Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.301
Filtrar
1.
Mycopathologia ; 189(4): 49, 2024 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-38864956

RESUMEN

Aspergillosis encompasses a wide range of clinical conditions based on the interaction between Aspergillus and the host. It ranges from colonization to invasive aspergillosis. The human lung provides an entry door for Aspergillus. Aspergillus has virulence characteristics such as conidia, rapid growth at body temperature, and the production of specific proteins, carbohydrates, and secondary metabolites that allow A. fumigatus to infiltrate the lung's alveoli and cause invasive aspergillosis. Alveolar epithelial cells play an important role in both fungus clearance and immune cell recruitment via cytokine release. Although the innate immune system quickly clears conidia in immunocompetent hosts, A. fumigatus has evolved multiple virulence factors in order to escape immune response such as ROS detoxifying enzymes, the rodlet layer, DHN-melanin and toxins. Bacterial co-infections or interactions can alter the immune response, impact Aspergillus growth and virulence, enhance biofilm formation, confound diagnosis, and reduce treatment efficacy. The gut microbiome's makeup influences pulmonary immune responses generated by A. fumigatus infection and vice versa. The real-time PCR for Aspergillus DNA detection might be a particularly useful tool to diagnose pulmonary aspergillosis. Metagenomics analyses allow quick and easy detection and identification of a great variety of fungi in different clinical samples, although optimization is still required particularly for the use of NGS techniques. This review will analyze the current state of aspergillosis in light of recent discoveries in the microbiota and mycobiota.


Asunto(s)
Aspergilosis , Micobioma , Humanos , Aspergilosis/microbiología , Aspergilosis/diagnóstico , Aspergilosis/inmunología , Aspergillus fumigatus/patogenicidad , Aspergillus fumigatus/genética , Aspergillus fumigatus/inmunología , Aspergillus/genética , Aspergillus/patogenicidad , Factores de Virulencia/genética , Microbiota , Virulencia , Metagenómica , Interacciones Huésped-Patógeno/inmunología
2.
J Int Med Res ; 52(5): 3000605241239857, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38757522

RESUMEN

Fungal orbital cellulitis is usually seen in immunocompromised individuals, and opportunistic pathogens are the main etiology. We herein report a case of fungal orbital cellulitis due to Aspergillus in a patient with no history of trauma. A 48-year-old man presented to the emergency room of our hospital with a 2-week history of periorbital swelling, conjunctival hyperemia, and chemosis of his right eye. The visual acuity of his right eye was 6/20, and the intraocular pressure was 44 mmHg. The main clinical findings were proptosis of the right ocular globe with conjunctival hyperemia and a palpable infratemporal orbital mass. Laboratory testing failed to detect the presence of a pathogenic infection, and the lesions on computed tomography images resembled those of a malignant tumor of the orbit. The diagnosis was finally confirmed by postoperative pathological examination, and the patient responded favorably to debridement combined with antifungal therapy. Histopathological examination may help to reveal the nature of this disease. Surgical removal of inflammatory lesions can serve as an important diagnostic and treatment method for fungal orbital cellulitis.


Asunto(s)
Antifúngicos , Aspergilosis , Huésped Inmunocomprometido , Tomografía Computarizada por Rayos X , Humanos , Masculino , Persona de Mediana Edad , Aspergilosis/diagnóstico , Aspergilosis/complicaciones , Aspergilosis/microbiología , Aspergilosis/inmunología , Antifúngicos/uso terapéutico , Celulitis Orbitaria/microbiología , Celulitis Orbitaria/diagnóstico , Desbridamiento , Infecciones Fúngicas del Ojo/diagnóstico , Infecciones Fúngicas del Ojo/microbiología
3.
Invest Ophthalmol Vis Sci ; 65(4): 44, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38687493

RESUMEN

Purpose: Fungal endophthalmitis is characterized by chronic inflammation leading to the partial or complete vision loss. Herein, we analyzed the transcriptomic landscape of Aspergillus flavus (A. flavus) endophthalmitis in C57BL/6 mice to understand the host-pathogen interactions. Methods: Endophthalmitis was induced by intravitreal injection of A. flavus spores in C57BL/6 mice and monitored for disease progression up to 72 hours. The enucleated eyeballs were subjected to histopathological analysis and mRNA sequencing using the Illumina Nextseq 2000. Pathway enrichment analysis was performed to further annotate the functions of differentially expressed genes (DEGs) and validation of cytokines was performed in vitreous of patients with fungal endophthalmitis using multiplex ELISA. Results: Transcriptomic landscape of A. flavus endophthalmitis revealed upregulated T-cell receptor signaling, PI3K-AKT, MAPK, NF-κB, JAK-STAT, and NOD like receptor signaling pathways. We observed significant increase in the T-cells during infection especially at 72 hours infection along with elevated expression levels of IL-6, IL-10, IL-12, IL-18, IL-19, IL-23, CCR3, and CCR7. Furthermore, host-immune response associated genes, such as T-cell interacting activating receptor, TNF receptor-associated factor 1, TLR1, TLR9, and bradykinin receptor beta 1, were enriched. Histopathological assessment validated the significant increase in inflammatory cells, especially T-cells at 72 hours post-infection along with increased disruption in the retinal architecture. Additionally, IL-6, IL-8, IL-17, TNF-α, and IL-1ß were also significantly elevated, whereas IL-10 was downregulated in vitreous of patients with Aspergillus endophthalmitis. Conclusions: Regulating T-cell influx could be a potential strategy to modulate the excessive inflammation in the retina and potentially aid in better vision recovery in fungal endophthalmitis.


