Fungal Invasive Co-Infection Due to Aspergillus fumigatus and Rhizopus arrhizus: A Rhino-Orbital Presentation.
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SUBMITTER: Ramirez-Hinojosa JP
PROVIDER: S-EPMC8704653 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A 61-year old lady with poorly-controlled type 2 diabetes mellitus was diagnosed with rhino-orbital-cerebral mucormycosis following presentation with sinusitis, ophthalmoplegia, proptosis and facial numbness. She was treated successfully with aggressive surgical intervention including orbital exenteration, accompanied by anti-fungal therapy with liposomal amphotericin B and posaconazole, followed by isavuconazole as salvage therapy. We discuss the challenges around optimising antifungal therapy of this lethal infection in the context of hepatic and renal toxicity.
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Project description:Mucormycosis is a fungal infection primarily afflicting immunocompromised or diabetic patients. Its presentation ranges from rhino-orbito-cerebral infections to disseminated mucormycosis with angioinvasion. We present a patient who developed a bowel obstruction one month after bone marrow transplant and was diagnosed with Rhizopus arrhizus diverticulitis despite antifungal therapy since transplantation. She underwent surgical removal with immediate fungal resurgence, declined further invasive intervention and was discharged on palliative isavuconazole. Seven months later she is alive with fungal containment.
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Project description:This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
2013-03-11 | E-ERAD-70 | biostudies-arrayexpress
Project description:Secreted fungal peptides are known to influence the interactions between the pathogen and host innate immunity. The aim of this study is to screen and evaluate secreted peptides from the fungus Rhizopus arrhizus var. delemar for their immunomodulatory activity. By using mass spectrometry and immuno-informatics analysis, we identified three secreted peptides CesT (S16), Colicin (S17), and Ca2+/calmodulin-dependent protein kinase/ligand (CAMK/CAMKL; S27). Culturing peripheral blood-derived monocytic macrophages (PBMMs) in the presence of S16 or S17 caused cell clumping, while culturing them with S27 resulted in the formation of spindle-shaped cells. S27-treated PBMMs showed cell cycle arrest at G0 phase and exhibited alternatively activated macrophage phenotype with pronounced reduction in scavenger receptors CD163 and CD206. Homology prediction indicated that IL-4/IL-13 is the immunomodulatory target of S27. Confirming this prediction, S27 initiated macrophage activation through phosphorylation of STAT-6; STAT-6 inhibition reversed the activity of S27 and reduced the formation of spindle-shaped PBMMs. Lastly, S27 treatment of PBMMs was associated with altered expression of key iron regulatory genes including hepcidin, ferroportin, transferrin receptor 1, and ferritin in a pattern consistent with increased cellular iron release; a condition known to enhance Rhizopus infection. Collectively, R. arrhizus var. delemar secretes peptides with immunomodulatory activities that support fungal pathogenesis. Targeting the IL-4/IL-13R/STAT-6 axis is a potential therapeutic approach to enhance the PBMM-mediated fungal phagocytosis. This represents a potential new approach to overcome lethal mucormycosis.
| S-EPMC8977774 | biostudies-literature
Project description:Invasive aspergillosis has been studied in laboratory by the means of plethora of distinct animal models. They were developed to address pathophysiology, therapy, diagnosis, or miscellaneous other concerns associated. However, there are great discrepancies regarding all the experimental variables of animal models, and a thorough focus on them is needed. This systematic review completed a comprehensive bibliographic analysis specifically-based on the technical features of rodent models infected with Aspergillus fumigatus. Out the 800 articles reviewed, it was shown that mice remained the preferred model (85.8% of the referenced reports), above rats (10.8%), and guinea pigs (3.8%). Three quarters of the models involved immunocompromised status, mainly by steroids (44.4%) and/or alkylating drugs (42.9%), but only 27.7% were reported to receive antibiotic prophylaxis to prevent from bacterial infection. Injection of spores (30.0%) and inhalation/deposition into respiratory airways (66.9%) were the most used routes for experimental inoculation. Overall, more than 230 distinct A. fumigatus strains were used in models. Of all the published studies, 18.4% did not mention usage of any diagnostic tool, like histopathology or mycological culture, to control correct implementation of the disease and to measure outcome. In light of these findings, a consensus discussion should be engaged to establish a minimum standardization, although this may not be consistently suitable for addressing all the specific aspects of invasive aspergillosis.
