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MSphere May 2024is the leading cause of severe mold infections in immunocompromised patients. This common fungus possesses innate attributes that allow it to evade the immune system,...
is the leading cause of severe mold infections in immunocompromised patients. This common fungus possesses innate attributes that allow it to evade the immune system, including its ability to survive the high copper (Cu) levels in phagosomes. Our previous work has revealed that under high Cu levels, the transcription factor AceA is activated, inducing the expression of the copper exporter CrpA to expel excess Cu. To identify additional elements in Cu resistance, we evolved wild-type and mutant Δ or Δ strains under increasing Cu concentrations. Sequencing of the resultant resistant strains identified both shared and unique evolutionary pathways to resistance. Reintroduction of three of the most common mutations in genes encoding Pma1 (plasma membrane H-ATPase), Gcs1 (glutamate cysteine-ligase), and Cpa1 (carbamoyl-phosphate synthetase), alone and in combination, into wild-type confirmed their additive role in conferring Cu resistance. Detailed analysis indicated that the mutation L424I preserves Pma1 H-ATPase activity under high Cu concentrations and that the mutation A37V confers a survival advantage to conidia in the presence of Cu. Interestingly, simultaneous mutations of all three genes did not alter virulence in infected mice. Our work has identified novel Cu-resistance pathways and provides an evolutionary approach for dissecting the molecular basis of adaptation to diverse environmental challenges.IMPORTANCE is the most common mold infecting patients with weakened immunity. Infection is caused by the inhalation of mold spores into the lungs and is often fatal. In healthy individuals, spores are engulfed by lung immune cells and destroyed by a combination of enzymes, oxidants, and high levels of copper. However, the mold can protect itself by pumping out excess copper with specific transporters. Here, we evolved under high copper levels and identified new genetic mutations that help it resist the toxic effects of copper. We studied how these mutations affect the mold's ability to resist copper and how they impact its ability to cause disease. This is the first such study in a pathogenic mold, and it gives us a better understanding of how it manages to bypass our body's defenses during an infection.
PubMed: 38814077
DOI: 10.1128/msphere.00253-24 -
Cureus Apr 2024Fosmanogepix, a prodrug of Manogepix (MGX), is a groundbreaking antifungal agent with broad-spectrum activity against yeasts, including and , as well as molds. It... (Review)
Review
Fosmanogepix, a prodrug of Manogepix (MGX), is a groundbreaking antifungal agent with broad-spectrum activity against yeasts, including and , as well as molds. It exhibits effectiveness against drug-resistant strains, such as strains resistant to and strains resistant to azoles. Furthermore, fosmanogepix shows activity against pathogens that typically resist other classes of drugs, such as , , and , although its efficacy against Mucorales varies. In animal models, fosmanogepix has demonstrated notable effectiveness against disseminated infections caused by various species, , and . It has also shown efficacy in pulmonary infection models involving , , , , and . Clinical trials have revealed excellent oral bioavailability (>90%), enabling a seamless transition between intravenous and oral formulations without compromising blood concentrations. Fosmanogepix exhibits favorable profiles in terms of drug interactions, tolerability, and extensive distribution in various tissues, making it an appealing choice for treating invasive fungal infections. This comprehensive review aims to examine the outcomes of published data on fosmanogepix, encompassing in vitro, in vivo, and clinical investigations.
PubMed: 38807795
DOI: 10.7759/cureus.59210 -
Infection and Drug Resistance 2024The role of -specific IgG antibody test in the diagnosis of non-neutropenic invasive pulmonary aspergillosis (IPA) is still uncertain, and related studies are also...
BACKGROUND
The role of -specific IgG antibody test in the diagnosis of non-neutropenic invasive pulmonary aspergillosis (IPA) is still uncertain, and related studies are also limited.
PURPOSE
This study aims to evaluate the quantitative test value of -specific IgG antibody in non-neutropenic IPA, which could provide additional evidence for related clinical diagnosis.
METHODS
This prospective study collected clinical data of suspected IPA patients from January, 2020 to December, 2022, and patients were divided into two groups, IPA and non-IPA. The study analyzed clinical characteristics and diagnostic value of -specific IgG antibody test, using the receiver operating characteristic (ROC) curve to evaluate diagnostic efficacy.
RESULTS
The study enrolled 59 IPA cases and 68 non-IPA cases, the average admission age of IPA group was 63.2±9.6 (33-79), and the gender ratio (male:female) of IPA group was 42:17. The proportion of patients with history of smoking and COPD were higher in IPA group (59.3% vs 39.7%, =0.027; 33.9% vs 14.7%, =0.011, respectively). The level of -specific IgG antibody in IPA group was significantly higher than non-IPA group (202.1±167.0 vs 62.6±58.0, <0.001). The area under the ROC curve was 0.799 (95%CI: 0.718, 0.865 <0.001), and the cut-off with best diagnostic efficacy was 91 AU/mL.
CONCLUSION
Immunological test plays an important role in the diagnosis of pulmonary aspergillosis, and -specific IgG antibody test has the good diagnostic value in non-neutropenic IPA.
PubMed: 38803521
DOI: 10.2147/IDR.S460513 -
Journal of Inflammation Research 2024To investigate the prevalence, risk factors and prognosis of invasive pulmonary aspergillosis (IPA) in patients with anti-melanoma differentiation-associated gene 5...
OBJECTIVE
To investigate the prevalence, risk factors and prognosis of invasive pulmonary aspergillosis (IPA) in patients with anti-melanoma differentiation-associated gene 5 positive dermatomyositis (anti-MDA5+ DM).
METHODS
A retrospective analysis was conducted in anti-MDA5+ DM patients diagnosed between January 2016 and March 2023. Patients with lower respiratory tract specimens were categorized into IPA+ and IPA- groups based on the presence of IPA and their clinical characteristics and prognoses then compared.
RESULTS
Of the 415 patients diagnosed with anti-MDA5+ DM, 28 cases had IPA (prevalence rate of 6.7%) with being the most common species. The patients were categorized into IPA+ (n=28) and IPA- (n=98) groups, with no significant age or gender-related differences (>0.05). The IPA+ group had a lower lymphocyte count, particularly the CD4+ T-cell count, and reduced serum albumin and higher serum ferritin levels ( all<0.05). An elevated bronchoalveolar lavage fluid (BALF) galactomannan level was found to be the sole independent risk factor for the occurrence of IPA (adjusted OR=2.191, =0.029) with a cut-off value of 0.585 and area under the curve of 0.779. The mortality rate in the IPA+ group was 25%. Compared to survivors, non-survivors in this group exhibited a higher incidence of rapidly progressive interstitial lung disease, lower lymphocyte counts, and increased co-infection with ( all<0.05).
CONCLUSION
IPA was not rare in patients with anti-MDA5+ DM, with elevated BALF galactomannan levels being an independent risk factor for IPA occurrence. Clinicians must exercise vigilance to identify patients exhibiting the aforementioned risk factors.
PubMed: 38800596
DOI: 10.2147/JIR.S460702 -
The World Allergy Organization Journal May 2024Fungi are known for their ability to cause allergies, but data on individual sensitization to them are insufficient. The purpose of the study was to carry out a...
BACKGROUND
Fungi are known for their ability to cause allergies, but data on individual sensitization to them are insufficient. The purpose of the study was to carry out a comprehensive analysis of the fungal allergens' sensitization profile in the Ukrainian population and to determine both population and individual sensitivity to these allergens.
METHODS
We utilized a set of ALEX allergy test data from 20,033 inhabitants of 17 regions of Ukraine from 1 to 89 years conducted in 2020-2022. A complex of programs in the Python language was developed and Bayesian network analysis was applied to determine the sensitivity combinations in individual patients to various fungal components.
RESULTS
Sensitivity to Alt a 1 dominated and was observed in 79.39% of patients, and 62.17% of them were sensitive solely to Alt a 1. Exclusive sensitivity to Mala s 6 was second in individual patient profiles with a frequency of 4.06%. Combined sensitivity to Alt a 1 - Asp f 3 was third with a share of 3.28%. Pen ch and Cla h extracts stimulated the production of the lowest median sIgE levels. The highest median sIgE levels were for Alt a 1, Mala s 11 and Asp f 6, respectively. Median sIgE levels increased in adults compared to children for all components of , as well as for Mala s 5 and Mala s 11. In the rest of the cases, they decreased in adults compared to children. The sensitization rates to fungi in general and specifically to were lower in the western parts of Ukraine, especially in the Carpathian region, situated within the Broad-leaved Forest zone. The results of Bayesian modeling revealed that in the case of Alt a 1, the simultaneous absence of sensitivity to Cla h 8, Mala s 11, Mala s 5 and Mala s 6 molecules could condition the presence of sensitization to the major allergen with a probability of 92.42%. In all other cases, there was a high probability of absence of sensitivity to particular allergen against the background of absence of sensitivity to other ones, which may indicate the independent development of sensitization to different fungal allergens.