Asunto(s)
Inmunidad Adaptativa , Aspergilosis , Aspergillus flavus , Citocinas , Modelos Animales de Enfermedad , Endoftalmitis , Infecciones Fúngicas del Ojo , Perfilación de la Expresión Génica , Inmunidad Innata , Ratones Endogámicos C57BL , Animales , Aspergillus flavus/genética , Ratones , Infecciones Fúngicas del Ojo/microbiología , Infecciones Fúngicas del Ojo/genética , Infecciones Fúngicas del Ojo/inmunología , Endoftalmitis/microbiología , Endoftalmitis/inmunología , Endoftalmitis/genética , Aspergilosis/microbiología , Aspergilosis/genética , Aspergilosis/inmunología , Inmunidad Adaptativa/genética , Inmunidad Innata/genética , Citocinas/metabolismo , Citocinas/genética , Transcriptoma , Ensayo de Inmunoadsorción Enzimática , Cuerpo Vítreo/microbiología
4.
Int Immunopharmacol ; 132: 112046, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38593508

RESUMEN

PURPOSE: To investigate the potential treatment of formononetin (FMN) on Aspergillus fumigatus (A. fumigatus) keratitis with anti-inflammatory and antifungal activity. METHODS: The effects of FMN on mice with A. fumigatus keratitis were evaluated through keratitis clinical scores, hematoxylin-eosin (HE) staining, and plate counts. The expression of pro-inflammatory factors was measured using RT-PCR, ELISA, or Western blot. The distribution of macrophages and neutrophils was explored by immunofluorescence staining. The antifungal properties of FMN were assessed through minimum inhibitory concentration (MIC), propidium iodide (PI) staining, fungal spore adhesion, and biofilm formation assay. RESULTS: In A. fumigatus keratitis mice, FMN decreased the keratitis clinical scores, macrophages and neutrophils migration, and the expression of TNF-α, IL-6, and IL-1ß. In A. fumigatus-stimulated human corneal epithelial cells (HCECs), FMN reduced the expression of IL-6, TNF-α, IL-1ß, and NLRP3. FMN also decreased the expression of thymic stromal lymphopoietin (TSLP) and thymic stromal lymphopoietin receptor (TSLPR). Moreover, FMN reduced the levels of reactive oxygen species (ROS) induced by A. fumigatus in HCECs. Furthermore, FMN inhibited A. fumigatus growth, prevented spore adhesion and disrupted fungal biofilm formation in vitro. In vivo, FMN treatment reduced the fungal load in mice cornea at 3 days post infection (p.i.). CONCLUSION: FMN demonstrated anti-inflammatory and antifungal properties, and exhibited a protective effect on mouse A. fumigatus keratitis.


Asunto(s)
Antiinflamatorios , Aspergilosis , Aspergillus fumigatus , Isoflavonas , Queratitis , Animales , Aspergillus fumigatus/efectos de los fármacos , Queratitis/tratamiento farmacológico , Queratitis/microbiología , Queratitis/inmunología , Aspergilosis/tratamiento farmacológico , Aspergilosis/inmunología , Isoflavonas/farmacología , Isoflavonas/uso terapéutico , Humanos , Ratones , Antiinflamatorios/uso terapéutico , Antiinflamatorios/farmacología , Citocinas/metabolismo , Antifúngicos/uso terapéutico , Antifúngicos/farmacología , Neutrófilos/inmunología , Neutrófilos/efectos de los fármacos , Modelos Animales de Enfermedad , Especies Reactivas de Oxígeno/metabolismo , Femenino , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Biopelículas/efectos de los fármacos , Ratones Endogámicos C57BL , Córnea/patología , Córnea/efectos de los fármacos , Córnea/microbiología
6.
Immunohorizons ; 6(1): 78-89, 2022 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-35064029

