Explore the vast range of titles available.

The significance of this study lies in its focused and in-depth analysis of the critical roles of the molecular chaperone Hsp90 in oxidative stress tolerance, metal ion homeostasis, and immune response regulation in Aspergillus fumigatus . Utilizing the Tet-on system to precisely modulate Hsp90 expression, this research demonstrates that Hsp90 is essential for the growth, development, and pathogenicity of this major opportunistic pathogen. Specifically, the study highlights Hsp90's crucial role in sustaining antioxidant enzyme activity, maintaining metal ion balance, and regulating immune responses—key factors that enable the fungus to survive and infect the host. These findings provide novel insights into the molecular mechanisms that underlie A. fumigatus 's resistance to oxidative stress and its evasion of host immunity, positioning Hsp90 as a promising therapeutic target for treating fungal infections. Furthermore, the results open new avenues for future investigations into the role of Hsp90 in fungal pathogenesis and immune modulation, potentially guiding the development of targeted antifungal therapies.

Magnaporthe oryzae is the causal agent of rice blast disease, a devastating problem worldwide. This fungus has caused breakdown of resistance conferred by newly developed commercial cultivars. To address how the rice blast fungus adapts itself to new resistance genes so quickly, we examined chromosomal locations of AVR-Pita, a subtelomeric gene family corresponding to the Pita resistance gene, in various isolates of M. oryzae (including wheat and millet pathogens) and its related species. We found that AVR-Pita (AVR-Pita1 and AVR-Pita2) is highly variable in its genome location, occurring in chromosomes 1, 3, 4, 5, 6, 7, and supernumerary chromosomes, particularly in rice-infecting isolates. When expressed in M. oryzae, most of the AVR-Pita homologs could elicit Pita-mediated resistance, even those from non-rice isolates. AVR-Pita was flanked by a retrotransposon, which presumably contributed to its multiple translocation across the genome. On the other hand, family member AVR-Pita3, which lacks avirulence activity, was stably located on chromosome 7 in a vast majority of isolates. These results suggest that the diversification in genome location of AVR-Pita in the rice isolates is a consequence of recognition by Pita in rice. We propose a model that the multiple translocation of AVR-Pita may be associated with its frequent loss and recovery mediated by its transfer among individuals in asexual populations. This model implies that the high mobility of AVR-Pita is a key mechanism accounting for the rapid adaptation toward Pita. Dynamic adaptation of some fungal plant pathogens may be achieved by deletion and recovery of avirulence genes using a population as a unit of adaptation.

Fungi constantly adapt to environmental changes in their various habitats. Asexual spore formation allows for quickly leaving an unfriendly habitat through dispersal into the air. The asexual developmental program of fungi enables the production of a large number of spores in a short period of time and in an energetically efficient manner. The SclB transcription factor is a key regulator of asexual growth and secondary metabolism in numerous fungal species. The mechanism through which SclB orchestrates the transition of the filamentous fungus Aspergillus nidulans from vegetative to asexual growth was revealed. This regulator directly in vivo controls itself as well as the expression of master genes for the asexual program, such as brlA for transcriptional control or ppoC for pheromone production. This study enhances the molecular understanding of how fungal asexual differentiation is initiated and coordinated, which supports the development of better strategies to control fungal pathogens, improving human health, safety, and crop management.

Gliotoxin (GT) plays a central role in the pathogenicity of Aspergillus fumigatus by enabling immune evasion and microbial competition, but its extreme toxicity also threatens the fungus itself. Although core GT biosynthetic and detoxification mechanisms are well studied, the full genetic network safeguarding against GT’s effects remains incompletely understood. This study identifies new RglT-regulated genes that contribute to GT self-protection and demonstrates that mitochondrial function is crucial for surviving GT exposure. Remarkably, similar protective pathways are active in both GT-producing and non-producing fungi, underscoring the ecological relevance of GT defense mechanisms. These findings deepen our understanding of fungal toxin tolerance and highlight mitochondria as a potential vulnerability that could be exploited for antifungal interventions.

