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Environmental Pollution (Barking, Essex... Jun 2024The co-cultivation of fungi with microalgae facilitates microalgae harvesting and enhances heavy metal adsorption. However, the mechanisms of fungal tolerance to cadmium...
The co-cultivation of fungi with microalgae facilitates microalgae harvesting and enhances heavy metal adsorption. However, the mechanisms of fungal tolerance to cadmium (Cd) have not yet been studied in detail. In this study, functional groups of fungi were analyzed under Cd stress using Fourier transform infrared spectrometer (FTIR), X-ray photoelectron spectroscopy (XPS), scanning electron microscope (SEM), and transmission electron microscope (TEM) to explore their morphology. Confocal laser scanning microscope (CLSM) was used to characterize the changes in the content of extracellular polysaccharides and proteins, and a decrease in the ratio of glutathione (GSH) to oxidized glutathione (GSSG) was monitored. The GSH and GSSG contents in mycelium were 7.4 and 7.9 times higher than that in the control, respectively. After 72 h of Cd treatment, the fungal extracellular polysaccharide and extracellular protein contents increased by 16 and 11.4 mg/g, respectively, compared to the control. This provided several functional groups for the complexation of Cd ions to enhance fungal Cd tolerance. The metabolomic and transcriptomic results revealed a total of 358 differential metabolites after 20, 48, and 72 h in the positive and negative ion modes, and the number of differential metabolites specific to each group was 104, 14, and 89, respectively. There were 927, 1167, and 1287 up-regulated genes, and 1301, 1480, and 1683 down-regulated genes at 20, 48, and 72 h, respectively. Energy metabolism, amino acid metabolism, and the ABC transport system are the key metabolic pathways for tolerance enhancement and heavy metal detoxification in fungi. The expression of S-cysteinosuccinic acid was significantly up-regulated after Cd stress and associated with enhanced fungal tolerance and resistance to Cd.
PubMed: 38852660
DOI: 10.1016/j.envpol.2024.124344 -
Communications Biology Jun 2024Aspergillus fumigatus represents a public health problem due to the high mortality rate in immunosuppressed patients and the emergence of antifungal-resistant isolates....
Aspergillus fumigatus represents a public health problem due to the high mortality rate in immunosuppressed patients and the emergence of antifungal-resistant isolates. Protein acetylation is a crucial post-translational modification that controls gene expression and biological processes. The strategic manipulation of enzymes involved in protein acetylation has emerged as a promising therapeutic approach for addressing fungal infections. Sirtuins, NAD-dependent lysine deacetylases, regulate protein acetylation and gene expression in eukaryotes. However, their role in the human pathogenic fungus A. fumigatus remains unclear. This study constructs six single knockout strains of A. fumigatus and a strain lacking all predicted sirtuins (SIRTKO). The mutant strains are viable under laboratory conditions, indicating that sirtuins are not essential genes. Phenotypic assays suggest sirtuins' involvement in cell wall integrity, secondary metabolite production, thermotolerance, and virulence. Deletion of sirE attenuates virulence in murine and Galleria mellonella infection models. The absence of SirE alters the acetylation status of proteins, including histones and non-histones, and triggers significant changes in the expression of genes associated with secondary metabolism, cell wall biosynthesis, and virulence factors. These findings encourage testing sirtuin inhibitors as potential therapeutic strategies to combat A. fumigatus infections or in combination therapy with available antifungals.
Topics: Aspergillus fumigatus; Sirtuins; Virulence; Animals; Mice; Aspergillosis; Acetylation; Fungal Proteins; Gene Expression Regulation, Fungal; Virulence Factors; Moths
PubMed: 38851817
DOI: 10.1038/s42003-024-06383-3 -
Macromolecular Bioscience Jun 2024The ubiquitous mold Aspergillus fumigatus (A. fumigatus) is one of the main fungal pathogens causing invasive infections in immunocompromised humans. Conventional...
The ubiquitous mold Aspergillus fumigatus (A. fumigatus) is one of the main fungal pathogens causing invasive infections in immunocompromised humans. Conventional antifungal agents exhibit limited efficacy and often cause severe side effects. Nanoparticle-based antifungal delivery provides a promising alternative, which can increase local drug concentration while mitigating toxicity, thereby enhancing treatment efficacy. Previous research underscores the potential of poly(glycidol)-based nanogels (NG) with negative surface charge as carriers for delivering antifungals to A. fumigatus hyphae. In this study, we tailored NG with 2-carboxyethyl acrylate (CEA) or with phosphoric acid 2-hydroxyethyl acrylate (PHA). We discovered that quenching with PHA clearly improved the adhesion of NG to hyphal surface and the internalization of NG into the hyphae under protein-rich conditions, surpassing the outcomes of non-quenched and CEA-quenched NG. This enhancement cannot be solely attributed to an increase in negative surface charge but appears to be contingent on the functional group of the quencher. Furthermore, we demonstrate that itraconazole-loaded, PHA-functionalized nanogels (NGxPHA-ITZ) showed lower MIC in vitro and superior therapeutic effect in vivo against A. fumigatus compared to pure itraconazole. This confirms NGxPHA as a promising antifungal delivery system. This article is protected by copyright. All rights reserved.
