Dr James Schaller
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Mold Illness, Biotoxins, Mycotoxins and Sick Buildings

Dr. James Schaller is the writer of three co-authored books and is a certified mold remediator and investigator. This is stunning rare mix of science and practical knowledge. He can notice in 5 minutes junk mold testing and junk remediation in reports. He tries to read closely to old and emerging experts in remediation and building defect science. Dr. Schaller is a full-time researcher and part-time clinician working as a pioneer in mold illness. However, with 27 books and 27 peer-reviewed journal articles, mold illness is not his only interest or a medical fetish.

Two of his most recent highly respected books, written with master builder and biochemist Dr. Gary Rosen, and do not take weeks to read. They have real-world images, and are not mere wordy abstraction texts. These books avoid boring narcissistic autobiography, the "discovery" of "new" treatments known by others for years or even decades, and do not force biochemistry into highly rigid and narrow thinking, which wastes immense patient time and money.

These books show the issue with mold is what we have known for a very long time — the danger of mycotoxin "powder chemicals" on the spores.

Aspergillus has many species. In my ERMI work, in which this test looks for 36 EPA chosen species by DNA in dust for a mere $200.00, I am finding a significant amount of Aspergillus fumigatus. which has many biotoxins to harm humans and their pets.

Here is a small sample of some applicable articles.

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[Indoor moulds: results of the environmental study in office rooms]

[Article in Polish]

Buczy?ska A, Cyprowski M, Piotrowska M, Szadkowska-Sta?czyk I.

Za?dad Srodowiskowych Zagroze? Zdrowia, Instytut Medycyny Pracy im. prof. J. Nofera, ?ód?. alina@imp.lodz.pl

BACKGROUND: The aim of the study was to quantitatively and qualitatively identify moulds occurring in the air of selected office rooms. MATERIAL AND METHODS: The study was conducted in the wintertime inside four office rooms with moisture trace and one control room. To assess mycological contamination of the air, triple samples were directly collected on Petri dishes (Malt Extract Agar medium) using a Burkard air sampler. Qualitative evaluation of moulds was based on the microscopic view and morphological features of colonies. RESULTS: Total number of moulds determined in the air of office rooms did not exceed the level of 4 x 10(2) cfu/m3. The highest concentration of moulds (3.44 x 10(2) cfu/m3) was found in the room that was also used as an archive. It was over tenfold higher than in the control room (0.33 x 10(2) cfu/m3). The qualitative analysis of moulds showed the presence of 15 species. Some of them, including Aspergillus fumigatus, Aspergillus versicolor, Aspergillus ochraceus, Cladosporium spp., Penicillium spp. and Alternaria spp., are recognized as potential health hazards to workers due to the production of mycotoxins and allergic reactions. CONCLUSIONS: The archive was the only room, where concentration of moulds slightly exceeded the reference value. To protect the health of workers who perform their duties in this place, the documents, which are an ideal place of mould growth, should be moved to a separate room. Respiratory complaints reported by workers could be associated with concentrations and species of moulds found in the office rooms under study.

Publication Types:
PMID: 18421934 [PubMed - indexed for MEDLINE]

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Association of ergot alkaloids with conidiation in Aspergillus fumigatus.

Coyle CM, Kenaley SC, Rittenour WR, Panaccione DG.

Division of Plant & Soil Sciences, West Virginia University, P.O. Box 6108, Morgantown, West Virginia 26506-6108, USA.

Ergot alkaloids are mycotoxins that affect the nervous and reproductive systems of exposed individuals through interactions with monoamine receptors. They have been studied more widely in ergot fungi and grass endophytes but also are found in Aspergillus fumigatus, an opportunistic human pathogen that reproduces and disseminates exclusively through conidia. The ergot alkaloids festucla-vine and fumigaclavines A, B and C are present in or on conidia of A. fumigatus. Cultures of the fungus that are free of conidia are difficult to obtain, obscuring comparisons of conidia versus vegetative hyphae as sources of the ergot alkaloids. To create conidiation-deficient strains of A. fumigatus we manipulated the bristle A gene (brlA), which controls vesicle formation or budding growth necessary for conidiation in Aspergillus spp. Disruption of brlA in A. fumigatus, via homologous recombination, resulted in a nonconidiating mutant that produced bristle-like structures instead of conidiophores and conidia. Moreover the disrupted strain failed to produce ergot alkaloids as verified by HPLC analyses. Complementation with a wild-type allele restored conidiation and ergot alkaloid production. These results suggest that ergot alkaloids are not produced within the vegetative mycelium of the fungus and are associated directly with conidiation.

