Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 17 de 17
Filter
Add more filters










Publication year range
1.
Article in English | MEDLINE | ID: mdl-31818813

ABSTRACT

There are limited treatment options for immunosuppressed patients with lethal invasive fungal infections due to Fusarium and Scedosporium Manogepix (MGX; APX001A) is a novel antifungal that targets the conserved Gwt1 enzyme required for localization of glycosylphosphatidylinositol-anchored mannoproteins in fungi. We evaluated the in vitro activity of MGX and the efficacy of the prodrug fosmanogepix (APX001) in immunosuppressed murine models of hematogenously disseminated fusariosis and pulmonary scedosporiosis. The MGX minimum effective concentration (MEC) for Scedosporium isolates was 0.03 µg/ml and ranged from 0.015 to 0.03 µg/ml for Fusarium isolates. In the scedosporiosis model, treatment of mice with 78 mg/kg and 104 mg/kg of body weight fosmanogepix, along with 1-aminobenzotriazole (ABT) to enhance the serum half-life of MGX, significantly increased median survival time versus placebo from 7 days to 13 and 11 days, respectively. Furthermore, administration of 104 mg/kg fosmanogepix resulted in an ∼2-log10 reduction in lung, kidney, or brain conidial equivalents/gram tissue (CE). Similarly, in the fusariosis model, 78 mg/kg and 104 mg/kg fosmanogepix plus ABT enhanced median survival time from 7 days to 12 and 10 days, respectively. A 2- to 3-log10 reduction in kidney and brain CE was observed. In both models, reduction in tissue fungal burden was corroborated with histopathological data, with target organs showing reduced or no abscesses in fosmanogepix-treated mice. Survival and tissue clearance were comparable to a clinically relevant high dose of liposomal amphotericin B (10 to 15 mg/kg). Our data support the continued development of fosmanogepix as a first-in-class treatment for infections caused by these rare molds.


Subject(s)
Aminopyridines/pharmacology , Antifungal Agents/pharmacology , Fusariosis/drug therapy , Fusarium/drug effects , Immunocompromised Host , Invasive Fungal Infections/drug therapy , Isoxazoles/pharmacology , Scedosporium/drug effects , Aminopyridines/blood , Aminopyridines/pharmacokinetics , Animals , Antifungal Agents/blood , Antifungal Agents/pharmacokinetics , Biological Availability , Brain/drug effects , Brain/immunology , Brain/microbiology , Drug Administration Schedule , Drug Combinations , Fusariosis/immunology , Fusariosis/microbiology , Fusariosis/mortality , Fusarium/growth & development , Fusarium/immunology , Half-Life , Humans , Invasive Fungal Infections/immunology , Invasive Fungal Infections/microbiology , Invasive Fungal Infections/mortality , Isoxazoles/blood , Isoxazoles/pharmacokinetics , Kidney/drug effects , Kidney/immunology , Kidney/microbiology , Lung/drug effects , Lung/immunology , Lung/microbiology , Male , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Prodrugs , Scedosporium/growth & development , Scedosporium/immunology , Survival Analysis , Triazoles/pharmacology
2.
Cell Microbiol ; 20(8): e12847, 2018 08.
Article in English | MEDLINE | ID: mdl-29582549

ABSTRACT

Lomentospora (Scedosporium) prolificans is an opportunistic pathogen capable of causing invasive infections in immunocompromised patients. The fungus is able to disseminate via the bloodstream finally arriving at the central nervous system producing neurological symptoms and, in many cases, patient death. In this context, microglial cells, which are the resident immune cells in the central nervous system, may play an important role in these infections. However, this aspect of anti-L. prolificans immunity has been poorly researched to date. Thus, the interactions and activity of microglial cells against L. prolificans were analysed, and the results show that there was a remarkable impairment in their performance regarding phagocytosis, the development of oxidative burst, and in the production of pro-inflammatory cytokines, compared with macrophages. Interestingly, L. prolificans displays great growth also when challenged with immune cells, even when inside them. We also proved that microglial phagocytosis of the fungus is highly dependent on mannose receptor and especially on dectin-1. Taken together, these data provide evidence for an impaired microglial response against L. prolificans and contribute to understanding the pathobiology of its neurotropism.