Invasive fungal infections kill more than 1.5 million people each year, with limited treatment options. There is no vaccine available in clinical use to prevent and control fungal infections. Our recent studies showed that a mutant of the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase in Cryptococcus neoformans , elicited superior protective Th1 host immunity. Here, we demonstrate that the heat-killed fbp1 Δ cells (HK-fbp1) can be harnessed to confer protection against a challenge by the virulent parental strain, even in animals depleted of CD4 + T cells. This finding is particularly important in the context of HIV/AIDS-induced immune deficiency. Moreover, we observed that HK-fbp1 vaccination induces significant cross-protection against challenge with diverse invasive fungal pathogens. Thus, our data suggest that HK-fbp1 has the potential to be a broad-spectrum vaccine candidate against invasive fungal infections in both immunocompetent and immunocompromised populations. Cryptococcus neoformans is a fungal pathogen that infects the lungs and then often disseminates to the central nervous system, causing meningitis. How Cryptococcus is able to suppress host immunity and escape the antifungal activity of macrophages remains incompletely understood. We reported that the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase, promotes Cryptococcus virulence by regulating host- Cryptococcus interactions. Our recent studies demonstrated that the fbp1 Δ mutant elicited superior protective Th1 host immunity in the lungs and that the enhanced immunogenicity of heat-killed fbp1 Δ yeast cells can be harnessed to confer protection against a subsequent infection with the virulent parental strain. We therefore examined the use of heat-killed fbp1 Δ cells in several vaccination strategies. Interestingly, the vaccine protection remains effective even in mice depleted of CD4 + T cells. This finding is particularly important in the context of HIV/AIDS-induced immune deficiency. Moreover, we observed that vaccinating mice with heat-killed fbp1 Δ induces significant cross-protection against challenge with diverse invasive fungal pathogens, including C. neoformans , C. gattii , and Aspergillus fumigatus , as well as partial protection against Candida albicans . Thus, our data suggest that the heat-killed fbp1Δ strain has the potential to be a suitable vaccine candidate against cryptococcosis and other invasive fungal infections in both immunocompetent and immunocompromised populations. IMPORTANCE Invasive fungal infections kill more than 1.5 million people each year, with limited treatment options. There is no vaccine available in clinical use to prevent and control fungal infections. Our recent studies showed that a mutant of the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase in Cryptococcus neoformans , elicited superior protective Th1 host immunity. Here, we demonstrate that the heat-killed fbp1 Δ cells (HK-fbp1) can be harnessed to confer protection against a challenge by the virulent parental strain, even in animals depleted of CD4 + T cells. This finding is particularly important in the context of HIV/AIDS-induced immune deficiency. Moreover, we observed that HK-fbp1 vaccination induces significant cross-protection against challenge with diverse invasive fungal pathogens. Thus, our data suggest that HK-fbp1 has the potential to be a broad-spectrum vaccine candidate against invasive fungal infections in both immunocompetent and immunocompromised populations.

Section Flavi encompasses both harmful and beneficial Aspergillus species, such as Aspergillus oryzae, used in food fermentation and enzyme production, and Aspergillus flavus, food spoiler and mycotoxin producer. Here, we sequence 19 genomes spanning section Flavi and compare 31 fungal genomes including 23 Flavi species. We reassess their phylogenetic relationships and show that the closest relative of A. oryzae is not A. flavus, but A. minisclerotigenes or A. aflatoxiformans and identify high genome diversity, especially in sub-telomeric regions. We predict abundant CAZymes (598 per species) and prolific secondary metabolite gene clusters (73 per species) in section Flavi. However, the observed phenotypes (growth characteristics, polysaccharide degradation) do not necessarily correlate with inferences made from the predicted CAZyme content. Our work, including genomic analyses, phenotypic assays, and identification of secondary metabolites, highlights the genetic and metabolic diversity within section Flavi.