Publication Types:
PMID: 18333504 [PubMed - indexed for MEDLINE]

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Mycological flora on tree fruits, crust, leaves and pollen Sorbus domestica L.

Kacániová M, Fikselová M.

Department of Microbiology, Slovak University of Agriculture in Nitra, Faculty of Biotechnology and Food Sciences, Tr. A. Hlinku 2, 949 71 Nitra, Slovak Republic. kacaniov@afnet.uniag.sk

Plant-microbial interactive relations with respect to determine mycoflora of the Sorbus domestica L.--fruits, crust, leaves and pollen were studied in 2 Slovak regions. On the fruit samples the genera Alternaria, Botrytis, Cladosporium, Mucor and Penicillium occurred, on the leaves the genera Alternaria, Cladosporium and Penicillium prevailed and on crust the genera Alternaria, Cladosporium, Penicillium and Trichoderma appeared to be dominant, respectively. Isolates from the Sorbus domestica L. fruits were present by 11 genera and 13 species of microscopic fungi and isolates from pollen such as Alternaria, Botrytis, Cladosporium, Penicillium, Mycelia, Mucor and Trichoderma appeared to be the most frequently occurring genera. On the basis of further taxonomic determination, from the genera Aspergillus were isolated and identified representatives of species A. clavatus, A. fumigatus, A. niger, A. ochraceus, A. terreus. It is necessary to point out that the isolated genera Aspergillus and Penicillium are considered as the most important producers of mycotoxins.

Publication Types:
PMID: 18247456 [PubMed - indexed for MEDLINE]

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Mycoflora and ochratoxin A producing strains of Aspergillus in Algerian wheat.

Riba A, Mokrane S, Mathieu F, Lebrihi A, Sabaou N.

Laboratoire de Recherche sur les Produits Bioactifs et la Valorisation de la Biomasse, Ecole Normale Supérieure de Kouba, BP 92 16050 Vieux Kouba, Alger, Algeria.

Wheat is a basic staple food for very large segments of the population of Algeria. The aim of this study is to analyse ochratoxin A (OTA)-producing mould and OTA-contaminated wheat. To evaluate the mycoflora and the potential for OTA production by Aspergillus strains, a total of 85 samples of wheat destined for human consumption were collected from two regions in Algeria (Tizi Ouzou and Setif) during the following phases: preharvest, storage in silos, and after processing. The mean value counts of fungi ranged from 275 to 1277 CFU g(-1). The dominant genus was Aspergillus, predominantly A. flavus, A. niger and A. versicolor. The other isolated species were A. ochraceus, A. alliaceus, A. carbonarius, A. terreus, A. fumigatus, A. candidus and Aspergillus spp. The occurrence and the levels of the genus Penicillium, Fusarium, Alternaria and Mucor were substantially lower than those of Aspergillus. The storage in silos shows high levels of Aspergillus (66 to 84%), especially A. flavus, but A. niger and other fungi were isolated at relatively low percentages. Equal distribution of the fungal contamination into the bran, flour and semolina fractions was observed from Flour Mill and Semolina Mill. The genus Aspergillus remained present at high levels at several phases of the production process. In addition, the ability to produce OTA by 135 isolates belonging to eleven species of Aspergillus and 23 isolates of Penicillium spp. was analyzed using fluorescent detection-based HPLC. Thus, it was found that 51 isolates (32.3%) were ochratoxigenic. All isolated strains of A. ochraceus (12) and A. alliaceus (6) produced OTA at concentrations ranging from 0.23 to 11.50 microg g(-1). Most of the A. carbonarius strains (80%) were OTA producers (0.01 to 9.35 microg g(-1)), whereas A. terreus (50%), A. niger (28%), A. fumigatus (40%), A. versicolor (18%) and Penicillium spp. (21.7%) were low level producers (0.01 to 0.07 microg g(-1)). The concentration of OTA was determined in 30 samples of wheat. OTA was detected in 12 (40%) of the samples at levels ranging from 0.21 to 41.55 microg kg(-1).

PMID: 18083262 [PubMed - indexed for MEDLINE]

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Toxigenic fungi and mycotoxins in mature corn silage.

Richard E, Heutte N, Sage L, Pottier D, Bouchart V, Lebailly P, Garon D.

Groupe Régional d'Etudes sur le Cancer, GRECAN-EA 1772, Université de Caen Basse-Normandie, Centre François Baclesse, Avenue Général Harris, BP 5026, 14076 Caen Cedex 05, France.

