #FascinatingMicrobes
Chaperone proteins regulate virulence in fungi
Proteins carry out most processes in living cells. Their abilities to function are dependent on each protein’s intricate 3D structure.
However, proteins are unstable and can unfold or aggregate together (denature) when environmental conditions are not optimal. For example, intense heat from a frying pan denatures egg protein, turning the egg opaque and solid.
Similarly in organisms, when cells are exposed to higher-than-ideal temperatures, the activities of chaperone proteins are boosted to help fold and stabilise proteins. This chaperone function prevents protein denaturation so that cells can continue to work.
When cells are exposed to high temperatures, the activity of chaperone proteins is boosted to help stabilise proteins.
One such chaperone is the heat shock protein 90 (Hsp90). In pathogenic fungi, Hsp90 stabilises proteins that cause virulence, which is why several research lines focus on this central regulator.
One way to inhibit pathogenic fungi is to target key proteins with anti-microbial drugs thus inhibiting their function, stopping microbial growth or causing cell death. However, we cannot target fungal Hsp90 in this way since our cells contain a very similar version of Hsp90. By inhibiting fungal Hsp90 during an infection, we would also inhibit our human version. Since Hsp90 is also essential for our survival, its inhibition is not an option.
Instead, one hypothesis is to identify other proteins through which Hsp90 regulates virulence. These candidates would need to be sufficiently different from human proteins to target them with anti-fungal drugs.
Tools and techniques to investigate Hsp90 interaction networks in fungi
Therefore, building networks of Hsp90 interactors in fungal pathogens is highly important. These networks will help answer the main questions of the field. Which genes or proteins interact with Hsp90? How do they interact with Hsp90? Do they regulate virulence?
The review “Hsp90 interaction networks in fungi – tools and techniques” published in FEMS Yeast Research outlines what is known about Hsp90 networks in pathogenic fungi and the biochemical tools and techniques available to discover these interaction networks.
Researchers can use collections—libraries—of fungal strains lacking specific genes to identify gene products that interact with Hsp90. Two-hybrid screens, affinity purifications and quantitative proteomics can identify direct and indirect protein interactors of Hsp90. These techniques have so far been used to explore Hsp90’s interactions in two fungi, Saccharomyces cerevisiae and Candida albicans.
While CRISPR-Cas technologies are yet to be used in fungal Hsp90 studies, they allow specific gene editing which is of particular value in hard-to-modify organisms. Additionally, comparing Hsp90 interaction networks between pathogenic and non-pathogenic fungi may shed light on the evolutionary basis of what causes an organism to become pathogenic.
Hsp90 – not yet well understood in pathogenic fungi but the key to new treatments?
Hsp90 has been studied to greatly different extents in different fungi. The chaperone is best understood in the non-pathogenic model yeast, S. cerevisiae, which has served as a model eukaryote for decades. In the most common cause of invasive Candida infection, C. albicans, Hsp90 is only moderately well understood. Very little is known about Hsp90 in other important and life-endangering fungi such as Candida glabrata, Candida parapsilosis, Cryptococcus neoformans and Aspergillus fumigatus.
The review presents how understanding Hsp90’s role in fungi will help reveal the fundamental biology of virulence. This knowledge can then potentially lead to new therapeutic strategies to counter the often unappreciated but severe burden of fungi on human health.
- Read the review “Hsp90 interaction networks in fungi—tools and techniques” by Crunden and Diezmann (2021) in FEMS Yeast Research.
Dr Julia Crunden obtained her MSci in Biochemistry from King’s College London, followed by a PhD with Dr Stephanie Diezmann at the Universities of Bath and Bristol. Her PhD thesis investigated the role of Hsp90 and uncovered its genetic and proteomic interaction networks in the fungal pathogen of humans, Candida glabrata. Her post-doctoral work at the University of Bristol continues investigating Hsp90 in Candida by working to find the molecular structure of Hsp90 and a key interactor in Candida albicans, the most common causative organism of life-threatening systemic Candida infections.
About this blog section
The section #FascinatingMicrobes for the #FEMSmicroBlog explains the science behind a paper and highlights the significance and broader context of a recent finding. One of the main goals is to share the fascinating spectrum of microbes across all fields of microbiology.
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