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MybA, a transcription factor involved in conidiation and conidial viability of the human pathogen Aspergillus fumigatus.
Valsecchi I, Sarikaya-Bayram Ö, Wong Sak Hoi J, Muszkieta L, Gibbons J, Prevost MC, Mallet A, Krijnse-Locker J, Ibrahim-Granet O, Mouyna I, Carr P, Bromley M, Aimanianda V, Yu JH, Rokas A, Braus GH, Saveanu C, Bayram Ö, Latgé JP
(2017) Mol Microbiol 105: 880-900
MeSH Terms: Aspergillosis, Aspergillus fumigatus, Cell Wall, Fungal Proteins, Gene Deletion, Gene Expression Regulation, Fungal, Humans, Membrane Proteins, Sequence Deletion, Spores, Fungal, Transcription Factors, Virulence
Show Abstract · Added March 21, 2018
Aspergillus fumigatus, a ubiquitous human fungal pathogen, produces asexual spores (conidia), which are the main mode of propagation, survival and infection of this human pathogen. In this study, we present the molecular characterization of a novel regulator of conidiogenesis and conidial survival called MybA because the predicted protein contains a Myb DNA binding motif. Cellular localization of the MybA::Gfp fusion and immunoprecipitation of the MybA::Gfp or MybA::3xHa protein showed that MybA is localized to the nucleus. RNA sequencing data and a uidA reporter assay indicated that the MybA protein functions upstream of wetA, vosA and velB, the key regulators involved in conidial maturation. The deletion of mybA resulted in a very significant reduction in the number and viability of conidia. As a consequence, the ΔmybA strain has a reduced virulence in an experimental murine model of aspergillosis. RNA-sequencing and biochemical studies of the ΔmybA strain suggested that MybA protein controls the expression of enzymes involved in trehalose biosynthesis as well as other cell wall and membrane-associated proteins and ROS scavenging enzymes. In summary, MybA protein is a new key regulator of conidiogenesis and conidial maturation and survival, and plays a crucial role in propagation and virulence of A. fumigatus.
© 2017 John Wiley & Sons Ltd.
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12 MeSH Terms
Zinc and Manganese Chelation by Neutrophil S100A8/A9 (Calprotectin) Limits Extracellular Aspergillus fumigatus Hyphal Growth and Corneal Infection.
Clark HL, Jhingran A, Sun Y, Vareechon C, de Jesus Carrion S, Skaar EP, Chazin WJ, Calera JA, Hohl TM, Pearlman E
(2016) J Immunol 196: 336-44
MeSH Terms: Adolescent, Adult, Aged, Animals, Aspergillus fumigatus, Biological Transport, Calgranulin A, Calgranulin B, Chelating Agents, Cornea, Disease Models, Animal, Humans, Hyphae, Keratitis, Leukocyte L1 Antigen Complex, Manganese, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Neutrophils, Phagocytosis, Pulmonary Aspergillosis, Spores, Fungal, Young Adult, Zinc
Show Abstract · Added February 5, 2016
Calprotectin, a heterodimer of S100A8 and S100A9, is an abundant neutrophil protein that possesses antimicrobial activity primarily because of its ability to chelate zinc and manganese. In the current study, we showed that neutrophils from calprotectin-deficient S100A9(-/-) mice have an impaired ability to inhibit Aspergillus fumigatus hyphal growth in vitro and in infected corneas in a murine model of fungal keratitis; however, the ability to inhibit hyphal growth was restored in S100A9(-/-) mice by injecting recombinant calprotectin. Furthermore, using recombinant calprotectin with mutations in either the Zn and Mn binding sites or the Mn binding site alone, we show that both zinc and manganese binding are necessary for calprotectin's antihyphal activity. In contrast to hyphae, we found no role for neutrophil calprotectin in uptake or killing of intracellular A. fumigatus conidia either in vitro or in a murine model of pulmonary aspergillosis. We also found that an A. fumigatus ∆zafA mutant, which demonstrates deficient zinc transport, exhibits impaired growth in infected corneas and following incubation with neutrophils or calprotectin in vitro as compared with wild-type. Collectively, these studies demonstrate a novel stage-specific susceptibility of A. fumigatus to zinc and manganese chelation by neutrophil-derived calprotectin.
Copyright © 2015 by The American Association of Immunologists, Inc.
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26 MeSH Terms
Chronic invasive fungal sinusitis associated with intranasal drug use.
Pekala KR, Clavenna MJ, Shockley R, Weiss VL, Turner JH
(2015) Laryngoscope 125: 2656-9
MeSH Terms: Administration, Intranasal, Aspergillosis, Aspergillus flavus, Debridement, Humans, Male, Nasal Surgical Procedures, Sinusitis, Substance-Related Disorders, Young Adult
Show Abstract · Added July 23, 2020
Chronic invasive fungal sinusitis (CIFS) is a rare but potentially aggressive form of invasive fungal disease that occurs in immunocompetent patients. We report a case of CIFS in an otherwise healthy young adult associated with intranasal illicit drug abuse. The patient presented with nonhealing nasal septal and palatal perforations. Biopsy demonstrated invasive Aspergillus flavus requiring surgical debridement and extended intravenous antifungal therapy. Tissue necrosis and ulceration related to intranasal drug use should be recognized as a potential risk factor for invasive fungal sinusitis.