To investigate the exposure of livestock and farm workers to mycotoxins during the last months of silage use, the mycoflora and the mycotoxins in a mature silage (11-months-old) were studied. A multimycotoxin method was developed to evaluate the toxigenic in vitro ability of fungal strains. The screening of potentially toxigenic fungi isolated from the mature silage showed that six Fusaria (Fusarium culmorum, Fusarium equiseti, Fusarium graminearum, Fusarium oxysporum, Fusarium solani and Fusarium verticillioides) and one Aspergillus (Aspergillus fumigatus) were able to produce mycotoxins on nutrient agar. Seven major mycotoxins (aflatoxin B(1), citrinin, deoxynivalenol, fumonisin B(1), gliotoxin, ochratoxin A and zearalenone) were also searched in the corn silage by high-performance liquid chromatography coupled to mass spectrometry (HPLC-MS). Among the three mycotoxins (citrinin, gliotoxin and deoxynivalenol) detected in the silage, gliotoxin, a strongly immunosuppressive mycotoxin, occurred in the mature silage at level up to 877 ppb, which was associated with the presence of A. fumigatus in the silage.

Publication Types:
PMID: 17655998 [PubMed - indexed for MEDLINE]

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Effects of Aspergillus fumigatus gliotoxin and methylprednisolone on human neutrophils: implications for the pathogenesis of invasive aspergillosis.

Orciuolo E, Stanzani M, Canestraro M, Galimberti S, Carulli G, Lewis R, Petrini M, Komanduri KV.

Department of Oncology, Transplant and Advances in Medicine, University of Pisa, Italy. orci@sssup.it

Aspergillus fumigatus (AF) is a ubiquitous mold and the most common cause of invasive aspergillosis (IA) in immunocompromised patients. In stem cell transplant recipients, IA now occurs most frequently in the setting of therapy with corticosteroids, including methylprednisolone (MP). We showed previously that gliotoxin (GT), an AF-derived mycotoxin, induces apoptosis in monocytes and dendritic cells, resulting in the suppression of AF-specific T cell responses. We examined the ability of GT to induce apoptosis in polymorphonuclear leukocytes (PMN) and assessed GT effects on important neutrophil functions, including phagocytic function, degranulation, myeloperoxidase activity, and the production of reactive oxygen species (ROS). In contrast to its effects on monocytes, PMN remained resistant to GT-mediated apoptosis. Although many essential neutrophil functions were unaffected, GT inhibited phagocytosis and also induced a decrease in ROS generation by PMN. In contrast, MP therapy potentiated ROS production, suggesting a mechanism that may facilitate tissue injury in IA. Distinct from its effects on untreated PMN, GT augmented ROS production in MP-treated PMN. Our results suggest that although GT may suppress the adaptive immune response, GT may also serve to increase PMN-mediated inflammation, which is likely to play an important role in tissue destruction in the setting of IA.

Publication Types:
PMID: 17626149 [PubMed - indexed for MEDLINE]

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Gliotoxin is a virulence factor of Aspergillus fumigatus: gliP deletion attenuates virulence in mice immunosuppressed with hydrocortisone.

Sugui JA, Pardo J, Chang YC, Zarember KA, Nardone G, Galvez EM, Müllbacher A, Gallin JI, Simon MM, Kwon-Chung KJ.

Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.

Gliotoxin is an immunosuppressive mycotoxin long suspected to be a potential virulence factor of Aspergillus fumigatus. Recent studies using mutants lacking gliotoxin production, however, suggested that the mycotoxin is not important for pathogenesis of A. fumigatus in neutropenic mice resulting from treatment with cyclophosphomide and hydrocortisone. In this study, we report on the pathobiological role of gliotoxin in two different mouse strains, 129/Sv and BALB/c, that were immunosuppressed by hydrocortisone alone to avoid neutropenia. These strains of mice were infected using the isogenic set of a wild type strain (B-5233) and its mutant strain (gliPDelta) and the the glip reconstituted strain (gliP(R)). The gliP gene encodes a nonribosomal peptide synthase that catalyzes the first step in gliotoxin biosynthesis. The gliPDelta strain was significantly less virulent than strain B-5233 or gliP(R) in both mouse models. In vitro assays with culture filtrates (CFs) of B-5233, gliPDelta, and gliP(R) strains showed the following: (i) deletion of gliP abrogated gliotoxin production, as determined by high-performance liquid chromatography analysis; (ii) unlike the CFs from strains B-5233 and gliP(R), gliPDelta CFs failed to induce proapoptotic processes in EL4 thymoma cells, as tested by Bak conformational change, mitochondrial-membrane potential disruption, superoxide production, caspase 3 activation, and phosphatidylserine translocation. Furthermore, superoxide production in human neutrophils was strongly inhibited by CFs from strain B-5233 and the gliP(R) strain, but not the gliPDelta strain. Our study confirms that gliotoxin is an important virulence determinant of A. fumigatus and that the type of immunosuppression regimen used is important to reveal the pathogenic potential of gliotoxin.