Subject(s)
Host-Pathogen Interactions , Immune Evasion , Microglia/immunology , Microglia/microbiology , Scedosporium/immunology , Scedosporium/pathogenicity , Animals , Cells, Cultured , Cytokines/metabolism , Macrophages/immunology , Macrophages/microbiology , Mice , Phagocytosis , Respiratory Burst , Scedosporium/growth & development
3.
Mycopathologia ; 183(1): 227-239, 2018 Feb.
Article in English | MEDLINE | ID: mdl-28639066

ABSTRACT

The airways of patients with cystic fibrosis (CF) are frequently colonized by various filamentous fungi, mainly Aspergillus fumigatus and Scedosporium species. To establish within the respiratory tract and cause an infection, these opportunistic fungi express pathogenic factors allowing adherence to the host tissues, uptake of extracellular iron, or evasion to the host immune response. During the colonization process, inhaled conidia and the subsequent hyphae are exposed to reactive oxygen species (ROS) and reactive nitrogen species (RNS) released by phagocytic cells, which cause in the fungal cells an oxidative stress and a nitrosative stress, respectively. To cope with these constraints, fungal pathogens have developed various mechanisms that protect the fungus against ROS and RNS, including enzymatic antioxidant systems. In this review, we summarize the different works performed on ROS- and RNS-detoxifying enzymes in fungi commonly encountered in the airways of CF patients and highlight their role in pathogenesis of the airway colonization or respiratory infections. The potential of these enzymes as serodiagnostic tools is also emphasized. In addition, taking advantage of the recent availability of the whole genome sequence of S. apiospermum, we identified the various genes encoding ROS- and RNS-detoxifying enzymes, which pave the way for future investigations on the role of these enzymes in pathogenesis of these emerging species since they may constitute new therapeutics targets.


Subject(s)
Enzymes/metabolism , Host-Pathogen Interactions , Immune Evasion , Lung Diseases, Fungal/microbiology , Oxidative Stress , Scedosporium/enzymology , Scedosporium/pathogenicity , Cystic Fibrosis/complications , Humans , Reactive Nitrogen Species/metabolism , Reactive Oxygen Species/metabolism , Scedosporium/immunology , Scedosporium/metabolism
4.
Proteomics Clin Appl ; 10(9-10): 1058-1067, 2016 10.
Article in English | MEDLINE | ID: mdl-27485921

ABSTRACT

PURPOSE: The study of the immunocompetent airways immune response may provide important information to improve the therapeutic efficacy against Lomentospora (Scedosporium) prolificans. So, this study aimed to identify the most prevalent conidial antigens of this multiresistant fungus recognized by healthy human salivary immunoglobulin A, and to study their expression and cross-reactivity with other fungal species. EXPERIMENTAL DESIGN: Twenty saliva from immunocompetent donors were used to detect and identify the immunoreactive proteins by 2D immunoblotting and LC-MS/MS. Moreover, anti-Aspergillus antibodies were purified to study their cross-reactivity. RESULTS: Ten proteins of L. prolificans conidia showed reactivity with more than 50% of the saliva samples. Among them, cyclophilin and enolase were the most prevalent antigens recognized by 85 and 80% of the samples, respectively. These enzymes were also identified on the cell wall surface of L. prolificans and on the immunomes of Scedosporium apiospermum and Scedosporium aurantiacum. Additionally, they showed cross-reactivity with the most common pathogenic filamentous fungus Aspergillus fumigatus. CONCLUSION AND CLINICAL RELEVANCE: These results show that the immunocompetent immune response might offer a pan-fungal recognition of conserved antigens such as enolase and cyclophilins, making them potential candidates for study as therapeutic targets.


