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International Journal of Biological... Dec 2023Fungal keratitis (FK) is a serious, potentially sight-threatening corneal infection, which is associated with poor prognosis. A20, also called TNFAIP3, plays significant...
Fungal keratitis (FK) is a serious, potentially sight-threatening corneal infection, which is associated with poor prognosis. A20, also called TNFAIP3, plays significant roles in the negative regulation of inflammation and immunity. However, the function of A20 in Aspergillus fumigatus (A. fumigatus) keratitis remains obscure. Herein, we found that the level of A20 is increased in human corneal epithelial cells (HCECs) and in mouse corneas with A. fumigatus infection, and that nuclear factor-κB (NF-κB) signaling is required for A20 upregulation. A20 overexpression inhibits A. fumigatus-mediated inflammatory responses, while A20 knockdown results in opposite effect. Mechanically, we showed that A20 inhibits NF-κB signaling and activates autophagy in infected HCECs. We also showed that inhibition of NF-κB signaling reverses the increased inflammatory responses in infected HCECs with A20 knockdown. Furthermore, autophagy blockage impedes the anti-inflammatory effect of A20 in A. fumigatus infected HCECs. Moreover, A20 ameliorates the corneal damage and inflammation in A. fumigatus infected mouse corneas. In conclusion, this study reveals that A20 alleviates A. fumigatus keratitis by activating autophagy and inhibiting NF-κB signaling. This suggests that exogenous use of A20 protein may be a potentially promising therapeutic strategy for FK treatment.
Topics: Animals; Mice; Humans; Aspergillus fumigatus; NF-kappa B; Epithelium, Corneal; Keratitis; Inflammation; Autophagy; Mice, Inbred C57BL
PubMed: 37879579
DOI: 10.1016/j.ijbiomac.2023.127640 -
Translational Vision Science &... Aug 2023To investigate the antifungal and anti-inflammatory effects of 0.01% hypochlorous acid (HCLO) on rats with Aspergillus fumigatus keratitis.
PURPOSE
To investigate the antifungal and anti-inflammatory effects of 0.01% hypochlorous acid (HCLO) on rats with Aspergillus fumigatus keratitis.
METHODS
The time-kill assay and broth microdilution procedures were used in vitro to demonstrate that 0.01% HCLO was fungicidal and fungistatic. The severity of the disease was evaluated in vivo using a clinical score and slit-lamp photographs. Fungal load, polymorphonuclear neutrophil infiltration, and the production of related proteins were determined using colony plate counting, in vivo confocal microscopy, periodic acid-Schiff staining, fungal fluorescence staining, immunofluorescence staining, myeloperoxidase assay, and Western blotting.
RESULT
In vitro, 0.01% HCLO can destroy A. fumigatus spores in 1 minute. The optical density of the 0.01% HCLO group was significantly lower than that of the phosphate-buffered saline control group (P < 0.01), and no visible mycelium was observed using a fluorescence microscope. 0.01% HCLO reduced the severity of A. fumigatus keratitis in rats by decreasing the clinical score, fungal loading (periodic acid-Schiff, plate count, and fungal fluorescence staining), and inhibiting neutrophil infiltration and activity (immunofluorescence staining and myeloperoxidase). Furthermore, the Western blot analysis revealed that 0.01% HCO decreased protein expression levels of tumor necrosis factor-α and IL-1β.
CONCLUSIONS
According to our findings, 0.01% HCLO can kill A. fumigatus spores in vitro. It has antifungal and anti-inflammatory effects on A. fumigatus keratitis in rats. It also inhibited A. fumigatus growth; decreased neutrophil infiltration, tumor necrosis factor-α, and IL-1β expression; and provided a potential treatment for fungal keratitis.
TRANSLATIONAL RELEVANCE
This study provides a potential treatment for fungal keratitis in the clinic.
Topics: Rats; Animals; Aspergillus fumigatus; Peroxidase; Hypochlorous Acid; Aspergillosis; Antifungal Agents; Tumor Necrosis Factor-alpha; Periodic Acid; Keratitis; Eye Infections, Fungal; Anti-Inflammatory Agents
PubMed: 37531113
DOI: 10.1167/tvst.12.8.3 -
Nature Communications Sep 2023The aromatic amino acid L-tryptophan (Trp) is essentially metabolized along the host and microbial pathways. While much is known about the role played by downstream...
The aromatic amino acid L-tryptophan (Trp) is essentially metabolized along the host and microbial pathways. While much is known about the role played by downstream metabolites of each pathways in intestinal homeostasis, their role in lung immune homeostasis is underappreciated. Here we have examined the role played by the Trp hydroxylase/5-hydroxytryptamine (5-HT) pathway in calibrating host and microbial Trp metabolism during Aspergillus fumigatus pneumonia. We found that 5-HT produced by mast cells essentially contributed to pathogen clearance and immune homeostasis in infection by promoting the host protective indoleamine-2,3-dioxygenase 1/kynurenine pathway and limiting the microbial activation of the indole/aryl hydrocarbon receptor pathway. This occurred via regulation of lung and intestinal microbiota and signaling pathways. 5-HT was deficient in the sputa of patients with Cystic fibrosis, while 5-HT supplementation restored the dysregulated Trp partitioning in murine disease. These findings suggest that 5-HT, by bridging host-microbiota Trp partitioning, may have clinical effects beyond its mood regulatory function in respiratory pathologies with an inflammatory component.
Topics: Humans; Animals; Mice; Tryptophan; Serotonin; Pneumonia; Mycoses; Microbiota; Aspergillosis; Influenza, Human
PubMed: 37717018
DOI: 10.1038/s41467-023-41536-8 -
Seminars in Respiratory and Critical... Feb 2024Aspergilli may cause various pulmonary diseases in humans, including allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis (CPA), and acute...
Aspergilli may cause various pulmonary diseases in humans, including allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis (CPA), and acute invasive pulmonary aspergillosis (IPA). In addition, chronic colonization may occur in cystic fibrosis (CF). represents the main pathogen, which may employ different morphotypes, for example, conidia, hyphal growth, and asexual sporulation, in the various diseases. These morphotypes determine the ease by which can adapt to stress by antifungal drug exposure, usually resulting in one or more resistance mutations. Key factors that enable the emergence of resistance include genetic variation and selection. The ability to create genetic variation depends on the reproduction mode, including, sexual, parasexual, and asexual, and the population size. These reproduction cycles may take place in the host and/or in the environment, usually when specific conditions are present. Environmental resistance is commonly characterized by tandem repeat (TR)-mediated mutations, while in-host resistance selection results in single-resistance mutations. Reported cases from the literature indicate that environmental resistance mutations are almost exclusively present in patients with IA indicating that the risk for in-host resistance selection is very low. In aspergilloma, single-point mutations are the dominant resistance genotype, while in other chronic diseases, for example, ABPA, CPA, and CF, both TR-mediated and single-resistance mutations are reported. Insights into the pathogenesis of resistance selection in various diseases may help to improve diagnostic and therapeutic strategies.
Topics: Humans; Antifungal Agents; Pulmonary Aspergillosis; Aspergillus fumigatus; Aspergillus; Aspergillosis, Allergic Bronchopulmonary; Cystic Fibrosis; Chronic Disease; Persistent Infection
PubMed: 38196063
DOI: 10.1055/s-0043-1776997 -
Cytokine Nov 2023To investigate the antifungal and anti-inflammatory effects of quercetin in Aspergillus fumigatus (A. fumigatus) keratitis.
PURPOSE
To investigate the antifungal and anti-inflammatory effects of quercetin in Aspergillus fumigatus (A. fumigatus) keratitis.
METHODS
Draize eye test was performed in mice to evaluate the toxicity of quercetin, and the antifungal effects on A. fumigatus were assessed via scanning electron microscopy (SEM), propidium iodide uptake, and adherence assay. In fungal keratitis (FK) mouse models, immunostaining was performed for investigating toll-like receptor 4 (TLR-4) expression and macrophage infiltration. Real-time PCR, ELISA, and Western blot were used to evaluate the expression of pro-inflammatory factors IL-1β, TNF-α, and IL-6 in infected RAW264.7 cells. Cells were also treated with TLR-4 siRNA or agonist CRX-527 to investigate mechanisms underlying the anti-inflammatory activity of quercetin.
RESULTS
Quercetin at 32 μM was non-toxic to corneal epithelial and significantly inhibited A. fumigatus growth and adhesion, and also altered the structure and reduced the number of mycelia. Quercetin significantly reduced macrophage infiltration in the mouse cornea, and attenuated the expression of TLR-4 in the corneal epithelium and stroma of mice with keratitis caused by A. fumigatus. In RAW264.7 cells infected by A. fumigatus, quercetin downregulated TLR-4 along with pro-inflammatory factors IL-1β, TNF-α, and IL-6. RAW cells with TLR-4 knockdown had reduced expression of factors after A. fumigatus infection, which was decreased even further with quercetin treatment. In contrast, cells with CRX-527 had elevated inflammatory factors compared to control, which was significantly attenuated in the presence of quercetin.
CONCLUSION
Quercetin plays a protective role in mouse A. fumigatus keratitis by inhibiting fungal load, disrupting hyphae structure, macrophage infiltration, and suppressing inflammation response in macrophages via TLR-4 mediated signaling pathway.
Topics: Mice; Animals; Aspergillus fumigatus; Toll-Like Receptor 4; Quercetin; Antifungal Agents; Interleukin-6; Tumor Necrosis Factor-alpha; Keratitis; Anti-Inflammatory Agents; Mice, Inbred C57BL
PubMed: 37677994
DOI: 10.1016/j.cyto.2023.156356 -
Journal of Fungi (Basel, Switzerland) Sep 2023Interactions between different kingdoms of microorganisms in humans are common but not well described. A recent analysis of the mycobiome has described the presence of... (Review)
Review
Interactions between different kingdoms of microorganisms in humans are common but not well described. A recent analysis of the mycobiome has described the presence of different fungi and their positive and/or negative interactions with bacteria and other fungi. In chronic respiratory diseases, these different microorganisms form mixed biofilms to live inside. The interactions between Gram-negative bacteria and filamentous fungi in these biofilms have attracted more attention recently. In this review, we analyse the microbiota of the respiratory tract of healthy individuals and patients with chronic respiratory disease. Additionally, we describe the regulatory mechanisms that rule the mixed biofilms of and Gram-negative bacteria and the effects of this biofilm on clinical presentations.
PubMed: 37755008
DOI: 10.3390/jof9090900 -
Microbial Biotechnology Nov 2023Iron is an essential element for all eukaryote organisms because of its redox properties, which are important for many biological processes such as DNA synthesis,... (Review)
Review
Iron is an essential element for all eukaryote organisms because of its redox properties, which are important for many biological processes such as DNA synthesis, mitochondrial respiration, oxygen transport, lipid, and carbon metabolism. For this reason, living organisms have developed different strategies and mechanisms to optimally regulate iron acquisition, transport, storage, and uptake in different environmental responses. Moreover, iron plays an essential role during microbial infections. Saccharomyces cerevisiae has been of key importance for decrypting iron homeostasis and regulation mechanisms in eukaryotes. Specifically, the transcription factors Aft1/Aft2 and Yap5 regulate the expression of genes to control iron metabolism in response to its deficiency or excess, adapting to the cell's iron requirements and its availability in the environment. We also review which iron-related virulence factors have the most common fungal human pathogens (Aspergillus fumigatus, Cryptococcus neoformans, and Candida albicans). These factors are essential for adaptation in different host niches during pathogenesis, including different fungal-specific iron-uptake mechanisms. While being necessary for virulence, they provide hope for developing novel antifungal treatments, which are currently scarce and usually toxic for patients. In this review, we provide a compilation of the current knowledge about the metabolic response to iron deficiency and excess in fungi.
Topics: Humans; Transcription Factors; Iron Deficiencies; Iron; Saccharomyces cerevisiae; Biological Transport; Gene Expression Regulation, Fungal; Trans-Activators; Saccharomyces cerevisiae Proteins; Basic-Leucine Zipper Transcription Factors
PubMed: 37804207
DOI: 10.1111/1751-7915.14346 -
Metabolites Nov 2023An KMM 4631 strain was previously isolated from a Pacific soft coral sp. sample and was found to be a source of a number of bioactive secondary metabolites. The aims...
An KMM 4631 strain was previously isolated from a Pacific soft coral sp. sample and was found to be a source of a number of bioactive secondary metabolites. The aims of this work are the confirmation of this strain' identification based on ITS, , , and regions/gene sequences and the investigation of secondary metabolite profiles of KMM 4631 culture and its co-cultures with KMM 4689, sp. KMM 4639, sp. KMM 4672, and KMM 4696 from the Collection of Marine Microorganisms (PIBOC FEB RAS, Vladivostok, Russia). Moreover, the DPPH-radical scavenging activity, urease inhibition, and cytotoxicity of joint fungal cultures' extracts on HepG2 cells were tested. The detailed UPLC MS qTOF investigation resulted in the identification and annotation of indolediketopiperazine, quinazoline, and tryptoquivaline-related alkaloids as well as a number of polyketides (totally 20 compounds) in the extract of KMM 4631. The metabolite profiles of the co-cultures of with , sp., and sp. were similar to those of , sp., and sp. monocultures. The metabolite profile of the co-culture of with differed from that of each monoculture and may be more promising for the isolation of new compounds.
PubMed: 37999234
DOI: 10.3390/metabo13111138 -
Current Clinical Microbiology Reports 2024Over recent decades, the number of outbreaks caused by fungi has increased for humans, plants (including important crop species) and animals. Yet this problem is... (Review)
Review
PURPOSE OF REVIEW
Over recent decades, the number of outbreaks caused by fungi has increased for humans, plants (including important crop species) and animals. Yet this problem is compounded by emerging antifungal drug resistance in pathogenic species. Resistance develops over time when fungi are exposed to drugs either in the patient or in the environment.
RECENT FINDINGS
Novel resistant variants of fungal pathogens that were previously susceptible are evolving (such as ) as well as newly emerging fungal species that are displaying antifungal resistance profiles (e.g. and ).
SUMMARY
This review highlights the important topic of emerging antifungal resistance in fungal pathogens and how it evolved, as well as how this relates to a growing public health burden.
PubMed: 38725545
DOI: 10.1007/s40588-024-00219-8 -
Journal of Clinical Medicine Sep 2023Chronic granulomatous disease (CGD) is an inborn error of immunity due to defects in the transport or function of subunits of nicotinamide adenine dinucleotide phosphate... (Review)
Review
Chronic granulomatous disease (CGD) is an inborn error of immunity due to defects in the transport or function of subunits of nicotinamide adenine dinucleotide phosphate oxidase, the enzyme that generates the phagocyte respiratory burst responsible for intracellular killing of engulfed micro-organisms. Patients present with infectious or inflammatory complications. Common bacterial pathogens include and complex. Fungal pathogens include species, particularly . Inflammatory complications most commonly manifest as inflammatory bowel disease or lung disease. Granulomata are the distinguishing histological feature. Haematopoietic stem cell transplantation (HSCT) was first considered for CGD in the early 1970's. Since then, refinements in transplant technique, donor selection, conditioning regimens, and graft engineering have widened the option of HSCT to most patients with CGD. This review charts the progress made in HSCT for CGD.
PubMed: 37763024
DOI: 10.3390/jcm12186083