RESUMEN

Aspergillus fumigatus is an opportunistic fungal pathogen that causes a wide spectrum of diseases in humans, including life-threatening invasive infections as well as several hypersensitivity respiratory disorders. Disease prevention is predicated on the host's ability to clear A. fumigatus from the lung while also limiting inflammation and preventing allergic responses. IL-27 is an important immunoregulatory cytokine, but its role during A. fumigatus infection remains poorly understood. In contrast to most infection settings demonstrating that IL-27 is anti-inflammatory, in this study we report that this cytokine plays a proinflammatory role in mice repeatedly infected with A. fumigatus We found that mice exposed to A. fumigatus had significantly enhanced secretion of IL-27 in their lungs. Genetic ablation of IL-27Rα in mice resulted in significantly higher fungal burdens in the lung during infection. The increased fungal growth in IL-27Rα-/- mice was associated with reduced secretion of IL-12, TNF-α, and IFN-γ, diminished T-bet expression, as well as a reduction in CD4+ T cells and their activation in the lung, demonstrating that IL-27 signaling promotes Th1 immune responses during repeated exposure to A. fumigatus In addition, infected IL-27Rα-/- mice displayed reduced accumulation of dendritic cells and exudate macrophages in their lungs, and these cells had a lower expression of MHC class II. Collectively, this study suggests that IL-27 drives type 1 immunity and is indispensable for inhibiting fungal growth in the lungs of mice repeatedly exposed to A. fumigatus, highlighting a protective role for this cytokine during fungal infection.


Asunto(s)
Aspergilosis/inmunología , Interleucinas/metabolismo , Pulmón/patología , Células TH1/inmunología , Animales , Aspergilosis/microbiología , Aspergilosis/patología , Aspergillus fumigatus/inmunología , Modelos Animales de Enfermedad , Interleucinas/genética , Pulmón/inmunología , Pulmón/microbiología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal
7.
J Immunol ; 208(3): 732-744, 2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-34996839

RESUMEN

Eosinophils are potent innate effector cells associated mainly with type 2 immune responses elicited by helminths and allergens. Their activity needs to be tightly controlled to prevent severe inflammation and tissue damage. Eosinophil degranulation and secretion of inflammatory effector molecules, including cytokines, chemokines, and lipid mediators, can be regulated by activating and inhibitory receptors on the cell surface. In this study, we investigated the modulation of proliferation, apoptosis, gene expression, and cytokine/chemokine secretion from IL-33-activated Mus musculus eosinophils on cross-linking of the transmembrane receptor Sialic acid-binding Ig-like lectin F (Siglec-F). Siglec-F contains an ITIM plus an ITIM-like motif in its intracellular tail and is mainly regarded as an inhibitory and apoptosis-inducing receptor. In vitro costimulation of bone marrow-derived eosinophils with anti-Siglec-F and IL-33 compared with treatment with either alone led to enhanced STAT6 phosphorylation, stronger induction of hypoxia/glycolysis-related proinflammatory genes, and elevated secretion of type 2 cytokines (IL-4, IL-13) and chemokines (CCL3, CCL4) with only minor effects on proliferation and apoptosis. Using a competitive mixed bone marrow chimera approach with wild-type and Siglec-F-deficient eosinophils, we observed no evidence for Siglec-F-regulated inhibition of Aspergillus fumigatus-elicited lung eosinophilia. Truncation of the Siglec-F cytoplasmic tail, but not mutation of the ITIM and ITIM-like motifs, ablated the effect of enhanced cytokine/chemokine secretion. This provides evidence for an ITIM phosphorylation-independent signaling pathway from the cytoplasmic tail of the Siglec-F receptor that enhances effector molecule release from activated eosinophils.


Asunto(s)
Aspergilosis/inmunología , Eosinofilia/inmunología , Eosinófilos/inmunología , Interleucina-33/metabolismo , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/metabolismo , Animales , Apoptosis/inmunología , Aspergilosis/patología , Aspergillus fumigatus/inmunología , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Células Cultivadas , Quimiocina CCL3/metabolismo , Quimiocina CCL4/metabolismo , Humanos , Interleucina-13/metabolismo , Interleucina-33/inmunología , Interleucina-4/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Factor de Transcripción STAT6/metabolismo , Lectinas Similares a la Inmunoglobulina de Unión a Ácido Siálico/genética
8.
Int Immunopharmacol ; 102: 108401, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34883353

RESUMEN

PURPOSE: Disulfiram, an inhibitor of gasdermin D-induced pore formation, is known to suppress interleukin (IL)-1ß secretion and pyroptosis. However, its effects on fungal keratitis remain unknown. Therefore, we investigated the role of disulfiram in Aspergillus fumigatus keratitis. METHODS: In vitro, Cell Count Kit-8 (CCK8) assay and cell scratch test were performed to determine optimal concentration. In vivo and in vitro experiments were conducted in a mouse model, human neutrophils, and mouse peritoneal macrophages. We pre-treated the mice or cells with disulfiram and infected them with A. fumigatus at specific times. We subsequently evaluated the development of fungal keratitis lesions, the recruitment of inflammatory cells, and the production of inflammatory cytokines using slit lamp microscopy, clinical evaluation, quantitative reverse transcription polymerase chain reaction, immunofluorescence staining, enzyme-linked immunosorbent assay, and western blotting. We also used slit lamp microscopy and clinical evaluation to assess the effect of natamycin with or without disulfiram. RESULTS: Disulfiram at 20 µM has no significant cytotoxic effect and does not affect cell migration. In the mouse model, disulfiram significantly suppressed inflammatory responses, reduced neutrophil and macrophage recruitment, and down-regulated myeloperoxidase and nitric oxide synthase levels at earlier stages of infection. Disulfiram had no effect on IL-1ß production and maturation, but it inhibited IL-1ß secretion in macrophages. Disulfiram combined with natamycin significantly increased corneal transparency in the mice model. CONCLUSION: Overall, disulfiram reduced the host immune response in fungal keratitis by attenuating neutrophil and macrophage recruitment and inhibiting IL-1ß secretion in macrophages. Disulfiram in combination with antifungal agents may serve as a novel therapeutic method for reducing corneal opacity in fungal keratitis.