Subject(s)
Aspergillus fumigatus/immunology , Cross Reactions , Cyclophilins/immunology , Immunoglobulin A/immunology , Phosphopyruvate Hydratase/immunology , Saliva/immunology , Scedosporium/immunology , Antigens, Fungal/immunology , Antigens, Fungal/metabolism , Cyclophilins/metabolism , Healthy Volunteers , Humans , Phosphopyruvate Hydratase/metabolism , Protein Transport , Scedosporium/metabolism , Spores, Fungal/immunology
5.
Med Mycol ; 54(8): 846-55, 2016 Nov 01.
Article in English | MEDLINE | ID: mdl-27343286

ABSTRACT

In this study, we analyzed the impact of immunization with the peptidorhamnomannan (PRM) from the cell wall of the fungus Scedosporium (Lomentospora) prolificans in a murine model of invasive scedosporiosis. Immunization with PRM decreased the survival of mice infected with S. prolificans. Immunization of mice with PRM led to decreased secretion of pro-inflammatory cytokines and chemokines but did not affect the secretion of IL-10. Mice immunized with PRM showed an increase in IgG1 secretion, which is an immunoglobulin linked to a nonprotective response. Splenocytes isolated from mice infected with S. prolificans and immunized with PRM showed no differences in the percentages of Th17 cells and no increase in the frequency of the CD4(+)CD62L(Low) T cell population. PRM-immunized mice showed a significant increase in the percentage of Treg cells. In summary, our results indicated that immunization with PRM did not assist or improve the immunological response against S. prolificans infection. PRM exacerbated the infection process by reducing the inflammatory response, thereby facilitating colonization, virulence and dissemination by the fungus.


Subject(s)
Glycoproteins/metabolism , Immunosuppressive Agents/metabolism , Mycoses/microbiology , Mycoses/pathology , Scedosporium/growth & development , Scedosporium/immunology , Animals , Disease Models, Animal , Female , Fungal Vaccines/administration & dosage , Fungal Vaccines/immunology , Immunoglobulin G/blood , Mice, Inbred BALB C , T-Lymphocytes, Regulatory/immunology
6.
Environ Microbiol ; 17(4): 1023-38, 2015 Apr.
Article in English | MEDLINE | ID: mdl-24684242

ABSTRACT

The dematiaceous (melanized) fungus Scedosporium prolificans is an emerging and frequently fatal pathogen of immunocompromised humans and which, along with the closely related fungi Pseudallescheria boydii, Scedosporium apiospermum and S. aurantiacum in the Pseudallescheria-Scedosporium complex, is a contributing aetiology to tsunami lung and central nervous system infections in near-drowning victims who have aspirated water laden with spores. At present, the natural habitat of the fungus is largely unknown, and accurate detection methods are needed to identify environmental reservoirs of infectious propagules. In this study, we report the development of a monoclonal antibody (mAb) (CA4) specific to S. prolificans, which does not cross-react with closely related fungi in the Pseudallescheria-Scedosporium complex or with a wide range of mould and yeast species pathogenic to humans. Using genome sequencing of a soil isolate and targeted gene disruption of the CA4 antigen-encoding gene, we show that mAb CA4 binds to the melanin-biosynthetic enzyme tetrahydroxynaphthalene reductase. Enzyme-deficient mutants produce orange-brown or green-brown spore suspensions compared with the black spore suspension of the wild-type strain. Using mAb CA4 and a mAb (HG12) specific to the related fungi P. boydii, P. apiosperma, S. apiospermum and S. aurantiacum, we demonstrate how the mAbs can be used in combination with a semiselective isolation procedure to track these opportunistic pathogens in environmental samples containing mixed populations of human pathogenic fungi. Specificity of mAb CA4 was confirmed by sequencing of the internally transcribed spacer 1 (ITS1)-5.8S-ITS2 rRNA-encoding regions of fungi isolated from estuarine muds.