Publication Types:
PMID: 17601876 [PubMed - indexed for MEDLINE]

PMCID: PMC2043361


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Gliotoxin production by clinical and environmental Aspergillus fumigatus strains.

Kupfahl C, Michalka A, Lass-Flörl C, Fischer G, Haase G, Ruppert T, Geginat G, Hof H.

Faculty for Clinical Medicine Mannheim, University of Heidelberg, Institute for Medical Microbiology and Hygiene, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany. claudio.kupfahl@imh.ma.uni-heidelberg.de

The mycotoxin gliotoxin is produced by fungi of the genus Aspergillus, including the important human pathogen Aspergillus fumigatus. Gliotoxin exerts a broad spectrum of immunosuppressive effects in vitro and is detectable in the sera of patients suffering from invasive aspergillosis. In order to correlate the pathogenic potential of A. fumigatus with the ability to produce gliotoxin and to investigate the taxonomic distribution of gliotoxin-producing Aspergillus strains among clinical isolates, a total of 158 Aspergillus isolates comprising four different species (A. fumigatus, n=100; A. terreus, n=27; A. niger, n=16; A. flavus, n=15) were collected from different medical centers (some originating from probable cases of aspergillosis) and from environmental samples in Germany and Austria. Remarkably, gliotoxin was detected in most culture filtrates of A. fumigatus of both clinical (98%) and environmental (96%) origin. The toxin was also detected, with decreasing frequency, in culture filtrates of A. niger (56%), A. terreus (37%), and A. flavus (13%). The highest gliotoxin concentrations were detected in A. fumigatus strains of clinical (max. 21.35 microg/ml, mean 5.75 microg/ml) and environmental (max. 26.25 microg/ml, mean 5.27 microg/ml) origin. Gliotoxin productivity of other Aspergillus species was significantly lower. Culture supernatants of A. fumigatus strains lacking gliotoxin production showed a significantly lower cytotoxicity on macrophage-like cells and T-cells in vitro. In contrast, lack of gliotoxin production in the other Aspergillus species tested had no significant influence on the cytotoxic effect of culture supernatant on these immune cells.

PMID: 17574915 [PubMed - indexed for MEDLINE]

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Aspergillus flavus: human pathogen, allergen and mycotoxin producer.

Hedayati MT, Pasqualotto AC, Warn PA, Bowyer P, Denning DW.

Department of Medical Mycology and Parasitology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

Aspergillus infections have grown in importance in the last years. However, most of the studies have focused on Aspergillus fumigatus, the most prevalent species in the genus. In certain locales and hospitals, Aspergillus flavus is more common in air than A. fumigatus, for unclear reasons. After A. fumigatus, A. flavus is the second leading cause of invasive aspergillosis and it is the most common cause of superficial infection. Experimental invasive infections in mice show A. flavus to be 100-fold more virulent than A. fumigatus in terms of inoculum required. Particularly common clinical syndromes associated with A. flavus include chronic granulomatous sinusitis, keratitis, cutaneous aspergillosis, wound infections and osteomyelitis following trauma and inoculation. Outbreaks associated with A. flavus appear to be associated with single or closely related strains, in contrast to those associated with A. fumigatus. In addition, A. flavus produces aflatoxins, the most toxic and potent hepatocarcinogenic natural compounds ever characterized. Accurate species identification within Aspergillus flavus complex remains difficult due to overlapping morphological and biochemical characteristics, and much taxonomic and population genetics work is necessary to better understand the species and related species. The flavus complex currently includes 23 species or varieties, including two sexual species, Petromyces alliaceus and P. albertensis. The genome of the highly related Aspergillus oryzae is completed and available; that of A. flavus in the final stages of annotation. Our understanding of A. flavus lags far behind that of A. fumigatus. Studies of the genomics, taxonomy, population genetics, pathogenicity, allergenicity and antifungal susceptibility of A. flavus are all required.

Publication Types:
PMID: 17526826 [PubMed - indexed for MEDLINE]

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Occurrence of ochratoxin A and ochratoxigenic mycoflora in corn and corn based foods and feeds in some South American countries.

Magnoli CE, Astoreca AL, Chiacchiera SM, Dalcero AM.