Asunto(s)
Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergillus fumigatus/efectos de los fármacos , Disulfiram/uso terapéutico , Inflamación/inmunología , Interleucina-1beta/metabolismo , Queratitis/tratamiento farmacológico , Animales , Aspergilosis/inmunología , Aspergilosis/microbiología , Aspergillus fumigatus/inmunología , Femenino , Técnica del Anticuerpo Fluorescente , Inflamación/microbiología , Queratitis/inmunología , Queratitis/microbiología , Ratones , Ratones Endogámicos C57BL
9.
Front Immunol ; 12: 785883, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34868070

RESUMEN

The ubiquitous mold Aspergillus fumigatus is the major etiologic agent of invasive aspergillosis, a life-threatening infection amongst immune compromised individuals. An increasing body of evidence indicates that effective disposal of A. fumigatus requires the coordinate action of both cellular and humoral components of the innate immune system. Early recognition of the fungal pathogen, in particular, is mediated by a set of diverse soluble pattern recognition molecules (PRMs) that act as "ancestral antibodies" inasmuch as they are endowed with opsonic, pro-phagocytic and killing properties. Pivotal is, in this respect, the contribution of the complement system, which functionally cooperates with cell-borne pattern recognition receptors (PRRs) and other soluble PRMs, including pentraxins. Indeed, complement and pentraxins form an integrated system with crosstalk, synergism, and regulation, which stands as a paradigm of the interplay between PRMs in the mounting and orchestration of antifungal immunity. Following upon our past experience with the long pentraxin PTX3, a well-established immune effector in the host response to A. fumigatus, we recently reported that this fungal pathogen is targeted in vitro and in vivo by the short pentraxin Serum Amyloid P component (SAP) too. Similar to PTX3, SAP promotes phagocytosis and disposal of the fungal pathogen via complement-dependent pathways. However, the two proteins exploit different mechanisms of complement activation and receptor-mediated phagocytosis, which further extends complexity and integration of the complement-pentraxin crosstalk in the immune response to A. fumigatus. Here we revisit this crosstalk in light of the emerging roles of SAP as a novel PRM with antifungal activity.


Asunto(s)
Aspergilosis/inmunología , Aspergilosis/metabolismo , Aspergillus fumigatus/inmunología , Proteína C-Reactiva/metabolismo , Activación de Complemento/inmunología , Proteínas del Sistema Complemento/inmunología , Componente Amiloide P Sérico/inmunología , Animales , Aspergilosis/microbiología , Biomarcadores , Susceptibilidad a Enfermedades/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad Innata , Componente Amiloide P Sérico/metabolismo
10.
PLoS Comput Biol ; 17(12): e1009645, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34898608

RESUMEN

Aspergillus fumigatus is an important human fungal pathogen and its conidia are constantly inhaled by humans. In immunocompromised individuals, conidia can grow out as hyphae that damage lung epithelium. The resulting invasive aspergillosis is associated with devastating mortality rates. Since infection is a race between the innate immune system and the outgrowth of A. fumigatus conidia, we use dynamic optimization to obtain insight into the recruitment and depletion of alveolar macrophages and neutrophils. Using this model, we obtain key insights into major determinants of infection outcome on host and pathogen side. On the pathogen side, we predict in silico and confirm in vitro that germination speed is an important virulence trait of fungal pathogens due to the vulnerability of conidia against host defense. On the host side, we found that epithelial cells, which have been underappreciated, play a role in fungal clearance and are potent mediators of cytokine release. Both predictions were confirmed by in vitro experiments on established cell lines as well as primary lung cells. Further, our model affirms the importance of neutrophils in invasive aspergillosis and underlines that the role of macrophages remains elusive. We expect that our model will contribute to improvement of treatment protocols by focusing on the critical components of immune response to fungi but also fungal virulence traits.