Subject(s)
Antibodies, Monoclonal/immunology , Fungal Proteins/immunology , Oxidoreductases Acting on CH-CH Group Donors/immunology , Scedosporium/immunology , Scedosporium/pathogenicity , Base Sequence , Central Nervous System Infections/microbiology , Central Nervous System Infections/pathology , DNA, Intergenic/genetics , Fungal Proteins/genetics , Fungal Proteins/metabolism , Humans , Lung/microbiology , Lung/pathology , Melanins/biosynthesis , Near Drowning/microbiology , Oxidoreductases Acting on CH-CH Group Donors/genetics , Oxidoreductases Acting on CH-CH Group Donors/metabolism , Scedosporium/enzymology , Sequence Analysis, DNA , Soil Microbiology
7.
Fungal Biol ; 118(1): 94-105, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24433680

ABSTRACT

The filamentous fungus Scedosporium prolificans is an emerging multidrug resistant pathogen related to serious infections mainly affecting immunocompromised individuals. Considering that it is frequently isolated from anthropic environments and penetrates mainly through the airways, the human mucosal immune system may play an important protective role against S. prolificans. To advance in the search for biomarkers and targets both for diagnosis and treatment, we analysed the S. prolificans immunomes recognized by human salivary Immunoglobulin A. Using indirect immunofluorescence, it was observed that conidia were strongly recognized, while hyphae were not. By 2-D immunoblotting and peptide mass fingerprinting, 25 immunodominant antigens in conidia and 30 in hyphae were identified. These included catalase, putative glyceronetransferase, translation elongation factor-1α, serine/threonine protein kinase, putative superoxide dismutase, putative mitochondrial cyclophilin 1 and peptidyl-prolyl cis-trans isomerase in conidiospores, and putative Hsp60, ATP synthase ß chain, 40S ribosomal protein S0, citrate synthase and putative ATP synthase in hyphae. The functional study showed that metabolism - and protein fate - related enzymes were the most abundant antigens in conidia, whereas metabolism - , translation - , or energy production - related enzymes were in hyphae. The immunogenic proteins identified are proposed as candidates for the development of novel diagnostic tools or therapeutic strategies.


Subject(s)
Antibodies, Fungal/immunology , Antigens, Fungal/immunology , Immunoglobulin A/immunology , Saliva/immunology , Scedosporium/immunology , Fluorescent Antibody Technique, Indirect , Humans , Hyphae/immunology , Immunoblotting , Immunodominant Epitopes/immunology , Immunoelectrophoresis, Two-Dimensional , Mass Spectrometry , Spores, Fungal/immunology
8.
Curr Opin Pulm Med ; 19(6): 670-5, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24060984

ABSTRACT

PURPOSE OF REVIEW: This review summarizes some of the important recent findings concerning fungal airway infections in patients with cystic fibrosis (CF). For many years, both researchers and clinicians have focused on the problems in CF caused by chronic bacterial airway infection with organisms such as Haemophilus, Staphylococcus and Pseudomonas. However, until recently, the lack of sensitive culture techniques to isolate fungi in sputum, bronchoalveolar lavage fluid and other respiratory tract samples has limited the recognition of fungal species and their possible role in CF airway infections. RECENT FINDINGS: Recent studies using fungal-selective culture media and molecular techniques have shown a plethora of different fungal species in the sputum expectorated from CF patients. Cross-sectional studies have shown associations between Aspergillus and Candida in the sputum and worse lung function. The presence of allergic bronchopulmonary aspergillosis is likely to be a negative prognostic factor, but whether simple fungal colonization itself indicates future problems is not clear. Current research is now examining these epidemiological associations to try to determine the clinical implications. This will help determine whether fungal colonization/infection is associated with worse outcome in CF patients. SUMMARY: At present, there is no conclusive evidence that fungal organisms cause respiratory decline. Recent studies of antifungal therapy in CF patients have reported differing results, so further investigations in this area are needed.