© 2015 The American Laryngological, Rhinological and Otological Society, Inc.
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MeSH Terms
The fumagillin gene cluster, an example of hundreds of genes under veA control in Aspergillus fumigatus.
Dhingra S, Lind AL, Lin HC, Tang Y, Rokas A, Calvo AM
(2013) PLoS One 8: e77147
MeSH Terms: Aspergillosis, Aspergillus fumigatus, Cyclohexanes, Fatty Acids, Unsaturated, Fungal Proteins, Gene Deletion, Gene Expression Regulation, Fungal, Genes, Fungal, Humans, Multigene Family, Sesquiterpenes
Show Abstract · Added February 19, 2015
Aspergillus fumigatus is the causative agent of invasive aspergillosis, leading to infection-related mortality in immunocompromised patients. We previously showed that the conserved and unique-to-fungi veA gene affects different cell processes such as morphological development, gliotoxin biosynthesis and protease activity, suggesting a global regulatory effect on the genome of this medically relevant fungus. In this study, RNA sequencing analysis revealed that veA controls the expression of hundreds of genes in A. fumigatus, including those comprising more than a dozen known secondary metabolite gene clusters. Chemical analysis confirmed that veA controls the synthesis of other secondary metabolites in this organism in addition to gliotoxin. Among the secondary metabolite gene clusters regulated by veA is the elusive but recently identified gene cluster responsible for the biosynthesis of fumagillin, a meroterpenoid known for its anti-angiogenic activity by binding to human methionine aminopeptidase 2. The fumagillin gene cluster contains a veA-dependent regulatory gene, fumR (Afu8g00420), encoding a putative C6 type transcription factor. Deletion of fumR results in silencing of the gene cluster and elimination of fumagillin biosynthesis. We found expression of fumR to also be dependent on laeA, a gene encoding another component of the fungal velvet complex. The results in this study argue that veA is a global regulator of secondary metabolism in A. fumigatus, and that veA may be a conduit via which chemical development is coupled to morphological development and other cellular processes.
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11 MeSH Terms
The index case for the fungal meningitis outbreak in the United States.
Pettit AC, Kropski JA, Castilho JL, Schmitz JE, Rauch CA, Mobley BC, Wang XJ, Spires SS, Pugh ME
(2012) N Engl J Med 367: 2119-25
MeSH Terms: Aspergillosis, Aspergillus fumigatus, Brain, Cerebellum, Cerebral Infarction, Cerebrospinal Fluid, Diagnosis, Differential, Disease Outbreaks, Drug Contamination, Fatal Outcome, Glucocorticoids, Headache, Humans, Injections, Epidural, Intracranial Hemorrhages, Low Back Pain, Male, Meningitis, Fungal, Middle Aged, Tomography, X-Ray Computed, United States
Show Abstract · Added August 14, 2014
Persistent neutrophilic meningitis presents a diagnostic challenge, because the differential diagnosis is broad and includes atypical infectious causes. We describe a case of persistent neutrophilic meningitis due to Aspergillus fumigatus in an immunocompetent man who had no evidence of sinopulmonary or cutaneous disease. An epidural glucocorticoid injection was identified as a potential route of entry for this organism into the central nervous system, and the case was reported to the state health department.
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21 MeSH Terms
Eosinophilic pleural effusion complicating allergic bronchopulmonary aspergillosis.
Kirschner AN, Kuhlmann E, Kuzniar TJ
(2011) Respiration 82: 478-81
MeSH Terms: Adult, Anti-Inflammatory Agents, Aspergillosis, Allergic Bronchopulmonary, Aspergillus fumigatus, Asthma, Eosinophils, Humans, Male, Pleural Effusion, Prednisolone, Radiography, Thoracic, Sputum, Tomography, X-Ray Computed
Show Abstract · Added April 12, 2015
Allergic bronchopulmonary aspergillosis (ABPA) is primarily a disease of patients with cystic fibrosis or asthma, who typically present with bronchial obstruction, fever, malaise, and expectoration of mucus plugs. We report a case of a young man with a history of asthma who presented with cough, left-sided pleuritic chest pain and was found to have lobar atelectasis and an eosinophilic, empyematous pleural effusion. Bronchoscopy and sputum cultures grew Aspergillus fumigatus, and testing confirmed strong allergic response to this mold, all consistent with a diagnosis of ABPA. This novel and unique presentation of ABPA expands on the differential diagnosis of eosinophilic pleural effusions.
Copyright © 2011 S. Karger AG, Basel.
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13 MeSH Terms
Role of NADPH oxidase in host defense against aspergillosis.