Departamento de Microbiología e Inmunología, Facultad de Ciencias Exactas Físico Químicas y Naturales, Universidad Nacional de Río Cuarto, Ruta Nacional 36, km 601, Rio Cuarto, 5800, Cordoba, Argentina. cmagnoli@exa.unrc.edu.ar

Cereals and cereal- derived products constitute the base of human and animal feeding in South American countries. This review attempts to give an overview of the ochratoxin A (OTA) occurrence and potential sources of OTA contamination in those products. The environmental conditions as humidity and temperature in the colonization of the substrates by Aspergillus section Nigri isolated from corn kernels were also discussed. The available information on the ochratoxigenic mycoflora and OTA presence in corn, corn based food and feed is limited. Only few surveys have been carried out in Argentina, Ecuador and Brazil; which showed that Aspergillus niger aggregate and A. ochraceus species would be the main source of OTA. It's possible to emphasize that, the species A. carbonarius has not been isolated from these substrates and Penicillium verrucosum was isolated only from pig feeds of Argentinean samples in low percentage. Studies about the ecophysiology of ochratoxigenic fungi and OTA occurrence are in progress in Latin America to reduce the impact of this toxin in the food chain.

Publication Types:
PMID: 17390233 [PubMed - indexed for MEDLINE]

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Verruculogen associated with Aspergillus fumigatus hyphae and conidia modifies the electrophysiological properties of human nasal epithelial cells.

Khoufache K, Puel O, Loiseau N, Delaforge M, Rivollet D, Coste A, Cordonnier C, Escudier E, Botterel F, Bretagne S.

Laboratoire de Parasitologie-Mycologie, Hôpital Henri Mondor (AP-HP), Université Paris 12, and UMR BIPAR 956, Créteil, France. k_khoufache@yahoo.fr <k_khoufache@yahoo.fr>

BACKGROUND: The role of Aspergillus fumigatus mycotoxins in the colonization of the respiratory tract by conidia has not been studied extensively, even though patients at risk from invasive aspergillosis frequently exhibit respiratory epithelium damage. In a previous study, we found that filtrates of A. fumigatus cultures can specifically alter the electrophysiological properties of human nasal epithelial cells (HNEC) compared to those of non pathogenic moulds. RESULTS: We fractionated the organic phase of filtrate from 3-day old A. fumigatus cultures using high-performance liquid chromatography. The different fractions were tested for their ability to modify the electrophysiological properties of HNEC in an in vitro primary culture model.The fraction collected between 20 and 30 min mimicked the effects of the whole filtrate, i.e. decrease of transepithelial resistance and increase of potential differences, and contained secondary metabolites such as helvolic acid, fumagillin, and verruculogen. Only verruculogen (10(-8) M) had effects similar to the whole filtrate. We verified that verruculogen was produced by a collection of 67 human, animal, plant and environmental A. fumigatus isolates. Using MS-MS analysis, we found that verruculogen was associated with both mycelium and conidia extracts. CONCLUSION: Verruculogen is a secondary metabolite that modifies the electrophysiological properties of HNEC. The role of these modifications in the colonization and invasion of the respiratory epithelium by A. fumigatus on first contact with the epithelium remains to be determined.

Publication Types:
PMID: 17244350 [PubMed - indexed for MEDLINE]

PMCID: PMC1797047


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Gliotoxin from Aspergillus fumigatus affects phagocytosis and the organization of the actin cytoskeleton by distinct signalling pathways in human neutrophils.

Coméra C, André K, Laffitte J, Collet X, Galtier P, Maridonneau-Parini I.

INRA UR 66 Laboratoire de Pharmacologie et Toxicologie, 180 chemin de Tournefeuille, 31931 Toulouse Cedex 9, France. christine.comera@toulouse.inserm.fr

Gliotoxin is a mycotoxin having a considerable number of immuno-suppressive actions and is produced by several moulds such as Aspergillus fumigatus. In this study, we investigated its toxic effects on human neutrophils at concentrations corresponding to those found in the blood of patients with invasive aspergillosis. Incubation of the cells for 10min with 30-100ng/ml of gliotoxin inhibited phagocytosis of either zymosan or serum-opsonized zymosan without affecting superoxide production or the exocytosis of specific and azurophil granules. Gliotoxin also induced a significant re-organization of the actin cytoskeleton which collapsed around the nucleus leading to cell shrinkage and the disappearance of filopodia. This gliotoxin-induced actin phenotype was reversed by the cAMP antagonist Rp-cAMP and mimicked by pCPT-cAMP indicating that it probably resulted from the deregulation of intracellular cAMP homeostasis as previously described for gliotoxin-induced apoptosis. By contrast, gliotoxin-induced inhibition of phagocytosis was not reversed by Rp-cAMP but by arachidonic acid, another member of a known signalling pathway affected by the toxin. This suggests that gliotoxin can affect circulating neutrophils and favour the dissemination of A. fumigatus by inhibiting phagocytosis and the consequent killing of conidia.