CONCLUSIONS
Sensitivity to Alt a 1 dominated in the studied population with a lower rate in the western regions. The highest median sIgE levels were induced by Alt a 1, Mala s 11 and Asp f 6. Bayesian Analysis suggest a high probability of the independent development of sensitization to different fungal allergens. The idea that sensitization to one allergen may be protective against sensitization to another one(s) requires further clinical study.
PubMed: 38800499
DOI: 10.1016/j.waojou.2024.100908 -
Saudi Journal of Biological Sciences Jul 2024The inorganic colour layer based on iron oxide is affected by microorganisms (fungi) and leads to its deterioration due to feeding on the mineral elements through the...
The inorganic colour layer based on iron oxide is affected by microorganisms (fungi) and leads to its deterioration due to feeding on the mineral elements through the chemical composition of the colour in the presence of a suitable environment (medium). Damage occurs as a result of heavy metal elements being removed from the colour, leading to a defect in the chemical composition and the fading of the colours. The current study showed the effect of the different types of the most common fungi on oil paintings ( and ) after cultivating the different types of fungi and obtaining pure colonies for each fungus separately and conducting a fungal infection on experimental samples with preparing the old techniques, coloured with hematite red and goethite yellow. Each colour is mixed with different proportions of linseed oil (1, 2, 3). They were aged artificially and incubated at a temperature of 26 degrees and examined periodically until the fungi appeared on the surface in the form of colour spots ranging from very dark (severe infestation) to light (low infestation). The change in chemical composition was measured by Raman and EDX analyses of the samples before and after infection. Fungi showed the appearance of spoilage products from metal sulfides and metal carboxylates. The iron oxide ion decreased in both the red and the yellow colours, leading to a change after the fungal infection. Examination of the morphological surface using SEM, USB and measurement of colour change showed the change in the red colour more than the yellow and scattering of green and black colour dots on the surface of the sample. Correlation and Simple Linear Regression were applied for each colour before and after besides both colours together. It was found that these colours appeared around some of the fungal colonies as a result of the activities. Fungal species of some strains reduced Fe to Fe . This provides new insights into the role of microorganisms in the deterioration of painted surfaces.
PubMed: 38799718
DOI: 10.1016/j.sjbs.2024.104004 -
Redox Biology May 2024Fungal keratitis is a severely vision-threatening corneal infection, where the prognosis depends on both fungal virulence and host immune defense. Inappropriate host...
Fungal keratitis is a severely vision-threatening corneal infection, where the prognosis depends on both fungal virulence and host immune defense. Inappropriate host responses can induce substantial inflammatory damage to the cornea. Therefore, in the treatment of fungal keratitis, it is important to concurrently regulate the immune response while efforts are made to eliminate the pathogen. Ebselen is a widely studied organo-selenium compound and has been demonstrated to have antifungal, antibacterial, anti-inflammatory, and oxidative stress-regulatory properties. The effectiveness of ebselen for the treatment of fungal keratitis remains unknown. In this study, ebselen was demonstrated to produce a marked inhibitory effect on Aspergillus fumigatus (A. fumigatus), including spore germination inhibition, mycelial growth reduction, and fungal biofilm disruption. The antifungal activity of ebselen was related to the cell membrane damage caused by thioredoxin (Trx) system inhibition-mediated oxidative stress. On the contrary, ebselen enhanced the antioxidation of Trx system in mammalian cells. Further, ebselen was proven to suppress the expressions of inflammatory mediators (IL-1β, IL-6, TNF-α, COX-2, iNOS, and CCL2) and reduce the production of oxidative stress-associated indicators (ROS, NO, and MDA) in fungi-stimulated RAW264.7 cells. In addition, ebselen regulated PI3K/Akt/Nrf2 and p38 MAPK signaling pathways, which contributed to the improvement of inflammation and oxidative stress. Finally, we verified the therapeutic effect of ebselen on mouse fungal keratitis. Ebselen improved the prognosis and reduced the fungal burden in mouse corneas. Expressions of inflammatory mediators, as well as the infiltration of macrophages and neutrophils in the cornea were also obviously decreased by ebselen. In summary, ebselen exerted therapeutic effects by reducing fungal load and protecting host tissues in fungal keratitis, making it a promising treatment for fungal infections.