PubMed: 38850104
DOI: 10.1002/mabi.202400082 -
Frontiers in Cellular and Infection... 2024Lower respiratory tract infections represent prevalent ailments. Nonetheless, current comprehension of the microbial ecosystems within the lower respiratory tract...
BACKGROUND
Lower respiratory tract infections represent prevalent ailments. Nonetheless, current comprehension of the microbial ecosystems within the lower respiratory tract remains incomplete and necessitates further comprehensive assessment. Leveraging the advancements in metagenomic next-generation sequencing (mNGS) technology alongside the emergence of machine learning, it is now viable to compare the attributes of lower respiratory tract microbial communities among patients across diverse age groups, diseases, and infection types.
METHOD
We collected bronchoalveolar lavage fluid samples from 138 patients diagnosed with lower respiratory tract infections and conducted mNGS to characterize the lung microbiota. Employing various machine learning algorithms, we investigated the correlation of key bacteria in patients with concurrent bronchiectasis and developed a predictive model for hospitalization duration based on these identified key bacteria.
RESULT
We observed variations in microbial communities across different age groups, diseases, and infection types. In the elderly group, exhibited the highest relative abundance, followed by and . and emerged as the dominant genera at the genus level in the younger group, while and were prevalent species. Within the bronchiectasis group, dominant bacteria included , , and . Significant differences in the presence of were noted between the bronchiectasis group and the control group. In the group with concomitant fungal infections, the most abundant genera were and , with and as the predominant species. Notable differences were observed in the presence of , , , , and between the group with concomitant fungal infections and the bacterial group. Machine learning algorithms were utilized to select bacteria and clinical indicators associated with hospitalization duration, confirming the excellent performance of bacteria in predicting hospitalization time.
CONCLUSION
Our study provided a comprehensive description of the microbial characteristics among patients with lower respiratory tract infections, offering insights from various perspectives. Additionally, we investigated the advanced predictive capability of microbial community features in determining the hospitalization duration of these patients.
Topics: Humans; Machine Learning; Metagenomics; Middle Aged; Respiratory Tract Infections; Aged; Male; Female; Adult; Bacteria; Bronchoalveolar Lavage Fluid; Microbiota; High-Throughput Nucleotide Sequencing; Young Adult; Bronchiectasis; Aged, 80 and over; Metagenome; Adolescent; Lung; Hospitalization
PubMed: 38846353
DOI: 10.3389/fcimb.2024.1385562 -
IScience Jun 2024Hundreds of spores of are inhaled daily by human beings, representing a constant, possibly fatal, threat to respiratory health. The small size of spores suggests that...
Hundreds of spores of are inhaled daily by human beings, representing a constant, possibly fatal, threat to respiratory health. The small size of spores suggests that interactions with alveolar epithelial cells (AECs) are frequent; thus, we hypothesized that spore uptake by AECs is important for driving fungal killing and susceptibility to -related disease. Using single-cell approaches to measure spore uptake and its outcomes , we demonstrate that spores are internalized and killed by AECs during whole-animal infection. Moreover, comparative analysis of primary human AECs from healthy and chronic obstructive pulmonary disease (COPD) donors revealed significant alterations in the uptake and killing of spores in COPD-derived AECs. We conclude that AECs contribute to the killing of spores and that dysregulation of curative AEC responses in COPD may represent a driver of -related diseases.
PubMed: 38846001
DOI: 10.1016/j.isci.2024.109939 -
Applied and Environmental Microbiology Jun 2024Airborne triazole-resistant spores of the human fungal pathogen are a significant human health problem as the agricultural use of triazoles has been selecting for...