Publication Types:
PMID: 17196420 [PubMed - indexed for MEDLINE]

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Ergot alkaloids--biology and molecular biology.

Schardl CL, Panaccione DG, Tudzynski P.

Department of Plant Pathology, University of Kentucky, Lexington, KY 40546-0312, USA.

EA have been a major benefit, and a major detriment, to humans since early in recorded history. Their medicinal properties have been used, and continue to be used, to aid in childbirth, with new uses being found in the treatment of neurological and cardiovascular disorders. The surprisingly broad range of pharmaceutical uses for EA stems from their affinities for multiple receptors for three distinct neurotransmitters (serotonin, dopamine, and adrenaline), from the great structural diversity of natural EA, and from the application of chemical techniques that further expand that structural diversity. The dangers posed by EA to humans and their livestock stem from the ubiquity of ergot fungi (Claviceps species) as parasites of cereals, and of related grass endophytes (Epichloë, Neotyphodium, and Balansia species) that may inhabit pasture grasses and produce toxic levels of EA. Further concerns stem from saprophytic EA producers in the genera Aspergillus and Penicillium, especially A. fumigatus, an opportunistic pathogen of humans. Numerous fungal species produce EA with a wide variety of structures and properties. These alkaloids are associated with plants in the families Poaceae, Cyperaceae, and Convolvulaceae, apparently because these plants can have symbiotic fungi that produce EA. Pharmacological activities of EA relate to their specific structures. Known as potent vasoconstrictors, the ergopeptines include a lysergic acid substituent with an amide linkage to a complex cyclol-lactam ring structure generated from three amino acids. Simpler lysergyl amides and clavines are more apt to have oxytonic or psychotropic activities. One of the lysergyl amides is LSD (5), the most potent hallucinogen known. The EA biosynthetic pathway in Claviceps species has been studied extensively for many decades, and recent studies have also employed epichloës and A. fumigatus. The early pathway, shared among these fungi, begins with the action of an aromatic prenyl transferase, DMATrp synthase, which links a dimethylallyl chain to L-tryptophan. When the dmaW gene encoding DMATrp synthase was cloned and sequenced, the predicted product bore no identifiable resemblance to other known prenyl transferases. The dma W genes of Claviceps species are present in clusters of genes, several of which also have demonstrated roles in EA biosynthesis. In many other fungi, dma W homologues are identifiable in otherwise very different gene clusters. The roles of DMA Trp synthase homologues in these other fungi are probably quite variable. One of them is thought to prenylate the phenolic oxygen of L-tyrosine, and another catalyzes the unusual reverse prenylation reaction in the biosynthesis of fumigaclavine C(10), an EA characteristic of A. fumigatus. The second step of the EA pathway is N-methylation of DMATrp (12) to form 13, which is then subjected to a series of oxidation/oxygenation and reduction reactions to generate, in order, chanoclavine-I (16), agroclavine (19), and elymoclavine (6). Shunt reactions generate a wide variety of other clavines. Two epimerizations occur in this pathway: one from 12 to 16, the other from 16 to 19. Further oxidation of 6, catalyzed by the cytochrome-P450 CloA, generates lysergic acid (1). An unusual NRPS complex, lysergyl peptide synthetase (LPS), is responsible for linking 1 to three hydrophobic L-amino acids to generate the ergopeptide lactams. The LPS complex includes two polypeptides, one (LPS 2) possessing a single module for activation of 1, and the other (LPS 1) possessing three modules, each specifying one of the L-amino acids. Variations in LPS 1 sequences are associated with variations in the incorporated amino acids, leading to differences between strain chemotypes, and even multiple ergopeptines within strains. For example, C. purpurea P1 produces two distinct ergopeptines (ergotamine (4) and ergocryptine (Table I)), each of which is believed to be generated by multiple LPS 1 subunits encoded by separate, but related, genes (lpsA1 and lpsA2). The main ecological roles of EA in nature are probably to protect the fungi from consumption by vertebrate and invertebrate animals. The EA produced by plant-symbiotic fungi (such as epichloë endophytes) may protect the fungus by protecting the health and productivity of the host, which may otherwise suffer excessive grazing by animals. The EA, at levels typical of plants bearing these symbionts, can negatively affect the health of large mammals as well herbivorous insects. Some clavines have substantial anti-bacterial properties, which might protect the fungus and, in some cases, their host plants from infection. However, the fact that a large number of epichloë, and even several Claviceps species, produce no detectable EA indicates that the selection for their production is not universal. An unfortunate fact for many livestock producers is that some of the most popular forage grasses tend to possess EA-producing epichloë endophytes. Such endophytes are easily eliminated, but confer such fitness enhancements to their hosts that their presence is often preferred, despite the toxic EA. The future looks promising for continued interest in EA. Research continues into their pharmacological properties, medicinal uses, and structure-function relationships. New clavines and lysergic acid derivatives are identified regularly from new sources, such as marine animals. Also, programs are well underway to modify or replace epichloë endophytes of forage grasses in order to produce new grass cultivars that lack these toxins.