Asunto(s)
Células Epiteliales Alveolares/inmunología , Aspergilosis/inmunología , Interacciones Huésped-Patógeno/inmunología , Animales , Células Cultivadas , Biología Computacional , Femenino , Humanos , Inmunidad Innata/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Inmunológicos , Neutrófilos/inmunología , Esporas Fúngicas/inmunología
11.
mBio ; 12(6): e0282421, 2021 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-34781737

RESUMEN

The signaling pathways activated following interaction between dendritic cells (DCs) and a pathogen determine the polarization of effector T-cell and regulatory T-cell (Treg) responses to the infection. Several recent studies, mostly in the context of bacterial infections, have shown that the Wnt/ß-catenin pathway plays a major role in imparting tolerogenic features in DCs and in promotion of Treg responses. However, the significance of the Wnt/ß-catenin pathway's involvement in regulating the immune response to the fungal species is not known. Using Aspergillus fumigatus, a ubiquitous airborne opportunistic fungal species, we show here that fungi activate the Wnt/ß-catenin pathway in human DCs and are critical for mediating the immunosuppressive Treg responses. Pharmacological inhibition of this pathway in DCs led to inhibition of maturation-associated molecules and interleukin 10 (IL-10) secretion without affecting the majority of the inflammatory cytokines. Furthermore, blockade of Wnt signaling in DCs suppressed DC-mediated Treg responses in CD4+ T cells and downregulated both tumor necrosis factor alpha (TNF-α) and IL-10 responses in CD8+ T cells. Mechanistically, induction of ß-catenin pathway by A. fumigatus required C-type lectin receptors and promoted Treg polarization via the induction of programmed death-ligand 1 on DCs. Further investigation on the identity of fungal molecular patterns has revealed that the cell wall polysaccharides ß-(1, 3)-glucan and α-(1, 3)-glucan, but not chitin, possess the capacity to activate the ß-catenin pathway. Our data suggest that the Wnt/ß-catenin pathway is a potential therapeutic target to selectively suppress the Treg response and to sustain the protective Th1 response in the context of invasive aspergillosis caused by A. fumigatus. IMPORTANCE The balance between effector CD4+ T-cell and immunosuppressive regulatory T-cell (Treg) responses determines the outcome of an infectious disease. The signaling pathways that regulate human CD4+ T-effector versus Treg responses to the fungi are not completely understood. By using Aspergillus fumigatus, a ubiquitous opportunistic fungal species, we show that fungi activate the Wnt/ß-catenin pathway in human dendritic cells (DCs) that promotes Treg responses via induction of immune checkpoint molecule programmed death ligand 1 on DCs. Blockade of the Wnt/ß-catenin pathway in DCs led to the selective inhibition of Treg without affecting the Th1 response. Dissection of the identity of A. fumigatus pathogen-associated molecular patterns (PAMPs) revealed that cell wall polysaccharides exhibit selectivity in their capacity to activate the ß-catenin pathway in DCs. Our data thus provide a pointer that Wnt/ß-catenin pathway represents potential therapeutic target to selectively suppress Treg responses and to sustain protective a Th1 response against invasive fungal diseases.


Asunto(s)
Aspergilosis/inmunología , Aspergillus fumigatus/fisiología , Antígeno B7-H1/inmunología , Células Dendríticas/inmunología , Linfocitos T Reguladores/inmunología , beta Catenina/inmunología , Aspergilosis/genética , Aspergilosis/microbiología , Antígeno B7-H1/genética , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Humanos , Interleucina-10/genética , Interleucina-10/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología , Vía de Señalización Wnt , beta Catenina/genética
13.
Virulence ; 12(1): 1980-1996, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34338598

RESUMEN

Complement receptor 3 (CD11b/CD18) is an important receptor that mediates adhesion, phagocytosis and chemotaxis in various immunocytes. The conidia of the medically-important pathogenic fungus, Aspergillus fumigatus can be internalized into alveolar epithelial cells to disseminate its infection in immunocompromised host; however, the role of CR3 in this process is poorly understood. In the present study, we investigated the potential role of CR3 on A. fumigatus internalization into type II alveolar epithelial cells and its effect on host intracellular PA content induced by A. fumigatus. We found that CR3 is expressed in alveolar epithelial cells and that human serum and bronchoalveolar lavage fluid (BALF) could improve A. fumigatus conidial internalization into A549 type II alveolar epithelial cell line and mouse primary alveolar epithelial cells, which were significantly inhibited by the complement C3 quencher and CD11b-blocking antibody. Serum-opsonization of swollen conidia, but not resting conidia led to the increase of cellular phosphatidic acid (PA) in A549 cells during infection. Moreover, both conidial internalization and induced PA production were interfered by CD11b-blocking antibody and dependent on FAK activity, but not Syk in alveolar epithelial cells. Overall, our results revealed that CR3 is a critical modulator of Aspergillus fumigatus internalization into alveolar epithelial cells.


