The impact of fungal pathogens on human health is devastating. For fungi and other pathogens, a key determinant of virulence is the capacity to thrive at host temperatures, with elevated temperature in the form of fever as a ubiquitous host response to defend against infection. A prominent feature of cells experiencing heat stress is the increased expression of heat shock proteins (Hsps) that play pivotal roles in the refolding of misfolded proteins in order to restore cellular homeostasis. Transcriptional activation of this heat shock response is orchestrated by the essential heat shock transcription factor, Hsf1. Although the influence of Hsf1 on cellular stress responses has been studied for decades, many aspects of its regulation and function remain largely enigmatic. In this review, we highlight our current understanding of how Hsf1 is regulated and activated in the model yeast Saccharomyces cerevisiae, and highlight exciting recent discoveries related to its diverse functions under both basal and stress conditions. Given that thermal adaption is a fundamental requirement for growth and virulence in fungal pathogens, we also compare and contrast Hsf1 activation and function in other fungal species with an emphasis on its role as a critical regulator of virulence traits.

Human fungal pathogens are the causative agents of devastating diseases across the globe, and the increasing prevalence of drug resistance threatens to undermine the already limited treatment options. One prominent pathogen is the opportunistic fungus Candida albicans, which can cause both superficial and serious systemic infections in immunocompromised individuals. C. albicans antifungal drug resistance and antifungal tolerance are supported by diverse and expansive cellular stress response pathways. Some of the major players are the Ca2+-calmodulin-activated phosphatase calcineurin, the protein kinase C cell wall interity pathway, and the molecular chaperone heat shock protein 90. Beyond these core signal transducers, several other enzymes and transcription factors have been implicated in both tolerance and resistance. Here, we highlight some of the major stress response pathways, key advances in identifying chemical matter to inhibit these pathways, and implications for C. albicans persistence in the host.

"Fungi on Mars! ": a popular news heading that piques public interest and makes scientists' blood boil. While such a statement is laden with misinformation and light on evidence, the search for past and present extraterrestrial life is an ongoing scientific effort. Moreover, it is one that is increasingly gaining momentum with the recent collection of martian rock cores from Jezero Crater by NASA's Perseverance rover. Despite the increasingly sophisticated approaches guiding the search for microbial life on other planets, fungi remain relatively underexplored compared to their bacterial counterparts, highlighting a gap between the astrobiological and fungal research communities. Through a meeting in April 2021, the CIFAR Earth 4D and Fungal Kingdom research programs worked to bridge this divide by uniting experts in each field. CIFAR is a Canadian-based global research organization that convenes researchers across disciplines to address important questions facing science and humanity. The CIFAR Earth 4D: Subsurface Science & Exploration and Fungal Kingdom: Threats & Opportunities research programs were launched by CIFAR in July 2019, each made up of approximately two dozen international researchers who are experts in their fields. The Earth 4D program, led by co-directors John Mustard (Brown University, USA) and Barbara Sherwood Lollar (University of Toronto, Canada), aims to understand the complex chemical, physical, and biological interactions that occur within and between Earth's surface and subsurface to explore questions on the evolution of planets and life. The Fungal Kingdom program, led by co-directors Leah Cowen (University of Toronto, Canada) and Joseph Heitman (Duke University, USA), seeks to tackle the most pressing threats fungi pose to human health, agriculture, and biodiversity and to harness their extraordinary potential. The programs met to explore areas for synergy within four major themes: (1) the origins of life; (2) the evolution and diversification of life; (3) life in diverse and extreme environments; and (4) extinction: lessons learned and threats. This report covers the research discussed during the meeting across these four themes.

Human fungal pathogens are the causative agents of devastating diseases across the globe, and the increasing prevalence of drug resistance threatens to undermine the already limited treatment options. One prominent pathogen is the opportunistic fungus Candida albicans, which can cause both superficial and serious systemic infections in immunocompromised individuals. C. albicans antifungal drug resistance and antifungal tolerance are supported by diverse and expansive cellular stress response pathways. Some of the major players are the Ca2+-calmodulin-activated phosphatase calcineurin, the protein kinase C cell wall interity pathway, and the molecular chaperone heat shock protein 90. Beyond these core signal transducers, several other enzymes and transcription factors have been implicated in both tolerance and resistance. Here, we highlight some of the major stress response pathways, key advances in identifying chemical matter to inhibit these pathways, and implications for C. albicans persistence in the host.

The last several decades have witnessed a surge in drug-resistant fungal infections that pose a serious threat to human health. While there is a limited arsenal of drugs that can be used to treat systemic infections, scientific advances have provided renewed optimism for the discovery of novel antifungals. The development of chemical-genomic assays using Saccharomyces cerevisiae has provided powerful methods to identify the mechanism of action of molecules in a living cell. Advances in molecular biology techniques have enabled complementary assays to be developed in fungal pathogens, including Candida albicans and Cryptococcus neoformans. These approaches enable the identification of target genes for drug candidates, as well as genes involved in buffering drug target pathways. Here, we examine yeast chemical-genomic assays and highlight how such resources can be utilized to predict the mechanisms of action of compounds, to study virulence attributes of diverse fungal pathogens, and to bolster the antifungal pipeline.

Cryptococcus spp., in particular Cryptococcus neoformans and Cryptococcus gattii, have an enormous impact on human health worldwide. The global burden of cryptococcal meningitis is almost a quarter of a million cases and 181,000 deaths annually, with mortality rates of 100% if infections remain untreated. Despite these alarming statistics, treatment options for cryptococcosis remain limited, with only three major classes of drugs approved for clinical use. Exacerbating the public health burden is the fact that the only new class of antifungal drugs developed in decades, the echinocandins, displays negligible antifungal activity against Cryptococcus spp., and the efficacy of the remaining therapeutics is hampered by host toxicity and pathogen resistance. Here, we describe the current arsenal of antifungal agents and the treatment strategies employed to manage cryptococcal disease. We further elaborate on the recent advances in our understanding of the intrinsic and adaptive resistance mechanisms that are utilized by Cryptococcus spp. to evade therapeutic treatments. Finally, we review potential therapeutic strategies, including combination therapy, the targeting of virulence traits, impairing stress response pathways and modulating host immunity, to effectively treat infections caused by Cryptococcus spp. Overall, understanding of the mechanisms that regulate anti-cryptococcal drug resistance, coupled with advances in genomics technologies and high-throughput screening methodologies, will catalyse innovation and accelerate antifungal drug discovery.Cryptococcosis is a serious fungal infection for which treatment options are limited. In this Review, Cowen and colleagues discuss the current antifungal treatments available for cryptococcal infections, the challenges in developing new treatments, and ongoing efforts to identify novel therapies.

Cryptococcus spp., in particular Cryptococcus neoformans and Cryptococcus gattii, have an enormous impact on human health worldwide. The global burden of cryptococcal meningitis is almost a quarter of a million cases and 181,000 deaths annually, with mortality rates of 100% if infections remain untreated. Despite these alarming statistics, treatment options for cryptococcosis remain limited, with only three major classes of drugs approved for clinical use. Exacerbating the public health burden is the fact that the only new class of antifungal drugs developed in decades, the echinocandins, displays negligible antifungal activity against Cryptococcus spp., and the efficacy of the remaining therapeutics is hampered by host toxicity and pathogen resistance. Here, we describe the current arsenal of antifungal agents and the treatment strategies employed to manage cryptococcal disease. We further elaborate on the recent advances in our understanding of the intrinsic and adaptive resistance mechanisms that are utilized by Cryptococcus spp. to evade therapeutic treatments. Finally, we review potential therapeutic strategies, including combination therapy, the targeting of virulence traits, impairing stress response pathways and modulating host immunity, to effectively treat infections caused by Cryptococcus spp. Overall, understanding of the mechanisms that regulate anti-cryptococcal drug resistance, coupled with advances in genomics technologies and high-throughput screening methodologies, will catalyse innovation and accelerate antifungal drug discovery.Cryptococcosis is a serious fungal infection for which treatment options are limited. In this Review, Cowen and colleagues discuss the current antifungal treatments available for cryptococcal infections, the challenges in developing new treatments, and ongoing efforts to identify novel therapies.