Subject(s)
Antibodies, Fungal/isolation & purification , Antifungal Agents/therapeutic use , Aspergillosis/microbiology , Bronchoalveolar Lavage Fluid/microbiology , Candidiasis/microbiology , Cystic Fibrosis/microbiology , Sputum/microbiology , Aspergillosis/drug therapy , Aspergillosis/physiopathology , Aspergillus/immunology , Aspergillus/isolation & purification , Aspergillus fumigatus/isolation & purification , Candida/immunology , Candida/isolation & purification , Candidiasis/drug therapy , Candidiasis/physiopathology , Cystic Fibrosis/drug therapy , Cystic Fibrosis/physiopathology , DNA, Fungal , Female , Humans , Itraconazole/therapeutic use , Male , Pyrimidines/therapeutic use , Scedosporium/immunology , Scedosporium/isolation & purification , Triazoles/therapeutic use , Vital Capacity , Voriconazole
9.
Carbohydr Res ; 356: 260-4, 2012 Jul 15.
Article in English | MEDLINE | ID: mdl-22507831

ABSTRACT

Pseudallescheria boydii is an opportunistic fungus widespread in the environment, and has recently emerged as an agent of localized as well as disseminated infections in both immunocompromised and immunocompetent hosts. The host response to fungi is in part dependent on the activation of evolutionary conserved receptors including Toll-like receptors and phagocytic receptors. This review will discuss the isolation and structural characterization of α-glucans and rhamnomannans from P. boydii cell wall and their roles in the induction of innate immune response.


Subject(s)
Glucans/metabolism , Mannans/metabolism , Pseudallescheria/chemistry , Scedosporium/chemistry , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 4/metabolism , Cell Wall/chemistry , Cell Wall/immunology , Glucans/chemistry , Glucans/isolation & purification , Humans , Immunity, Innate , Macrophages/immunology , Macrophages/metabolism , Mannans/chemistry , Mannans/isolation & purification , Monocytes/immunology , Monocytes/metabolism , Mycoses/immunology , Mycoses/microbiology , Pseudallescheria/immunology , Scedosporium/immunology , Toll-Like Receptor 2/immunology , Toll-Like Receptor 4/immunology
10.
Med Mycol ; 48 Suppl 1: S22-31, 2010 Nov.
Article in English | MEDLINE | ID: mdl-21067326

ABSTRACT

Filamentous fungi especially Aspergillus spp. and Scedosporium spp. can colonize the lungs of cystic fibrosis (CF) patients. Persistent infection by these organisms may cause deterioration of lung function, mycetomas or local invasive disease. Although CF patients exert an excessive inflammatory response to inhaled bacteria, very little is known about the local innate immune response to filamentous fungi. In this paper, we review the innate immune response of respiratory tract of healthy individuals to filamentous fungi with some inference to CF patients and link the latter to existing data. We also report some preliminary findings on the in vitro antifungal responses of human phagocytes against Aspergillus spp. isolated from CF patients. Translation of these in vitro findings to appropriate in vivo systems and into clinical trials of immunomodulatory treatments may lead to improved strategies for appropriate innate host defenses in CF patients persistently infected with filamentous fungi.


Subject(s)
Aspergillus/immunology , Cystic Fibrosis/microbiology , Lung Diseases, Fungal/immunology , Phagocytes/immunology , Scedosporium/immunology , Cystic Fibrosis/immunology , Fungi/classification , Fungi/immunology , Humans , Immunity, Innate , Lung Diseases, Fungal/microbiology
11.
PLoS Negl Trop Dis ; 4(10): e853, 2010 Oct 19.
Article in English | MEDLINE | ID: mdl-20976055

ABSTRACT

Scedosporium apiospermum is part of the Pseudallescheria-Scedosporium complex. Peptidorhamnomannans (PRMs) are cell wall glycopeptides present in some fungi, and their structures have been characterized in S. apiospermum, S. prolificans and Sporothrix schenckii. Prior work shows that PRMs can interact with host cells and that the glycopeptides are antigenic. In the present study, three monoclonal antibodies (mAbs, IgG1) to S. apiospermum derived PRM were generated and their effects on S. apiospermum were examined in vitro and in vivo. The mAbs recognized a carbohydrate epitope on PRM. In culture, addition of the PRM mAbs increased S. apiospermum conidia germination and reduced conidial phagocytosis by J774.16 macrophages. In a murine infection model, mice treated with antibodies to PRM died prior to control animals. Thus, PRM is involved in morphogenesis and the binding of this glycopeptide by mAbs enhanced the virulence of the fungus. Further insights into the effects of these glycopeptides on the pathobiology of S. apiospermum may lead to new avenues for preventing and treating scedosporiosis.