Asunto(s)
Células Epiteliales Alveolares , Aspergillus fumigatus , Antígeno CD11b/inmunología , Quinasa 1 de Adhesión Focal/inmunología , Ácidos Fosfatidicos/química , Células A549 , Células Epiteliales Alveolares/inmunología , Células Epiteliales Alveolares/microbiología , Animales , Aspergilosis/inmunología , Antígenos CD18 , Humanos , Ratones , Opsonización , Esporas Fúngicas
14.
Int J Mol Sci ; 22(16)2021 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-34445184

RESUMEN

The microbiome, i.e., the communities of microbes that inhabit the surfaces exposed to the external environment, participates in the regulation of host physiology, including the immune response against pathogens. At the same time, the immune response shapes the microbiome to regulate its composition and function. How the crosstalk between the immune system and the microbiome regulates the response to fungal infection has remained relatively unexplored. We have previously shown that strict anaerobes protect from infection with the opportunistic fungus Aspergillus fumigatus by counteracting the expansion of pathogenic Proteobacteria. By resorting to immunodeficient mouse strains, we found that the lung microbiota could compensate for the lack of B and T lymphocytes in Rag1-/- mice by skewing the composition towards an increased abundance of protective anaerobes such as Clostridia and Bacteroidota. Conversely, NSG mice, with major defects in both the innate and adaptive immune response, showed an increased susceptibility to infection associated with a low abundance of strict anaerobes and the expansion of Proteobacteria. Further exploration in a murine model of chronic granulomatous disease, a primary form of immunodeficiency characterized by defective phagocyte NADPH oxidase, confirms the association of lung unbalance between anaerobes and Proteobacteria and the susceptibility to aspergillosis. Consistent changes in the lung levels of short-chain fatty acids between the different strains support the conclusion that the immune system and the microbiota are functionally intertwined during Aspergillus infection and determine the outcome of the infection.


Asunto(s)
Aspergilosis/inmunología , Aspergillus fumigatus/inmunología , Pulmón/microbiología , Inmunidad Adaptativa , Animales , Aspergilosis/microbiología , Aspergillus fumigatus/fisiología , Ácidos Grasos Volátiles/inmunología , Interacciones Huésped-Patógeno , Inmunidad Innata , Pulmón/inmunología , Ratones , Ratones Endogámicos C57BL , Microbiota
16.
J Immunol Res ; 2021: 5538612, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34222495

RESUMEN

PURPOSE: Aspergillus fumigatus, as an opportunistic fungus, has developed a series of escape mechanisms under the host's immune response to obtain nutrients and promote fungal growth in the hostile environment. The immune escape of pathogens may be through suppressing the inflammatory response mediated by regulatory T cells (Tregs). The aim of this study was to explore whether A. fumigatus influences Gasdermin-D-dependent pyroptosis of the lung by regulating Toll-like receptor 2-mediated regulatory T cell differentiation. METHODS: Collect peripheral blood from patients with A. fumigatus. ELISA kits we used to detect the expression levels of IL-1ß, IL-6, IL-2R, and IL-10 in the serum and flow cytometry to detect the percentage of CD4+CD25+Foxp3+ Tregs in the patients' peripheral blood mononuclear cells (PBMCs). The mouse model of A. fumigatus infection was constructed by tracheal instillation. The pathological changes in the lungs of the mice were observed under a microscope. The fungal load in the lung tissue was determined by the plate colony count. ELISA kit was used to detect the lung tissue homogenate proinflammatory cytokines TNF-α, IL-6, CCL2, and VEGF. Q-PCR was used for the detection of the expression of Foxp3 and TLR2 genes in the lung. Western blot was used for the detection of the expression of TLR2, Gasdermin-D (GSDMD), IL-1α, and IL-1ß in the lung. Flow cytometry was used to detect splenic CD4+CD25+FOXP3+ Tregs. Using magnetic beads to extract CD4+ T cells from mice spleen, the effects of A. fumigatus conidia or TLR2 inhibitor (C29) to differentiate CD4+ T cells in vitro were tested. RESULTS: The expression of Foxp3 and TLR2 in the lung tissue of mice infected with A. fumigatus increased, and we observed that the proportion of Tregs in both A. fumigatus infection patients and mice was upregulated. After using the CD25 neutralizing antibody, the number of Tregs in the mice spleen was significantly reduced. However, lung damage was reduced and the ability to clear lung fungi was enhanced. We found that the Tregs in TLR2-/- mice were significantly reduced and the nonlethal dose of A. fumigatus conidia did not cause severe lung damage in TLR2-/- mice. Compared with that of wild-type mice, the fungal burden in the lung of TLR2-deficient mice was reduced and the knockout of TLR2 changed the expression of GSDMD, IL-1α, and IL-1ß in A. fumigatus. In in vitro experiments, we found that the inhibition of TLR2 can reduce Treg differentiation. CONCLUSIONS: A. fumigatus triggers CD4+CD25+FOXP3+ Treg proliferation and differentiation by activating the TLR2 pathway, which may be a potential mechanism for evading host defenses in A. fumigatus. This effect can modulate GSDMD-dependent pyroptosis and may partly involve TRL2 signaling.