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Project description:Microbial secondary metabolites, including isocyanide moieties, have been extensively mined for their repertoire of bioactive properties. Although the first naturally occurring isocyanide (xanthocillin) was isolated from the fungus Penicillium notatum over half a century ago, the biosynthetic origins of fungal isocyanides remain unknown. Here we report the identification of a family of isocyanide synthases (ICSs) from the opportunistic human pathogen Aspergillus fumigatus Comparative metabolomics of overexpression or knockout mutants of ICS candidate genes led to the discovery of a fungal biosynthetic gene cluster (BGC) that produces xanthocillin (xan). Detailed analysis of xanthocillin biosynthesis in A. fumigatus revealed several previously undescribed compounds produced by the xan BGC, including two novel members of the melanocin family of compounds. We found both the xan BGC and a second ICS-containing cluster, named the copper-responsive metabolite (crm) BGC, to be transcriptionally responsive to external copper levels and further demonstrated that production of metabolites from the xan BGC is increased during copper starvation. The crm BGC includes a novel type of fungus-specific ICS-nonribosomal peptide synthase (NRPS) hybrid enzyme, CrmA. This family of ICS-NRPS hybrid enzymes is highly enriched in fungal pathogens of humans, insects, and plants. Phylogenetic assessment of all ICSs spanning the tree of life shows not only high prevalence throughout the fungal kingdom but also distribution in species not previously known to harbor BGCs, indicating an untapped resource of fungal secondary metabolism.IMPORTANCE Fungal ICSs are an untapped resource in fungal natural product research. Their isocyanide products have been implicated in plant and insect pathogenesis due to their ability to coordinate transition metals and disable host metalloenzymes. The discovery of a novel isocyanide-producing family of hybrid ICS-NRPS enzymes enriched in medically and agriculturally important fungal pathogens may reveal mechanisms underlying pathogenicity and afford opportunities to discover additional families of isocyanides. Furthermore, the identification of noncanonical ICS BGCs will enable refinement of BGC prediction algorithms to expand on the secondary metabolic potential of fungal and bacterial species. The identification of genes related to ICS BGCs in fungal species not previously known for secondary metabolite-producing capabilities (e.g., Saccharomyces spp.) contributes to our understanding of the evolution of BGC in fungi.
| S-EPMC5974471 | biostudies-literature
Project description:PurposeTo present the different clinical manifestations of rhino-orbital mucormycosis (ROM) co-infection in severe COVID-19 patients.Study designProspective observational clinical study METHODS: Among 32,814 patients hospitalized with the diagnosis of COVID-19 between March 2020 and December 2020 in our center, eleven microbiologically confirmed ROM co-infection cases in severe COVID-19 patients were evaluated.ResultsThere were nine men and two women with a mean age of 73.1 ± 7.7 years. Eight patients had uncontrolled type 2 diabetes with a mean diagnosis duration of 12.1 ± 4.4 years. All patients had COVID-19-associated acute respiratory distress syndrome and received corticosteroids. The mean time interval between COVID-19 diagnosis and ROM diagnosis was 14.4 ± 4.3 days. Seven patients (63.6%) had orbital apex syndrome, and four patients (36.4%) presented with orbital cellulitis. Endophthalmitis was detected in 54.5% of patients, and two of these patients developed retinoschisis. CT scan/MRI revealed sino-orbital involvement in all patients, and three of these had cerebral involvement at initial presentation. All patients received intravenous and retrobulbar liposomal amphotericin B and had undergone radical debridement of involved sinuses. Intravitreal liposomal amphotericin B injected in patients with endophthalmitis. Despite all measures, 63.6% of patients expired.ConclusionsSevere COVID-19 is associated with a significant incidence of ROM with higher mortality rates due to immune dysregulation and the widespread use of steroids. Physicians should be aware of the possibility of this infection in patients with COVID-19. An aggressive multidisciplinary approach can help to reduce mortality.