Airborne triazole-resistant spores of the human fungal pathogen are a significant human health problem as the agricultural use of triazoles has been selecting for cross-resistance to life-saving clinical triazoles. However, how to quantify exposure to airborne triazole-resistant spores remains unclear. Here, we describe a method for cost-effective wide-scale outdoor air sampling to measure both spore abundance as well as antifungal resistance fractions. We show that prolonged outdoor exposure of sticky seals placed in delta traps, when combined with a two-layered cultivation approach, can regionally yield sufficient colony-forming units (CFUs) for the quantitative assessment of aerial resistance levels at a spatial scale that was up to now unfeasible. When testing our method in a European pilot sampling 12 regions, we demonstrate that there are significant regional differences in airborne CFU numbers, and the triazole-resistant fraction of airborne spores is widespread and varies between 0 and 0.1 for itraconazole (∼4 mg/L) and voriconazole (∼2 mg/L). Our efficient and accessible air sampling protocol opens up extensive options for fine-scale spatial sampling and surveillance studies of airborne IMPORTANCE is an opportunistic fungal pathogen that humans and other animals are primarily exposed to through inhalation. Due to the limited availability of antifungals, resistance to the first choice class of antifungals, the triazoles, in can make infections by this fungus untreatable and uncurable. Here, we describe and validate a method that allows for the quantification of airborne resistance fractions and quick genotyping of TR-types. Our pilot study provides proof of concept of the suitability of the method for use by citizen-scientists for large-scale spatial air sampling. Spatial air sampling can open up extensive options for surveillance, health-risk assessment, and the study of landscape-level ecology of , as well as investigating the environmental drivers of triazole resistance.
PubMed: 38842339
DOI: 10.1128/aem.00271-24 -
Zeitschrift Fur Naturforschung. C,... Jun 2024Aspergillosis is one of the most common fungal infections that can threaten individuals with immune compromised condition. Due to the increasing resistance of pathogens...
Aspergillosis is one of the most common fungal infections that can threaten individuals with immune compromised condition. Due to the increasing resistance of pathogens to the existing antifungal drugs, it is difficult to tackle such disease conditions. Whereas, nikkomycin is an emerging safe and effective antifungal drug which causes fungal cell wall disruption by inhibiting chitin synthase. Hence, the study aims at the development of nikkomycin loaded PEG coated PLGA nanoparticles for its increased antifungal efficiency and inhibiting infections. The P-PLGA-Nik NPs were synthesized by w/o/w double emulsification method which resulted in a particle size of 208.3 ± 15 nm with a drug loading of 52.97 %. The NPs showed first order diffusion-controlled drug release which was sustained for 24 h. These nanoparticle's antifungal efficacy was tested using the CLSI - M61 guidelines and the MIC defined against and was found to be >32 μg/ml which was similar to the nikkomycin MIC. The hyphal tip bursting showed the fungal cell wall disruption. The non-cytotoxic and non-haemolytic nature highlights the drug safety profile.
PubMed: 38842117
DOI: 10.1515/znc-2023-0185 -
Journal of Medical Microbiology Jun 2024The fungal pathogen can induce prolonged colonization of the lungs of susceptible patients, resulting in conditions such as allergic bronchopulmonary aspergillosis and...
The fungal pathogen can induce prolonged colonization of the lungs of susceptible patients, resulting in conditions such as allergic bronchopulmonary aspergillosis and chronic pulmonary aspergillosis. Analysis of the secretome released during sub-lethal infection of larvae may give an insight into products released during prolonged human colonisation. larvae were infected with and the metabolism of host carbohydrate and proteins and production of fungal virulence factors were analysed. Label-free qualitative proteomic analysis was performed to identify fungal proteins in larvae at 96 hours post-infection and also to identify changes in the proteome as a result of infection. Infected larvae demonstrated increasing concentrations of gliotoxin and siderophore and displayed reduced amounts of haemolymph carbohydrate and protein. Fungal proteins (399) were detected by qualitative proteomic analysis in cell-free haemolymph at 96 hours and could be categorized into seven groups, including virulence ( = 25), stress response ( = 34), DNA repair and replication ( = 39), translation ( = 22), metabolism ( = 42), released intracellular ( = 28) and cellular development and cell cycle ( = 53). Analysis of the Gallerial proteome at 96 hours post-infection revealed changes in the abundance of proteins associated with immune function, metabolism, cellular structure, insect development, transcription/translation and detoxification. Characterizing the impact of the fungal secretome on the host may provide an insight into how damages tissue and suppresses the immune response during long-term pulmonary colonization.
Topics: Animals; Aspergillus fumigatus; Larva; Moths; Fungal Proteins; Secretome; Proteomics; Virulence Factors; Proteome; Hemolymph; Virulence; Aspergillosis
PubMed: 38836745
DOI: 10.1099/jmm.0.001844 -
Therapeutic Advances in Infectious... 2024, a widespread fungus in the natural environment, poses a significant threat to human health by entering the human body the airways and causing a disease called... (Review)
Review
BACKGROUND
, a widespread fungus in the natural environment, poses a significant threat to human health by entering the human body the airways and causing a disease called aspergillosis. This study comprehensively analyzed data on aspergillosis in published articles from mainland China to investigate the prevalence of , and risk factors, mortality rate, and underlying condition associated with aspergillosis.