► NDV-3 is safe and generally well-tolerated in healthy adults. ► NDV-3 elicits quick and robust B- and T-cell immune responses. ► A single dose induces an anamnestic rather than priming immune response. ► T-cell response includes increases in PBMCs producing IFN-γ and/or IL-17A. ► A second dose further enhances the B- and T-cell immune response. The investigational vaccine, NDV-3, contains the N-terminal portion of the Candida albicans agglutinin-like sequence 3 protein (Als3p) formulated with an aluminum hydroxide adjuvant in phosphate-buffered saline. Preclinical studies demonstrated that the Als3p vaccine antigen protects mice from oropharyngeal, vaginal and intravenous challenge with C. albicans and other selected species of Candida as well as both intravenous challenge and skin and soft tissue infection with Staphylococcus aureus. The objectives of this first-in-human Phase I clinical trial were to evaluate the safety, tolerability and immunogenicity of NDV-3 at two different antigen levels compared to a saline placebo. Forty healthy, adult subjects were randomized to receive one dose of NDV-3 containing either 30 or 300μg of Als3p, or placebo. NDV-3 at both dose levels was safe and generally well-tolerated. Anti-Als3p total IgG and IgA1 levels for both doses reached peak levels by day 14 post vaccination, with 100% seroconversion of all vaccinated subjects. On average, NDV-3 stimulated peripheral blood mononuclear cell (PBMC) production of both IFN-γ and IL-17A, which peaked at day 7 for subjects receiving the 300μg dose and at day 28 for those receiving the 30μg dose. Six months after receiving the first dose of NDV-3, nineteen subjects received a second dose of NDV-3 identical to their first dose to evaluate memory B- and T-cell immune responses. The second dose resulted in a significant boost of IgG and IgA1 titers in >70% of subjects, with the biggest impact in those receiving the 30μg dose. A memory T-cell response was also noted for IFN-γ in almost all subjects and for IL-17A in the majority of subjects. These data support the continued investigation of NDV-3 as a vaccine candidate against Candida and S. aureus infections.

Development of multicellular eukaryotes involves transcriptional reprogramming to drive cell fate transitions. This study identified PRC2 as a critical regulator of cell fate in the model filamentous fungus Neurospora crassa , where it silences a subset of sexual development genes. Loss of regulation by PRC2 triggers a major reprogramming event in which genes specifying sexual tissues cannot be repressed, causing a homeotic transition. These results provide novel insights into the role of PRC2-mediated regulation in the fungal kingdom and uncover a critical checkpoint regulating complex multicellular development.

Microbial effectors are small secreted proteins that help pathogens establish disease within the host environment. In biotrophic fungi, secreted chorismate mutases (CMs) like Cmu1 suppress the production of salicylic acid (SA), a key plant hormone involved in resistance against biotrophic pathogens. Since Cmu1 and its homologs are exclusively found in biotrophic pathogens, secreted CMs have been considered a hallmark of biotrophy. Surprisingly, we identified a secreted CM, encoded by SsCM1 , in the predominantly necrotrophic fungus Sclerotinia sclerotiorum . Structural and functional studies suggest SsCM1 is likely a functional homolog acquired from bacteria and specifically acts to suppress the production of antimicrobial compounds that would otherwise enhance plant resistance to necrotrophs. Unlike Cmu1, SsCM1 localizes to plastids, inversely regulates SA, and is conserved more broadly across the fungal kingdom. Thus, our findings reveal a new branch of plastid-localized CMs in necrotrophs, offering new avenues for the development of potential broad-spectrum antimicrobial treatments targeting this pathogen group.

Chronic pulmonary aspergillosis (CPA) and its hallmark fungal balls (aspergillomas) represent a debilitating and difficult-to-treat respiratory disease, affecting millions worldwide. Here, we provide the first integrated multi-omics profile of surgically resected fungal balls from 61 CPA patients, revealing these structures not as mere fungal colonies, but as resilient, cross-kingdom biofilms teeming with bacterial co-colonizers, particularly Pseudomonas aeruginosa and Haemophilus influenzae . Our findings uncover a dynamic battlefield where fungi and bacteria engage in metabolic cross-feeding, chemical warfare, and competition for nutrients such as iron. We demonstrate that the host mounts a potent but dysregulated immune response characterized by chronic neutrophilic inflammation and failed resolution, driving tissue damage and disease persistence. Our data provide a foundation for novel therapeutic strategies aimed at disrupting microbial synergy, modulating host inflammation, and breaking the cycle of chronic infection, an approach that could significantly improve outcomes for patients with this refractory disease.