Asunto(s)
Aspergilosis/inmunología , Linfocitos T Reguladores/inmunología , Receptor Toll-Like 2/metabolismo , Animales , Aspergilosis/microbiología , Aspergilosis/patología , Aspergillus fumigatus/inmunología , Diferenciación Celular/inmunología , Modelos Animales de Enfermedad , Interacciones Microbiota-Huesped/inmunología , Humanos , Evasión Inmune , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Activación de Linfocitos , Masculino , Ratones , Ratones Noqueados , Proteínas de Unión a Fosfato/metabolismo , Piroptosis/inmunología , Linfocitos T Reguladores/metabolismo , Receptor Toll-Like 2/genética
17.
Front Immunol ; 12: 675294, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34322116

RESUMEN

Aspergillus fumigatus airway infections are associated with increased rates of hospitalizations and declining lung function in patients with chronic lung disease. While the pathogenesis of invasive A. fumigatus infections is well studied, little is known about the development and progression of airway infections. Previous studies have demonstrated a critical role for the IL-1 cytokines, IL-1α and IL-1ß in enhancing pulmonary neutrophil recruitment during invasive aspergillosis. Here we use a mouse model of A. fumigatus airway infection to study the role of these IL-1 cytokines in immunocompetent mice. In the absence of IL-1 receptor signaling, mice exhibited reduced numbers of viable pulmonary neutrophils and increased levels of neutrophil apoptosis during fungal airway infection. Impaired neutrophil viability in these mice was associated with reduced pulmonary and systemic levels of G-CSF, and treatment with G-CSF restored both neutrophil viability and resistance to A. fumigatus airway infection. Taken together, these data demonstrate that IL-1 dependent G-CSF production plays a key role for host resistance to A. fumigatus airway infection through suppressing neutrophil apoptosis at the site of infection.


Asunto(s)
Aspergilosis/inmunología , Aspergillus fumigatus/patogenicidad , Pulmón/inmunología , Neutrófilos/fisiología , Aspergilosis Pulmonar/inmunología , Receptores de Interleucina-1/fisiología , Animales , Apoptosis/inmunología , Quimiocinas/metabolismo , Factor Estimulante de Colonias de Granulocitos/metabolismo , Humanos , Interleucina-1alfa , Interleucina-1beta , Pulmón/patología , Macrófagos , Ratones , Ratones Endogámicos C57BL , Infiltración Neutrófila , Neutrófilos/inmunología
18.
Invest Ophthalmol Vis Sci ; 62(9): 12, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-34236384

RESUMEN

Purpose: To determine the role of scavenger receptor expressed by endothelial cell-1 (SREC-Ⅰ) in vitro and in a mouse model of Aspergillus fumigatus keratitis. Methods: SREC-Ⅰ mRNA and protein expression were tested in both normal and A fumigatus stimulated human corneal epithelial cells (HCECs). Immunofluorescence was used to detect SREC-Ⅰ expression in human corneas with or without A fumigatus infection. HCECs were incubated with SREC-Ⅰ small interfering RNA, then the mRNA levels of LOX-1, IL-1ß, and TNF-α were detected after A fumigatus stimulation. A mouse fungal keratitis (FK) model was established and SREC-Ⅰ mRNA and protein expression were detected by RT-PCR, Western blot and immunofluorescence. The severity of FK was evaluated by clinical score. CLCX1, LOX-1, IL-1ß, and TNF-α mRNA expression levels were tested before and after anti-SREC-Ⅰ treatment. Results: SREC-Ⅰ expressed in normal and A fumigatus treated HCECs and human corneal epithelium. In vitro experiment showed that SREC-Ⅰ mRNA and protein levels were significantly increased after A fumigatus stimulation. SREC-Ⅰ small interfering RNA treatment inhibited the expressions of LOX-1, IL-1ß, and TNF-α in HCECs. The expressions of CLCX1, LOX-1, IL-1ß, and TNF-α were elevated in mice with A fumigatus keratitis, which could be decreased by SREC-Ⅰ-neutralizing antibody treatment. Conclusions: SREC-Ⅰ is a key mediator in inflammatory response induced by A fumigatus keratitis. SREC-Ⅰ blockade could be a potential therapeutic approach for FK.