Grimm MJ, Vethanayagam RR, Almyroudis NG, Lewandowski D, Rall N, Blackwell TS, Segal BH
(2011) Med Mycol 49 Suppl 1: S144-9
MeSH Terms: Animals, Aspergillosis, Aspergillus, Granulomatous Disease, Chronic, Host-Pathogen Interactions, Humans, Immunity, Innate, Inflammation, Mice, NADPH Oxidases, Neutrophils, Phenotype, Protein Isoforms, T-Lymphocytes
Show Abstract · Added March 5, 2014
NADPH oxidase plays a critical role in antimicrobial host defense, as evident in chronic granulomatous disease (CGD), an inherited disorder of the NADPH oxidase characterized by severe bacterial and fungal diseases. Invasive aspergillosis and other moulds are the major cause of mortality in CGD. We also learn from CGD patients that NADPH oxidase plays an important role in regulating inflammation; CGD patients are prone to developing inflammatory diseases such as inflammatory bowel disease, obstructive granulomata of the genitourinary tract, and hypersensitivity pneumonitis. Indeed, the NADPH oxidase plays an essential role in calibrating innate and T-cell responses to control the growth of inhaled fungi while protecting against excessive and injurious inflammation. Knowledge gained on the mechanisms by which NADPH oxidase kills fungi and regulates inflammation may lead to new therapeutics for CGD and will have broad relevance to understanding host-pathogen interactions between mammals and ubiquitous moulds to which we are continually exposed.
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14 MeSH Terms
Acute airway obstruction and necrotizing tracheobronchitis from invasive mycosis.
Putnam JB, Dignani C, Mehra RC, Anaisse EJ, Morice RC, Libshitz HI
(1994) Chest 106: 1265-7
MeSH Terms: Adult, Airway Obstruction, Anemia, Aplastic, Aspergillosis, Bone Marrow Transplantation, Bronchitis, Humans, Immunocompromised Host, Male, Tracheitis
Show Abstract · Added March 27, 2014
Necrotizing tracheobronchitis and acute airway obstruction from invasive mycosis developed in a patient who had undergone bone marrow transplantation. The infectious process obstructed the airway and disintegrated the walls of the right mainstem bronchus and pulmonary artery. The airway was cleared using rigid bronchoscopy to extract the detritus. The patient died of hemorrhage after rupture of the pulmonary artery through the right mainstem bronchus.
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10 MeSH Terms
Mycotic pseudoaneurysm of an aortic bypass graft and contiguous vertebral osteomyelitis due to Aspergillus fumigatus.
Brandt SJ, Thompson RL, Wenzel RP
(1985) Am J Med 79: 259-62
MeSH Terms: Aged, Amphotericin B, Aneurysm, Infected, Aortic Aneurysm, Aspergillosis, Aspergillus fumigatus, Coronary Artery Bypass, Humans, Male, Osteomyelitis, Spinal Diseases
Show Abstract · Added March 5, 2014
Fungal osteomyelitis is rare in patients who are not immunocompromised. This report documents that Aspergillus vertebral osteomyelitis may, however, be associated with infection of an adjacent prosthetic vascular graft in the absence of overt immunosuppression. A 73-year-old man is described with a mycotic pseudoaneurysm of a Dacron aortic bypass graft and contiguous vertebral osteomyelitis due to Aspergillus fumigatus. The patient was successfully treated with resection of the infected graft and administration of amphotericin B in a total dose of 2 g. Infection may have occurred intraoperatively as a result of inoculation with airborne fungal elements.
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11 MeSH Terms
Influence of corticosteroid on experimentally induced keratomycosis.
O'Day DM, Ray WA, Head WS, Robinson RD, Williams TE
(1991) Arch Ophthalmol 109: 1601-4
MeSH Terms: Animals, Aspergillosis, Aspergillus fumigatus, Candida albicans, Candidiasis, Colony Count, Microbial, Disease Models, Animal, Eye Infections, Fungal, Fusarium, Keratitis, Rabbits, Triamcinolone Acetonide
Show Abstract · Added March 5, 2014
To assess the effect of corticosteroid on the establishment of experimentally induced keratomycoses, rabbits were injected subconjunctivally with triamcinolone acetonide on two successive days before inoculation with Candida albicans, Aspergillus fumigatus, or Fusarium solanae. Whereas isolate recovery rates declined steadily in normal control corneas, they remained stable over 15 days in corticosteroid-treated corneas. Clinically, inflammation was equivalent (A fumigatus and F solanae) or significantly less (C albicans; P = .001) until the 10th day. At 15 days, inflammation in corticosteroid-treated corneas was significantly worse in animals infected with A fumigatus (P = .003) or F solanae (P = .02). Inflammatory signs correlated inconsistently with isolate recovery. Pathogenicity of the infecting organism appears to be important in determining the degree to which corticosteroid is able to mask clinical signs of infection while enhancing fungal replication.
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12 MeSH Terms