Subject(s)
Antibodies, Fungal/immunology , Antibodies, Monoclonal/immunology , Antibody-Dependent Enhancement , Glycoproteins/immunology , Mycoses/microbiology , Mycoses/mortality , Scedosporium/pathogenicity , Animals , Antibodies, Fungal/isolation & purification , Antibodies, Monoclonal/isolation & purification , Cell Line , Disease Models, Animal , Epitopes/immunology , Female , Macrophages/microbiology , Mice , Mice, Inbred BALB C , Mycoses/immunology , Phagocytosis , Scedosporium/growth & development , Scedosporium/immunology , Survival Analysis
12.
Med Mycol ; 47(4): 433-40, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19184770

ABSTRACT

Scedosporium apiospermum and Scedosporium prolificans cause therapy-refractory infections in immunocompromised and immunocompetent hosts. While innate immune response is believed to be critical for the host defense against these fungi, its role has only recently been elucidated. Undefined pathogen-associated molecular patterns on the surface of conidia and hyphae are recognized by pattern-recognition receptors (PRRs) on the membrane of phagocytes, and the signal is transmitted intracellularly. PRRs that are important in the recognition of both fungal species are human Toll-like receptors (or Toll receptors in Drosophila melanogaster) and dectin-1. These induce signals responsible for the activation of genes leading to an effective host defense, especially those encoding pro-inflammatory cytokines. Both species are efficiently phagocytosed and elicit an oxidative burst by neutrophils and monocytes. While cytokines, such as interleukin-15, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor and interferon-gamma, have been found in vitro to variably modulate antifungal activity of human phagocytes, cytokines in vivo activities are less well documented. Certain antifungal agents exert immunopharmacological effects on phagocytes against S. apiospermum and S. prolificans. Translation of these in vitro findings to appropriate in vivo systems and into clinical trials may lead to improved strategies for augmenting innate host defenses in patients infected with these emerging pathogens.


Subject(s)
Mycoses/immunology , Mycoses/microbiology , Scedosporium/immunology , Cytokines/immunology , Humans , Immunity, Innate , Phagocytes/immunology
13.
Int J Biol Macromol ; 42(2): 93-102, 2008 Mar 01.
Article in English | MEDLINE | ID: mdl-17996291

ABSTRACT

Isolated from the mycelium of Scedosporium prolificans were complex glycoproteins (RMP-Sp), with three structurally related components (HPSEC). RMP-Sp contained 35% protein and 62% carbohydrate with Rha, Ara, Man, Gal, Glc, and GlcNH(2) in a 18:1:24:8:6:5 molar ratio. Methylation analysis showed mainly nonreducing end- of Galp (13%), nonreducing end- (9%), 2-O- (13%), and 3-O-subst. Rhap (7%), nonreducing end- (11%), 2-O- (10%), 3-O- (14%), and 2,6-di-O-subst. Manp units (13%). Mild reductive beta-elimination of RMP-Sp gave alpha-l-Rhap-(1-->2)-alpha-l-Rhap-(1-->3)-alpha-l-Rhap-(1-->3)-alpha-d-Manp-(1-->2)-d-Man-ol, with Man-ol substituted at O-6 with beta-d-Galp units, a related pentasaccharide lacking beta-d-Galp units, and beta-d-Galp-(1-->6)-[alpha-d-Manp-(1-->2)]-d-Man-ol in a 16:3:1w/w ratio. Traces of Man-ol and Rha-ol were detected. ESI-MS showed HexHex-ol and Hex(3-6)Hex-ol components. Three rhamnosyl units were peeled off successively from the penta- and hexasaccharide by ESI-MS-MS. The carbohydrate epitopes of RMP-Sp differ from those of the glycoprotein of Pseudallescheria boydii, a related opportunistic pathogen.