METHODS
Published articles were retrieved from Google Scholar, PubMed, and Science Direct online search engines. In the 101 analyzed studies, 3558 isolates were meticulously collected and classified. GraphPad Prism 8 was used to statistically examine the epidemiology and clinical characteristics of aspergillosis.
RESULTS
was prominently reported ( = 2679, 75.14%), followed by ( = 437, 12.25%), ( = 219, 6.14%), and ( = 119, 3.33%). Of a total of 9810 patients, 7513 probable cases accounted for the highest number, followed by confirmed cases ( = 1956) and possible cases ( = 341). In patients, cough emerged as the most common complaint ( = 1819, 18.54%), followed by asthma ( = 1029, 10.48%) and fever (1024, 10.44%). Of total studies, invasive pulmonary aspergillosis (IPA) was reported in 47 (45.53%) studies, exhibiting an increased prevalence in Beijing ( = 12, 25.53%), Guangdong ( = 7, 14.89%), and Shanghai ( = 6, 12.76%). Chronic pulmonary aspergillosis (CPA) was reported in 14 (13.86%) studies. Among the total of 14 studies, the occurrence of CPA was 5 (35.71%) in Beijing and 3 (21.42%) in Shanghai. Allergic bronchopulmonary aspergillosis (ABPA), was reported at a lower frequency ( = 8, 7.92%), Guangdong recorded a relatively high number ( = 3, 37.5%), followed by Beijing ( = 2, 25.0%), and Shanghai ( = 1, 12.5%). Percentage of death reported: IPA had the highest rate ( = 447, 68.87%), followed by CPA ( = 181, 27.88%) and ABPA ( = 14, 2.15%). Among the aspergillosis patients, 6220 had underlying conditions, including chronic lung disease ( = 3765, 60.53%), previous tuberculosis ( = 416, 6.68%), and organ transplant or organ failure ( = 648, 10.41%). Aspergillosis was also found in patients using corticosteroid therapy ( = 622, 10.0%).
CONCLUSION
This review sheds light on the prevalence patterns of species, risk factors of aspergillosis, and gaps in surveillance that could be helpful for the control and treatment of aspergillosis and guide the researchers in future studies.
REGISTRATION
This systematic review was prospectively registered on PROSPERO: Registration ID CRD42023476870.
PubMed: 38835831
DOI: 10.1177/20499361241252537 -
MBio Jun 2024Group III hybrid histidine kinases are fungal-specific proteins and part of the multistep phosphorelay, representing the initial part of the high osmolarity glycerol...
UNLABELLED
Group III hybrid histidine kinases are fungal-specific proteins and part of the multistep phosphorelay, representing the initial part of the high osmolarity glycerol (HOG) pathway. TcsC, the corresponding kinase in was expected to be a cytosolic protein but is targeted to the nucleus. Activation of TcsC by the antifungal fludioxonil has lethal consequences for the fungus. The agent triggers a fast and TcsC-dependent activation of SakA and later on a redistribution of TcsC to the cytoplasm. High osmolarity also activates TcsC, which then exits the nucleus or concentrates in spot-like, intra-nuclear structures. The sequence corresponding to the N-terminal 208 amino acids of TcsC lacks detectable domains. Its loss renders TcsC cytosolic and non-responsive to hyperosmotic stress, but it has no impact on the antifungal activity of fludioxonil. A point mutation in one of the three putative nuclear localization sequences, which are present in the N-terminus, prevents the nuclear localization of TcsC, but not its ability to respond to hyperosmotic stress. Hence, this striking intracellular localization is no prerequisite for the role of TcsC in the adaptive response to hyperosmotic stress, instead, TcsC proteins that are present in the nuclei seem to modulate the cell wall composition of hyphae, which takes place in the absence of stress. The results of the present study underline that the spatiotemporal dynamics of the individual components of the multistep phosphorelay is a crucial feature of this unique signaling hub.
IMPORTANCE
Signaling pathways enable pathogens, such as , to respond to a changing environment. The TcsC protein is the major sensor of the high osmolarity glycerol (HOG) pathway of and it is also the target of certain antifungals. Insights in its function are therefore relevant for the pathogenicity and new therapeutic treatment options. TcsC was expected to be cytoplasmic, but we detected it in the nucleus and showed that it translocates to the cytoplasm upon activation. We have identified the motif that guides TcsC to the nucleus. An exchange of a single amino acid in this motif prevents a nuclear localization, but this nuclear targeting is no prerequisite for the TcsC-mediated stress response. Loss of the N-terminal 208 amino acids prevents the nuclear localization and renders TcsC unable to respond to hyperosmotic stress demonstrating that this part of the protein is of crucial importance.
PubMed: 38832777
DOI: 10.1128/mbio.01184-24