| S-EPMC8165350 | biostudies-literature
Project description:In immunocompromised individuals, Aspergillus fumigatus causes invasive fungal disease that is often difficult to treat. Exactly how immune mechanisms control A. fumigatus in immunocompetent individuals remains unclear. Here, we use transparent zebrafish larvae to visualize and quantify neutrophil and macrophage behaviors in response to different A. fumigatus strains. We find that macrophages form dense clusters around spores, establishing a protective niche for fungal survival. Macrophages exert these protective effects by inhibiting fungal germination, thereby inhibiting subsequent neutrophil recruitment and neutrophil-mediated killing. Germination directly drives fungal clearance as faster-growing CEA10-derived strains are killed better in vivo than slower-growing Af293-derived strains. Additionally, a CEA10 pyrG-deficient strain with impaired germination is cleared less effectively by neutrophils. Host inflammatory activation through Myd88 is required for killing of a CEA10-derived strain but not sufficient for killing of an Af293-derived strain, further demonstrating the role of fungal-intrinsic differences in the ability of a host to clear an infection. Altogether, we describe a new role for macrophages in the persistence of A. fumigatus and highlight the ability of different A. fumigatus strains to adopt diverse modes of virulence.
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Project description:Fungal endocarditis (FE) accounts for ~50% of the mortality rate associated with predisposing host conditions. Despite optimal therapeutic strategies, the survival rate remains low. FE is mostly caused by Candida albicans and Aspergillus fumigatus. Previous valvular surgery is the most essential risk factor for Aspergillus endocarditis, which observed in 40-50% of cases. However, native valve FE caused by Aspergillus is uncommon, with only a few reported cases. We hereby report a case of native valve FE caused by A. fumigatus with complications following Wegener's disease and prostate cancer. The patient survived after successful management with the combination of surgical and medical therapy. Aspergillus endocarditis is a rare and fatal fungal infection. Despite difficulties in diagnosis and treatment, medical intervention with antifungal therapy and immediate surgical intervention are essential to achieve desirable outcomes.
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Project description:Ergothioneine (EGT; 2-mercaptohistidine trimethylbetaine) is a trimethylated and sulphurised histidine derivative which exhibits antioxidant properties. Here we report that deletion of Aspergillus fumigatus egtA (AFUA_2G15650), which encodes a trimodular enzyme, abrogated EGT biosynthesis in this opportunistic pathogen. EGT biosynthetic deficiency in A. fumigatus significantly reduced resistance to elevated H2O2 and menadione, respectively, impaired gliotoxin production and resulted in attenuated conidiation. Quantitative proteomic analysis revealed substantial proteomic remodelling in ?egtA compared to wild-type under both basal and ROS conditions, whereby the abundance of 290 proteins was altered. Specifically, the reciprocal differential abundance of cystathionine ?-synthase and ?-lyase, respectively, influenced cystathionine availability to effect EGT biosynthesis. A combined deficiency in EGT biosynthesis and the oxidative stress response regulator Yap1, which led to extreme oxidative stress susceptibility, decreased resistance to heavy metals and production of the extracellular siderophore triacetylfusarinine C and increased accumulation of the intracellular siderophore ferricrocin. EGT dissipated H2O2 in vitro, and elevated intracellular GSH levels accompanied abrogation of EGT biosynthesis. EGT deficiency only decreased resistance to high H2O2 levels which suggests functionality as an auxiliary antioxidant, required for growth at elevated oxidative stress conditions. Combined, these data reveal new interactions between cellular redox homeostasis, secondary metabolism and metal ion homeostasis.
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