Asunto(s)
Aspergilosis/genética , Aspergillus fumigatus/aislamiento & purificación , Infecciones Fúngicas del Ojo/genética , Regulación de la Expresión Génica/genética , Inmunidad Innata/genética , Queratitis/genética , ARN Mensajero/genética , Receptores Depuradores de Clase F/genética , Adulto , Aspergilosis/inmunología , Aspergilosis/microbiología , Western Blotting , Células Cultivadas , Infecciones Fúngicas del Ojo/inmunología , Infecciones Fúngicas del Ojo/microbiología , Femenino , Humanos , Queratitis/inmunología , Queratitis/microbiología , Masculino , Persona de Mediana Edad , Receptores Depuradores de Clase F/biosíntesis
19.
BMC Infect Dis ; 21(1): 537, 2021 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-34098877

RESUMEN

BACKGROUND: Invasive aspergillosis of the central nervous system is a rare but increasingly prevalent disease. We present the unusual case of an immunosuppressed patient suffering from unexpected superinfected invasive aspergillosis with cerebral, pulmonal, and adrenal manifestations, mimicking a metastasized bronchial carcinoma. This report reveals the importance of including aspergillosis in the differential diagnosis of a cerebral mass lesion in the light of unspecific clinical findings. CASE PRESENTATION: A 58-year-old immunocompromised female presented to our emergency department with a single tonic-clonic seizure. Imaging showed a ring enhancing cerebral mass with perifocal edema and evidence of two smaller additional hemorrhagic cerebral lesions. In the setting of a mass lesion in the lung, and additional nodular lesions in the left adrenal gland the diagnosis of a metastasized bronchus carcinoma was suspected and the cerebral mass resected. However, histology did not reveal any evidence for a neoplastic lesion but septate hyphae consistent with aspergillus instead and microbiological cultures confirmed concomitant staphylococcal infection. CONCLUSIONS: A high index of suspicion for aspergillus infection should be maintained in the setting of immunosuppression. Clinical and radiological findings are often unspecific and even misleading. Definite confirmation usually relies on tissue diagnosis with histochemical stains. Surgical resection is crucial for establishing the diagnosis and guiding therapy with targeted antifungal medications.


Asunto(s)
Aspergilosis/diagnóstico , Neoplasias Encefálicas/diagnóstico , Infecciones Fúngicas del Sistema Nervioso Central/diagnóstico , Sobreinfección/diagnóstico , Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Aspergilosis/inmunología , Aspergilosis/patología , Aspergillus/aislamiento & purificación , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Infecciones Fúngicas del Sistema Nervioso Central/tratamiento farmacológico , Infecciones Fúngicas del Sistema Nervioso Central/inmunología , Infecciones Fúngicas del Sistema Nervioso Central/patología , Diagnóstico Diferencial , Femenino , Humanos , Huésped Inmunocomprometido , Persona de Mediana Edad , Staphylococcus/aislamiento & purificación , Sobreinfección/tratamiento farmacológico , Sobreinfección/inmunología , Sobreinfección/patología
20.
Front Immunol ; 12: 659752, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34122417

RESUMEN

Aspergillus fumigatus causes life-threatening opportunistic infections in immunocompromised patients. As therapeutic outcomes of invasive aspergillosis (IA) are often unsatisfactory, the development of targeted immunotherapy remains an important goal. Linking the innate and adaptive immune system, dendritic cells are pivotal in anti-Aspergillus defense and have generated interest as a potential immunotherapeutic approach in IA. While monocyte-derived dendritic cells (moDCs) require ex vivo differentiation, antigen-pulsed primary myeloid dendritic cells (mDCs) may present a more immediate platform for immunotherapy. To that end, we compared the response patterns and cellular interactions of human primary mDCs and moDCs pulsed with an A. fumigatus lysate and two A. fumigatus proteins (CcpA and Shm2) in a serum-free, GMP-compliant medium. CcpA and Shm2 triggered significant upregulation of maturation markers in mDCs and, to a lesser extent, moDCs. Furthermore, both A. fumigatus proteins elicited the release of an array of key pro-inflammatory cytokines including TNF-α, IL-1ß, IL-6, IL-8, and CCL3 from both DC populations. Compared to moDCs, CcpA- and Shm2-pulsed mDCs exhibited greater expression of MHC class II antigens and stimulated stronger proliferation and IFN-γ secretion from autologous CD4+ and CD8+ T-cells. Moreover, supernatants of CcpA- and Shm2-pulsed mDCs significantly enhanced the oxidative burst in allogeneic neutrophils co-cultured with A. fumigatus germ tubes. Taken together, our in vitro data suggest that ex vivo CcpA- and Shm2-pulsed primary mDCs have the potential to be developed into an immunotherapeutic approach to tackle IA.


Asunto(s)
Aspergillus fumigatus/inmunología , Células Dendríticas/inmunología , Proteínas Fúngicas/inmunología , Activación de Linfocitos/inmunología , Estallido Respiratorio/inmunología , Linfocitos T/inmunología , Aspergilosis/inmunología , Aspergilosis/metabolismo , Aspergilosis/microbiología , Aspergillus fumigatus/metabolismo , Aspergillus fumigatus/fisiología , Diferenciación Celular/inmunología , Células Cultivadas , Citocinas/inmunología , Citocinas/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/microbiología , Antígenos de Histocompatibilidad Clase II/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Interacciones Huésped-Patógeno/inmunología , Humanos , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Monocitos/inmunología , Linfocitos T/metabolismo , Linfocitos T/microbiología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA