The roles of ergosterol in the regulation of membrane fluidity and structure, as well its role as a target for the activity of antifungals, have been known for decades. Two recent studies, however, ...demonstrated that ergosterol is an immunologically active lipid that induces pyroptosis and that virtually all steps of its biosynthetic process are potential drug targets. In combination, those two reports strongly indicate that the biological relevance of ergosterol is broader than the current literature suggests.
The invasive diseases caused by fungi, the so-called systemic mycoses, profoundly impact human health. ...the Global Action Fund for Fungal Infections (GAFFI) also highlights the devastating impact ...of focal fungal diseases in individuals who often have intact immune systems. According to the Centers for Disease Control and Prevention (CDC), fungi are among the leading causes of opportunistic infections affecting patients with HIV/AIDS 16. ...they afflict the poorest people without access to safe drinking water, sanitation, and basic health services. ...neglected tropical diseases can cause severe pain and disability throughout life, with long-term consequences for patients and families of the affected person.
In the past few years, fungal diseases caused estimated over 1.6 million deaths annually and over one billion people suffer from severe fungal diseases (Brown et al., 2012; Anonymous, 2017b). Public ...health surveillance of fungal diseases is generally not compulsory, suggesting that most estimates are conservative (Casadevall, 2017; Anonymous, 2017a). Fungal disease can also damage plants and crops, causing major losses in agricultural activities and food production (Savary et al., 2012). Animal pathogenic fungi are threatening bats, amphibians and reptiles with extinction (Casadevall, 2017). It is estimated that fungi are the highest threat for animal-host and plant-host species, representing the major cause (approximately 65%) of pathogen-driven host loss (Fisher et al., 2012). In this complex scenario, it is now clear that the global warming and accompanying climate changes have resulted in increased incidence of many fungal diseases (Garcia-Solache and Casadevall, 2010). On the basis of all these factors, concerns on the occurrence of a pandemic of fungal origin in a near future have been raised (Casadevall, 2017). In this context, to stop forgetting and underestimating fungal diseases is mandatory.
Extracellular vesicles (EVs) have garnered much interest in the cell biology and biomedical research fields. Many studies have reported the existence of EVs in all types of living cells, including in ...fifteen different fungal genera. EVs play diverse biological roles, from the regulation of physiological events and response to specific environmental conditions to the mediation of highly complex interkingdom communications. This review will provide a historical perspective on EVs produced by fungi and an overview of the recent discoveries in the field. We will also review the current knowledge about EV biogenesis and cargo, their role in cell-to-cell interactions, and methods of EV analysis. Finally, we will discuss the perspectives of EVs as vehicles for the delivery of biologically active molecules.
Affected individuals may have significant mental health issues associated with this rare and chronic condition 4. Another way of measuring the impact of fungi on public health is to determine their ...overall burden of disease using the disability-adjusted life year (DALY). ...the Coronavirus Disease 2019 (COVID-19) pandemic exacerbated the epidemiology of fungal diseases 19, proving the concept that globally transmitted diseases can make worse an already complex epidemiologic scenario. In a broader analysis, a relatively recent study on the 28 most transformative medicines approved for clinical use by the US Food and Drug Administration (FDA) between 1985 and 2009 revealed that approximately 80% of the medicines in this group could be traced back to one or several basic discoveries 24. ...although innovation-oriented programs are of unquestionable relevance, continued fostering of fundamental research is indispensable to generate translational tools.
The immunological potential of extracellular vesicles produced by Gram-negative bacteria, the so-called outer-membrane vesicles (OMVs), can be improved by genetic engineering, resulting in vesicles ...containing multiple immunogens. The potential of this approach for the development of a vaccine candidate for enteric fever was recently demonstrated by G. Gasperini, R. Alfini, V. Arato, F. Mancini, et al. (Infect Immun 89:e00699-20, 2021, https://doi.org/10.1128/IAI.00699-20). This commentary will discuss the use of OMVs to generate vaccines for enteric fever and the promise of this approach for prevention of other infectious diseases.
According to the Global Fund for Fungal Infections (GAFFI), several key antifungals also are not available or not even registered in multiple regions where fungal diseases are most lethal 2. ...Investment/death ratios for each disease corresponded to approximate values of 2,458 (meningococcal meningitis), 1,315 (malaria), 334 (tuberculosis), 276 (diarrheal diseases), and 31 (cryptococcal meningitis). https://doi.org/10.1371/journal.pntd.0006479.g001 Funding for fungal diseases The current scenario is incompatible with an optimistic perspective, as illustrated by the most recent edition of the Global Funding of Innovation for Neglected Diseases (G-Finder) Report 18. According to statistics obtained from WHO’s public databases, cryptococcal meningitis is the fourth most deadly infectious disease (excluding HIV), after tuberculosis (approximately 1,700,000 deaths 19), diarrheal diseases (approximately 525,000 deaths 20), and malaria (approximately 438,000 deaths 21). Analysis of publication records and reported funding in the fields of tuberculosis, malaria, cryptococcosis, paracoccidioidomycosis, mycetoma, sporotrichosis, and chromoblastomycosisa. https://doi.org/10.1371/journal.pntd.0006479.t001 We further examined the authors' statements of financial support for major international agencies with a history of support of research into neglected diseases 23, such as the National Institutes of Health, USA, the Bill and Melinda Gates Foundation, the National Natural Science Foundation of China, the Wellcome Trust, the Medical Research Council, the European Commission, and the European Research Council.
Once inside phagocytic cells, C. neoformans can either survive and replicate in the phagolysome, or it can once again reach the extracellular space by exiting these cells without killing them 7, 8. ...Since the extracellular environment is neutral/alkaline whereas the intracellular (phagolysosome) is acidic, adaptation of C. neoformans to both environments is a critical feature for its survival and virulence in the host. ...fungal GlcCer is a virulence determinant with a characteristic chemical structure and synthesized by fungal specific enzymes. Since it is produced by a variety of pathogenic fungi, targeting fungal GlcCer should improve the outcome of fungal infection diseases.
Fungal extracellular vesicles (EVs) have attracted increased attention in recent years. Originated from a serendipitous discovery, the initial observation of fungal EVs resulted in a set of data ...repetitively rejected by several scientific journals, which raised questions about their authenticity. However, after the most fundamental experimental issues related to their observation were addressed, fungal EVs were characterized in dozens of species and became an emerging field. In this essay, we will discuss these fundamental findings and the potential of fungal EVs for the development of vaccines and antifungals.
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