Publication Types:
PMID: 17133714 [PubMed - indexed for MEDLINE]

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Toxic micromycetes in grain raw material during its processing.

Lugauskas A, Raila A, Railiene M, Raudoniene V.

Laboratory of Biodeterioration Research, Institute of Botany, Zaliuju ezeru 49, LT-08406 Vilnius, Lithuania. lugauskas@botanika.lt

In 2003-2005 micromycetes were isolated and identified from wheat, barley, rye, buckwheat grain brought into mills or from processing enterprises. Contamination of the produced flour with micromycete propagules (cfu g(-1)), changes in micromycete diversity and abundance in the course of flour storage, preparation and baking of bread, production of groats or other food products and fodder were determined. Most attention was given to widely distributed micromycetes, known producers of toxins: Alternaria alternata, Aspergillus candidus, A. clavatus, A. flavus, A. fumigatus, A. niger, A. oryzae, A. (=Eurotium) repens, Fusarium culmorum, F. equiseti, F. graminearum, F. moniliforme, F. oxysporum, F. poae, F. sporotrichioides, Penicillium brevicompactum, P. chrysogenum, P. cyclopium, P. daleae, P. expansum, P. funiculosum, P. roqueforti, P. urticae, P. verruculosum, P. viridicatum, Phoma exiqua, Rhizomucor pusillus, Rhizopus stolonifer, Trichothecium roseum. Abilities of these micromycetes to produce secondary toxic metabolites were determined as well as possible hazard caused to people consuming the contaminated products.

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PMID: 16841886 [PubMed - indexed for MEDLINE]

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Effect of N-chlorotaurine on Aspergillus, with particular reference to destruction of secreted gliotoxin.

Reeves EP, Nagl M, O'Keeffe J, Kelly J, Kavanagh K.

Medical Mycology Unit, National Institute for Cellular Biotechnology, Department of Biology, NUI Maynooth, Co. Kildare, Ireland. emer.reeves@nuim.ie

The fungistatic and fungicidal activity of N-chlorotaurine (NCT), a long-lived oxidant produced by stimulated neutrophils, was investigated. Physiological concentrations (75-100 microM) of NCT showed clear fungicidal activity against a range of Aspergillus isolates. Moreover, killing by NCT was significantly increased in the presence of ammonium chloride, explained by the formation of monochloramine by halogenation of ammonium. One clinical isolate of Aspergillus fumigatus was characterized for the production of the immunosuppressive agent gliotoxin, and NCT was shown to cause destruction of gliotoxin, possibly via reduction of the disulphide bridge. Because of its endogenous nature and its high antifungal activity, NCT appears to be a good choice for topical treatment of Aspergillus infections, and the results of this study further substantiate its therapeutic efficacy.

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PMID: 16772419 [PubMed - indexed for MEDLINE]

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A new and rapid bioassay for the detection of gliotoxin and related epipolythiodioxopiperazines produced by fungi.

Grovel O, Kerzaon I, Petit K, Robiou Du Pont T, Pouchus YF.

S.M.A.B., Université de Nantes, Pôle Mer et Littoral - Faculté de Pharmacie, BP53508- 44035 Nantes cedex 01, France. olivier.grovel@univ-nantes.fr

Gliotoxin is an immunosuppressive cytotoxin produced by numerous environmental or pathogenic fungal species. For this reason, it is one of the mycotoxins which must be systematically searched for in samples for biological control. In this study, a new, rapid and sensitive method for detecting gliotoxin has been developed. This bioassay is based on the induction of morphological changes in cultured cells (human KB cell line) by gliotoxin. Interpretation of the assay can be carried out after 1 h of incubation, either by direct microscopic observation, or with an automated microplate-reader at 630 nm. The limit of detection is 18-20 ng of gliotoxin in the well, depending on the used observation method. A high degree of specificity of the detection is brought about by the ability of the reducing reactant dithiothreitol to inhibit the biological activities of epipolythiodioxopiperazines (ETPs), such as gliotoxin, by reducing their polysulfide bridge. The bioassay allows a rapid primary screening of samples and a semi-quantitative evaluation of the gliotoxin concentration in extracts. The method has been used to study the gliotoxin production by different fungal strains, allowing to highlight 3 strains of Aspergillus fumigatus producing gliotoxin in various extracts.