PubMed: 38796864
DOI: 10.1016/j.redox.2024.103206 -
Journal of Fungi (Basel, Switzerland) May 2024Invasive fungal infections have recently been recognized by the WHO as a major health, epidemiological, and economic issue. Their high mortality rates and the emergence... (Review)
Review
Invasive fungal infections have recently been recognized by the WHO as a major health, epidemiological, and economic issue. Their high mortality rates and the emergence of drug resistance have driven the development of new molecules, including olorofim, an antifungal belonging to a new family of compounds, the orotomides. A review was conducted on the PubMed database and the ClinicalTrials.gov website to summarize the microbiological profile of olorofim and its role in the treatment of filamentous fungal infections. Twenty-four articles were included from the search and divided into two groups: an "in vitro" group focusing on minimum inhibitory concentration (MIC) results for various fungi and an "in vivo" group evaluating the pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and tolerability of olorofim in animal models of fungal infection and in humans. Olorofim demonstrated in vitro and in vivo activity against numerous filamentous fungi, including azole-resistant , various dermatophytes, and endemic and dimorphic fungi. in vitro results showed higher MICs for certain species and dematiaceous fungi and ; further in vivo studies are needed. Published PK-PD data in humans are limited. The results of the ongoing phase III clinical trial are eagerly awaited to evaluate olorofim's clinical impact.
PubMed: 38786700
DOI: 10.3390/jof10050345 -
Journal of Fungi (Basel, Switzerland) Apr 2024The mold employs two high-affinity uptake systems, reductive iron assimilation (RIA) and siderophore-mediated iron acquisition (SIA), for the acquisition of the...
The mold employs two high-affinity uptake systems, reductive iron assimilation (RIA) and siderophore-mediated iron acquisition (SIA), for the acquisition of the essential trace element iron. SIA has previously been shown to be crucial for virulence in mammalian hosts. Here, we show that a lack of AcuK or AcuM, transcription factors required for the activation of gluconeogenesis, decreases the production of both extra- and intracellular siderophores in . The lack of AcuM or AcuK did not affect the expression of genes involved in RIA and SIA, suggesting that these regulators do not directly regulate iron homeostasis genes, but indirectly affect siderophore production through their influence on metabolism. Consistent with this, acetate supplementation reversed the intracellular siderophore production defect of Δ and Δ. Moreover, Δ and Δ displayed a similar growth defect under iron limitation and iron sufficiency, which suggests they have a general role in carbon metabolism apart from gluconeogenesis. In agreement with a potential role of the glyoxylate cycle in adaptation to iron starvation, transcript levels of the malate synthase-encoding were found to be upregulated by iron limitation that is partially dependent on AcuK and AcuM. Together, these data demonstrate the influence of iron availability on carbon metabolism.
PubMed: 38786682
DOI: 10.3390/jof10050327 -
Journal of Fungi (Basel, Switzerland) Apr 2024Neutrophil and (alveolar) macrophage immunity is considered crucial for eliminating . Data derived from bronchoalveloar lavage (BAL) characterizing the human...
Neutrophil and (alveolar) macrophage immunity is considered crucial for eliminating . Data derived from bronchoalveloar lavage (BAL) characterizing the human immuno-pulmonary response to are non-existent. To obtain a comprehensive picture of the immune pathways involved in chronic pulmonary aspergillosis (CPA), we performed proteome analysis on AL of 9 CPA patients and 17 patients with interstitial lung disease (ILD). The dihydrorhodamine (DHR) test was also performed on BAL and blood neutrophils from CPA patients and compared to blood neutrophils from healthy controls (HCs). BAL from CPA patients primarily contained neutrophils, while ILD BAL was also characterized by a large fraction of lymphocytes; these differences likely reflecting the different immunological etiologies underlying the two disorders. BAL and blood neutrophils from CPA patients displayed the same oxidative burst capacity as HC blood neutrophils. Hence, immune evasion by involves other mechanisms than impaired neutrophil oxidative burst capacity per se. CPA BAL was enriched by proteins associated with innate immunity, as well as, more specifically, with neutrophil degranulation, Toll-like receptor 4 signaling, and neutrophil-mediated iron chelation. Our data provide the first comprehensive target organ-derived immune data on the human pulmonary immune response to .
PubMed: 38786669
DOI: 10.3390/jof10050314