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BackgroundAspergillus fumigatus is a well-known opportunistic pathogen that causes a range of diseases including the often-fatal disease, invasive pulmonary aspergillosis (IPA), in immunocompromised populations. The severity of IPA is dependent on both host- and pathogen-derived signaling molecules that mediate host immunity and fungal growth. Oxylipins are bioactive oxygenated fatty acids known to influence host immune response and Aspergillus developmental programs. Aspergillus synthesizes 8-HODE and 5,8-diHODE that have structural similarities to 9-HODE and 13-HODE, which are known ligands of the host G-protein-coupled receptor G2A (GPR132).Materials and methodsOxylipins were extracted from infected lung tissue to assess fungal oxylipin production and the Pathhunter β-arrestin assay was used to assess agonist and antagonist activity by fungal oxylipins on G2A. An immunocompetent model of A. fumigatus infection was used to assess changes in survival and immune responses for G2A-/- mice.ResultsHere we report that Aspergillus oxylipins are produced in lung tissue of infected mice and in vitro ligand assays suggest 8-HODE is a G2A agonist and 5,8-diHODE is a partial antagonist. To address the hypothesis that G2A could be involved in the progression of IPA, we assessed the response of G2A-/- mice to A. fumigatus infection. G2A-/- mice showed a survival advantage over wild-type mice; this was accompanied by increased recruitment of G2A-/- neutrophils and increased levels of inflammatory markers in A. fumigatus-infected lungs.ConclusionsWe conclude that G2A suppresses host inflammatory responses to Aspergillus fumigatus although it remains unclear if fungal oxylipins are involved in G2A activities.

Aspergillus fumigatus can cause invasive pulmonary aspergillosis (IPA). Fungicidal azoles and fungistatic caspofungin (CAS) are the first- and second-line therapies, respectively, used to treat IPA. Treatment of A. fumigatus with CAS or micafungin induces the production of the oxylipin 5,8-diHODE by the fungal oxygenase PpoA. For this article, we investigated the influence of ppo genes, which encode the fatty acid oxygenases responsible for oxylipin biosynthesis, on CAS tolerance. The influence of PpoA and PpoC on CAS tolerance is mediated by MpkA phosphorylation and protein kinase A (PKA) activity. RNAseq transcriptional profiling and the label-free quantitative proteomics of the ppoA and ppoC mutants showed that differentially expressed genes and proteins are related to secondary metabolites and carbohydrate metabolism. We also characterized two clinical isolates, CM7555 and IFM61407, which decrease and increase susceptibility to CAS, respectively. CM7555 does not exhibit increased oxylipin production in the presence of CAS but oxylipin induction upon CAS exposure is increased in IFM61407, suggesting that oxylipins are not the only mechanism involved in CAS tolerance in these isolates. Upon CAS exposure, CM7555 has higher MpkA phosphorylation and PKA activity than IFM61407. Our results reveal the different aspects and genetic determinants involved in A. fumigatus CAS tolerance.

A novel and environmentally friendly magnetic iron zeolite (MIZ) core–shell were successfully fabricated using municipal solid waste incineration bottom ash-derived zeolite (MWZ) coated with Fe3O4 and innovatively investigated as a heterogeneous persulfate (PS) catalyst. The morphology and structure composition of as-prepared catalysts were characterised, and it was proved that the core–shell structure of MIZ was successfully synthesised by coating Fe3O4 uniformly on the MWZ surface. The tetracycline hydrochloride (TCH) degradation experiment indicate that the optimum equimolar amount of iron precursors was 3 mmol (MIZ-3). Compared with other systems, MIZ-3 possessed a superior catalytic performance, and the degradation efficiency of TCH (50 mg·L−1) in the MIZ-3/PS system reached 87.3%. The effects of reaction parameters on the catalytic activity of MIZ-3, including pH, initial concentration of TCH, temperature, the dosage of catalyst, and Na2S2O8, were assessed. The catalyst had high stability according to three recycling experiments and the leaching test of iron ions. Furthermore, the working mechanism of the MIZ-3/PS system to TCH was discussed. The electron spin resonance (ESR) results demonstrated that the reactive radicals generated in the MIZ-3/PS system were sulphate radical (${\rm S}{\rm O}_4^- \bullet$ S O 4 − ∙) and hydroxyl radical (•OH). This work provided a novel strategy for TCH degradation under PS with a broad perspective on the fabrication of non-toxic and low-cost catalysts in practical wastewater treatment. [ABSTRACT FROM AUTHOR]

Aspergillus fumigatus is a ubiquitous opportunistic pathogen. We have previously reported that volatile organic compounds (VOCs) produced by A. fumigatus cause delays in metamorphosis, morphological abnormalities, and death in a Drosophila melanogaster eclosion model. Here, we developed A. fumigatus deletion mutants with blocked oxylipin biosynthesis pathways (∆ppoABC) and then exposed the third instar larvae of D. melanogaster to a shared atmosphere with either A. fumigatus wild-type or oxylipin mutant cultures for 15 days. Fly larvae exposed to VOCs from wild-type A. fumigatus strains exhibited delays in metamorphosis and toxicity, while larvae exposed to VOCs from the ∆ppoABC mutant displayed fewer morphogenic delays and higher eclosion rates than the controls. In general, when fungi were pre-grown at 37 °C, the effects of the VOCs they produced were more pronounced than when they were pre-grown at 25 °C. GC–MS analysis revealed that the wild-type A. fumigatus Af293 produced more abundant VOCs at higher concentrations than the oxylipin-deficient strain Af293∆ppoABC did. The major VOCs detected from wild-type Af293 and its triple mutant included isopentyl alcohol, isobutyl alcohol, 2-methylbutanal, acetoin, and 1-octen-3-ol. Unexpectedly, compared to wild-type flies, the eclosion tests yielded far fewer differences in metamorphosis or viability when flies with immune-deficient genotypes were exposed to VOCs from either wild-type or ∆ppoABC oxylipin mutants. In particular, the toxigenic effects of Aspergillus VOCs were not observed in mutant flies deficient in the Toll (spz6) pathway. These data indicate that the innate immune system of Drosophila mediates the toxicity of fungal volatiles, especially via the Toll pathway. [ABSTRACT FROM AUTHOR]