PMID: 16451813 [PubMed - indexed for MEDLINE]

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Quantification of phagocytosis of Aspergillus conidia by macrophages using a novel antibody-independent assay.

Luther K, Rohde M, Heesemann J, Ebel F.

Max-von-Pettenkofer-Institut, Ludwig-Maximilians-Universität, Pettenkofer-Strasse 9a, 80336 Munich, Germany.

The pathogenic mould Aspergillus fumigatus can cause severe infections in immunocompromised patients. Phagocytosis of inhaled conidia is an early and crucial event in the defense of A. fumigatus infections. Here we describe a novel antibody-independent assay for quantification of phagocytosis, that in this study has been applied to different Aspergillus species, but that is in principle suitable for many fungi.

Publication Types:
PMID: 16412526 [PubMed - indexed for MEDLINE]

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Mycotoxigenicity of clinical and environmental Aspergillus fumigatus and A. flavus isolates.

Kosalec I, Pepeljnjak S.

Department of Microbiology Faculty of Pharmacy and Biochemistry University of Zagreb, Zagreb, Croatia. ikosalec@pharma.hr

Clinical isolates of fifty strains of A. fumigatus and 30 strains of A. flavus from immmunocompromised patients from the hematological unit were analyzed for mycotoxin production and compared with the same number of environmental isolates (from soil, compost, and air). Only 9 (18%) strains of A. fumigatus produced gliotoxin in a mean concentration 2.22 mg mL-1 (range 0.5-5 mg mL-1). Aflatoxin B1 was detected in 7 (23%) isolates (range from 0.02 to 1.2 mg L-1) and aflatoxin G1 in one (3%) of clinical A. flavus isolates (0.12 mg L-1). In the group of environmental isolates, 11 (37%) were positive for aflatoxin B1 production (range from 0.02 to 1.2 mg L-1) and one for aflatoxin G1 (0.02 mg L-1). Bioautoantibiogram ("bioassay in situ") on TLC plates against Bacillus subtilis NCTC 8236 showed that only gliotoxin-producing strains have bactericidal activity of Rf values corresponding to gliotoxin. The secondary-metabolite profiles of clinical and environmental A. fumigatus and A. flavus isolates were homogeneous, except for gliotoxin production, which was detected only in the group of clinical isolates of A. fumigatus (18%).

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PMID: 16375826 [PubMed - indexed for MEDLINE]

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Verruculogen production in airborne and clinical isolates of Aspergillus fumigatus Fres.

Kosalec I, Klari? MS, Pepeljnjak S.

Department of Microbiology Faculty of Pharmacy and Biochemistry University of Zagreb, Zagreb, Croatia. ikosalec@pharma.hr

Among airborne aspergilli sampled in outdoor air of the Zagreb area (2002/2003), Aspergillus niger (v. Teigh.) and A. fumigatus (Fres.) were the most abundant species (20-30%), with low mean annual concentrations (0.21-1.04 CFU m-3). Higher concentrations of A. fumigatus were observed in autumn and winter (0.5-1.05 CFU m-3) than in spring and summer (0-0.4 CFU m-3). On the other hand, A. fumigatus was found to be the most frequent isolate from upper and/or lower respiratory tracts of imunocompromised patients in many studies. This species produces several mycotoxins, including the tremorgenic mycotoxin verruculogen that can be found in spores and during myceliar growth. Verruculogen production ability was tested on 30 airborne and 33 clinical isolates of A. fumigatus. In both groups, high percentage of verruculogen-producing strains was noticed (84% of airborne and 91% of clinical isolates). Verruculogen production was not significantly different in the groups of airborne isolates (0.34+/-0.16 mg mL-1), and clinical isolates (0.26+/-0.19 mg mL-1).

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PMID: 16375825 [PubMed - indexed for MEDLINE]

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Frequency and species distribution of gliotoxin-producing Aspergillus isolates recovered from patients at a tertiary-care cancer center.

Lewis RE, Wiederhold NP, Lionakis MS, Prince RA, Kontoyiannis DP.

University of Houston College of Pharmacy, Texas Medical Center Campus, 1441 Moursund St. #423, Houston, TX 77030, USA. rlewis@uh.edu

Aspergillus isolates (n = 103) collected from cancer patients were screened to determine the taxonomic distribution and quantity of gliotoxin production. Gliotoxin was detected in 93% of Aspergillus fumigatus, 75% of A. niger, 25% of A. terreus, and 4% of A. flavus cultures. Gliotoxin concentrations were highest in cultures of A. fumigatus.

PMID: 16333108 [PubMed - indexed for MEDLINE]

PMCID: PMC1317213



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