Subject(s)
Epitopes/chemistry , Epitopes/immunology , Glycoproteins/chemistry , Glycoproteins/immunology , Scedosporium/immunology , Scedosporium/pathogenicity , Carbohydrate Sequence , Magnetic Resonance Spectroscopy , Oligosaccharides/chemistry , Scedosporium/chemistry , Spectrometry, Mass, Electrospray Ionization
14.
Med Mycol ; 43(3): 253-60, 2005 May.
Article in English | MEDLINE | ID: mdl-16010852

ABSTRACT

While Aspergillus spp. have been the most frequent filamentous fungi causing infections in immunocompromised patients, Scedosporium spp. are emerging as life-threatening pathogens. We studied the effects of interferon gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF) alone or combined on the antifungal activities of human polymorphonuclear leukocytes (PMN) against Scedosporium apiospermum and Scedosporium prolificans. We paralleled these activities to those against Aspergillus fumigatus and Aspergillus flavus. Incubation of PMN with IFN-gamma and GM-CSF for 22 h enhanced PMN-induced hyphal damage of both Aspergillus spp. and S. prolificans (p < 0.05) but not of S. apiospermum. However, hyphae of S. apiospermum were damaged significantly more after incubation with PMN that had been treated with IFN-gamma and GM-CSF for 2 h. In addition, incubation of PMN with GM-CSF for 2 h enhanced PMN oxidative burst measured as superoxide anion (O2-) production in response to nonopsonized hyphae of A. flavus and Scedosporium spp. (p < 0.05). In contrast, after 2 h, IFN-gamma and GM-CSF alone did not enhance PMN O2- in response to opsonized hyphae of A. flavus and Scedosporium spp.; however, the combination of IFN-gamma and GM-CSF showed significant enhancement against these species. Thus, IFN-gamma and GM-CSF, particularly in combination, demonstrate a species- and time-dependent augmentation of PMN responses to Scedosporium spp.


Subject(s)
Aspergillus flavus/immunology , Aspergillus fumigatus/immunology , Cytotoxicity, Immunologic , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Interferon-gamma/pharmacology , Neutrophils/immunology , Scedosporium/immunology , Cytotoxicity, Immunologic/drug effects , Drug Synergism , Humans , Hyphae/immunology , Neutrophils/metabolism , Respiratory Burst/drug effects , Species Specificity , Time Factors
15.
Cytokine ; 31(1): 1-8, 2005 Jul 07.
Article in English | MEDLINE | ID: mdl-15935692

ABSTRACT

Fusarium spp. and Scedosporium spp. have emerged as important fungal pathogens that are frequently resistant to antifungal compounds. We investigated the effects of human interleukin-15 (IL-15) on human polymorphonuclear leukocyte (PMNL) activity against Fusarium solani and Fusarium oxysporum as well as Scedosporium prolificans and Scedosporium apiospermum. IL-15 (100 ng/ml) significantly enhanced PMNL-induced hyphal damage of both Fusarium spp. and S. prolificans after incubation for 22 h (P < 0.01) but not S. apiospermum. In addition, IL-15 enhanced PMNL oxidative respiratory burst evaluated as superoxide anion production in response to S. prolificans but not to the other fungi after 2 h incubation. IL-15 increased interleukin-8 (IL-8) release from PMNLs challenged with hyphae of F. solani and S. prolificans (P< or = 0.04). Release of tumor necrosis factor-alpha was not affected. The species-dependent enhancement of hyphal damage and induction of IL-8 release suggest that IL-15 plays an important role in the immunomodulation of host response to these emerging fungal pathogens.