Invasive aspergillosis is a common opportunistic infection, causing >50% mortality in infected immunocompromised patients. The specific molecular mechanisms of the innate immune system that prevent pathogenesis of invasive aspergillosis in immunocompetent individuals are not fully understood. Here, we used a zebrafish larva-Aspergillus infection model to identify cyclooxygenase (COX) enzyme signaling as one mechanism that promotes host survival. Larvae exposed to the pan-COX inhibitor indomethacin succumb to infection at a significantly higher rate than control larvae. COX signaling is both macrophage- and neutrophil-mediated. However, indomethacin treatment has no effect on phagocyte recruitment. Instead, COX signaling promotes phagocyte-mediated inhibition of germination and invasive hyphal growth. Increased germination and invasive hyphal growth is also observed in infected F0 crispant larvae with mutations in genes encoding for COX enzymes (ptgs2a/b). Protective COX-mediated signaling requires the receptor EP2 and exogenous prostaglandin E2 (PGE2) rescues indomethacin-induced decreased immune control of fungal growth. Collectively, we find that COX signaling activates the PGE2-EP2 pathway to increase control A. fumigatus hyphal growth by phagocytes in zebrafish larvae. Author summary: Invasive aspergillosis causes mortality in >50% of infected patients. It is caused by a free-living fungus Aspergillus fumigatus which releases thousands of airborne spores. While healthy individuals clear inhaled spores efficiently, in immunocompromised individuals these spores grow into filamentous hyphae and destroy lungs and other tissues causing invasive aspergillosis. The immune mechanisms that control this fungal growth in healthy people are still largely unknown. Here, we used a larval zebrafish model of A. fumigatus infection to determine that cyclooxygenase enzymes, which are the target of non-steroidal anti-inflammatory drugs such as aspirin and ibuprofen, are important to control the fungus. Innate immune cells use cyclooxygenase signaling to prevent hyphal growth and tissue destruction. Our study provides new insights into the mechanisms that immune cells deploy to stop invasive growth of A. fumigatus and inform development of future strategies to combat invasive aspergillosis. [ABSTRACT FROM AUTHOR]

A novel and environmentally friendly magnetic iron zeolite (MIZ) core-shell were successfully fabricated using municipal solid waste incineration bottom ash-derived zeolite (MWZ) coated with Fe 3 O 4 and innovatively investigated as a heterogeneous persulfate (PS) catalyst. The morphology and structure composition of as-prepared catalysts were characterised, and it was proved that the core-shell structure of MIZ was successfully synthesised by coating Fe 3 O 4 uniformly on the MWZ surface. The tetracycline hydrochloride (TCH) degradation experiment indicate that the optimum equimolar amount of iron precursors was 3 mmol (MIZ-3). Compared with other systems, MIZ-3 possessed a superior catalytic performance, and the degradation efficiency of TCH (50 mg·L -1 ) in the MIZ-3/PS system reached 87.3%. The effects of reaction parameters on the catalytic activity of MIZ-3, including pH, initial concentration of TCH, temperature, the dosage of catalyst, and Na 2 S 2 O 8 , were assessed. The catalyst had high stability according to three recycling experiments and the leaching test of iron ions. Furthermore, the working mechanism of the MIZ-3/PS system to TCH was discussed. The electron spin resonance (ESR) results demonstrated that the reactive radicals generated in the MIZ-3/PS system were sulphate radical ( S O 4 - ∙ ) and hydroxyl radical (•OH). This work provided a novel strategy for TCH degradation under PS with a broad perspective on the fabrication of non-toxic and low-cost catalysts in practical wastewater treatment.

Continued progress to move evidence-based best practices into community and regulatory animal welfare standards depends in part on developing common metrics to assess cost, benefit, and relative value. Here we describe a model approach to evidence-based evaluation and an example of comprehensive cost-benefit assessment for a common element of environmental enrichment plans for laboratory-housed nonhuman primates. Foraging devices encourage a species-typical activity that dominates the time budget of primates outside captivity and provide inherent cognitive challenges, physical activity demands, and multi-sensory stimulation. However, their implementation is not standard, and is challenged by perception of high costs and labor; nutritional and health concerns; and identification of best practices in implementation (that is, device types, food type, frequency of delivery and rotation). To address these issues, we directly compared monkeys' engagement with different foraging devices and the comprehensive cost of implementing foraging opportunities. We recorded 14 adult male cynomolgus monkeys' interactions with 7 types of devices filled with a range of enrichment foods. All devices elicited foraging behavior, but there were significant differences among them both initially and over subsequent observations. Devices that afforded opportunity for extraction of small food items and that posed manipulative challenge elicited greater manipulation. The cost of providing a foraging opportunity to a single monkey is roughly US$1, with approximately 80% attributable to labor. This study is the first to perform a rigorous cost-benefit analysis and comparison of common foraging devices included in environmental enrichment. Its broader significance lies in its contribution to the development of methods to facilitate improvement in evidence-based practices and common standards to enhance laboratory animal welfare.