Subject(s)
Fusarium/immunology , Interleukin-15/pharmacology , Neutrophils/drug effects , Neutrophils/immunology , Scedosporium/immunology , Humans , Hyphae/metabolism , Interleukin-8/metabolism , Superoxides/metabolism , Tumor Necrosis Factor-alpha/metabolism
16.
Infect Immun ; 71(11): 6472-8, 2003 Nov.
Article in English | MEDLINE | ID: mdl-14573669

ABSTRACT

Scedosporium apiospermum (Pseudallescheria boydii) is an emerging opportunistic filamentous fungus that causes serious infections in both immunocompetent and immunocompromised patients. To gain insight into the immunopathogenesis of infections due to S. apiospermum, the antifungal activities of human polymorphonuclear leukocytes (PMNs), mononuclear leukocytes (MNCs), and monocyte-derived macrophages (MDMs) against two clinical isolates of S. apiospermum were evaluated. Isolate SA54A was amphotericin B resistant and was the cause of a fatal disseminated infection. Isolate SA1216 (cultured from a successfully treated localized subcutaneous infection) was susceptible to amphotericin B. MDMs exhibited similar phagocytic activities against conidia of both isolates. However, PMNs and MNCs responded differently to the hyphae of these two isolates. Serum opsonization of hyphae resulted in a higher level of superoxide anion (O(2)(-)) release by PMNs in response to SA54A (amphotericin B resistant) than that seen in response to SA1216 (amphotericin B susceptible; P < 0.001). Despite this increased O(2)(-) production, PMNs and MNCs induced less hyphal damage to SA54A than to SA1216 (P < 0.001). To investigate the potential mechanisms responsible for these differences, hyphal damage was evaluated in the presence of antifungal oxidative metabolites as well as in the presence of a series of inhibitors and scavengers of antifungal PMN function. Mannose, catalase, superoxide dismutase, dimethyl sulfoxide, and heparin had no effect on PMN-induced hyphal damage to either of the two isolates. However, azide, which inhibits PMN myeloperoxidase activity, significantly reduced hyphal damage to SA1216 (P < 0.01) but not to SA54A. Hyphae of SA1216 were slightly more susceptible to oxidative pathway products, particularly HOCl, than those of SA54A. Thus, S. apiospermum is susceptible to antifungal phagocytic function to various degrees. The selective inhibitory pattern of azide with respect to hyphal damage and the parallel susceptibility to HOCl suggests an important difference in susceptibilities to myeloperoxidase products that may be related to the various levels of pathogenicity and amphotericin B resistance of S. apiospermum.


Subject(s)
Phagocytes/immunology , Scedosporium/immunology , Adult , Amphotericin B/pharmacology , Catalase/physiology , Humans , Hydrogen Peroxide/pharmacology , Hyphae/immunology , Hypochlorous Acid/pharmacology , Leukocytes, Mononuclear/immunology , Neutrophils/immunology , Peroxidase/physiology , Phagocytosis , Respiratory Burst , Scedosporium/drug effects , Scedosporium/metabolism , Superoxides/metabolism
17.
Antimicrob Agents Chemother ; 46(7): 2234-7, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12069979

ABSTRACT

Scedosporium prolificans and Scedosporium apiospermum (Pseudallescheria boydii) cause pulmonary and disseminated infections refractory to most currently used antifungal agents in immunocompromised patients. We therefore investigated the potential antifungal activities of the triazoles itraconazole (ITC), voriconazole (VRC), and posaconazole (PSC) in combination with human polymorphonuclear leukocytes (PMNs) against the hyphae of these fungal pathogens. A colorimetric assay with (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]2H-tetrazolium-5-carboxanilide) sodium salt was used for the measurement of hyphal damage as an indicator of antifungal activity. We found that the newer triazoles VRC and PSC displayed synergistic effects with PMNs against S. prolificans hyphae after 24 h (P < 0.05), whereas the effect of ITC in combination with PMNs was additive (P < 0.01). All three triazoles displayed additive antifungal activities in combination with PMNs against S. apiospermum hyphae (P < 0.05). The synergistic or additive effects that these triazoles exhibited, combined with the antifungal activities of human PMNs, may have important therapeutic implications for the management of infections due to S. prolificans and S. apiospermum.


Subject(s)
Antifungal Agents/pharmacology , Hyphae/drug effects , Neutrophils/immunology , Scedosporium/drug effects , Adult , Humans , Itraconazole/pharmacology , Pyrimidines/pharmacology , Scedosporium/immunology , Triazoles/pharmacology , Voriconazole
SELECTION OF CITATIONS
SEARCH DETAIL
...