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1.
J Immunol Res ; 2021: 9742832, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34761009

RESUMEN

Chromoblastomycosis (CBM) is a neglected human disease, caused by different species of pigmented dematiaceous fungi that cause subcutaneous infections. This disease has been considered an occupational disease, occurring among people working in the field of agriculture, particularly in low-income countries. In 1914, the first case of CBM was described in Brazil, and although efforts have been made, few scientific and technological advances have been made in this area. In the field of fungi and host cell relationship, a very reduced number of antigens were characterized, but available data suggest that ectoantigens bind to the cell membrane of host cells and modulate the phagocytic, immunological, and microbicidal responses of immune cells. Furthermore, antigens cleave extracellular proteins in tissues, allowing fungi to spread. On the contrary, if phagocytic cells are able to present antigens in MHC molecules to T lymphocytes in the presence of costimulation and IL-12, a Th1 immune response will develop and a relative control of the disease will be observed. Despite knowledge of the resistance and susceptibility in CBM, up to now, no effective vaccines have been developed. In the field of chemotherapy, most patients are treated with conventional antifungal drugs, such as itraconazole and terbinafine, but these drugs exhibit limitations, considering that not all patients heal cutaneous lesions. Few advances in treatment have been made so far, but one of the most promising ones is based on the use of immunomodulators, such as imiquimod. Data about a standard treatment are missing in the medical literature; part of it is caused by the existence of a diversity of etiologic agents and clinical forms. The present review summarizes the advances made in the field of CBM related to the diversity of pathogenic species, fungi and host cell relationship, antigens, innate and acquired immunity, clinical forms of CBM, chemotherapy, and diagnosis.


Asunto(s)
Cromoblastomicosis/inmunología , Interacciones Microbiota-Huesped/inmunología , Inmunidad/inmunología , Animales , Antifúngicos/inmunología , Antígenos/inmunología , Humanos , Factores Inmunológicos/inmunología
2.
Biomolecules ; 11(8)2021 08 13.
Artículo en Inglés | MEDLINE | ID: mdl-34439875

RESUMEN

Usually caused by Candida albicans, buccal candidiasis begins with the morphological transition between yeast and hyphal cells. Over time and without the correct treatment, it can be disseminated through the bloodstream becoming a systemic infection with high mortality rates. C. albicans already shows resistance against antifungals commonly used in treatments. Therefore, the search for new drugs capable of overcoming antifungal resistance is essential. Histatin 5 (Hst5) is an antimicrobial peptide of the Histatin family, that can be found naturally in human saliva. This peptide presents high antifungal activity against C. albicans. However, Hst5 action can be decreased for interaction with enzymes and metal ions present in the oral cavity. The current work aims to bring a brief review of relevant aspects of the pathogenesis and resistance mechanisms already reported for C. albicans. In addition, are also reported here the main immune responses of the human body and the most common antifungal drugs. Finally, the most important aspects regarding Histatin 5 and the benefits of its interaction with metals are highlighted. The intention of this review is to show the promising use of Hst5 metallopeptides in the development of effective drugs.


Asunto(s)
Antifúngicos/inmunología , Candida albicans , Candidiasis , Farmacorresistencia Fúngica , Histatinas/inmunología , Saliva/inmunología , Animales , Candida albicans/inmunología , Candida albicans/fisiología , Candidiasis/tratamiento farmacológico , Candidiasis/inmunología , Humanos
3.
Sci Rep ; 11(1): 13619, 2021 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-34193926

RESUMEN

Cryptococcal meningitis is a life-threatening disease among immune compromised individuals that is caused by the opportunistic fungal pathogen Cryptococcus neoformans. Previous studies have shown that the fungus is phagocytosed by dendritic cells (DCs) and trafficked to the lysosome where it is killed by both oxidative and non-oxidative mechanisms. While certain molecules from the lysosome are known to kill or inhibit the growth of C. neoformans, the lysosome is an organelle containing many different proteins and enzymes that are designed to degrade phagocytosed material. We hypothesized that multiple lysosomal components, including cysteine proteases and antimicrobial peptides, could inhibit the growth of C. neoformans. Our study identified the contents of the DC lysosome and examined the anti-cryptococcal properties of different proteins found within the lysosome. Results showed several DC lysosomal proteins affected the growth of C. neoformans in vitro. The proteins that killed or inhibited the fungus did so in a dose-dependent manner. Furthermore, the concentration of protein needed for cryptococcal inhibition was found to be non-cytotoxic to mammalian cells. These data show that many DC lysosomal proteins have antifungal activity and have potential as immune-based therapeutics.


Asunto(s)
Antifúngicos/inmunología , Criptococosis/inmunología , Cryptococcus neoformans/inmunología , Células Dendríticas/inmunología , Lisosomas/inmunología , Proteínas/inmunología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos BALB C , Fagocitosis
4.
Eur J Immunol ; 50(11): 1712-1728, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32558930

RESUMEN

Pulmonary mucosal immune response is critical for preventing opportunistic Aspergillus fumigatus infections. Although fungus-specific CD4+ T cells in blood are described to reflect the actual host-pathogen interaction status, little is known about Aspergillus-specific pulmonary T-cell responses. Here, we exploit the domestic pig as human-relevant large animal model and introduce antigen-specific T-cell enrichment in pigs to address Aspergillus-specific T cells in the lung compared to peripheral blood. In healthy, environmentally Aspergillus-exposed pigs, the fungus-specific T cells are detectable in blood in similar frequencies as observed in healthy humans and exhibit a Th1 phenotype. Exposing pigs to 106 cfu/m3 conidia induces a long-lasting accumulation of Aspergillus-specific Th1 cells locally in the lung and also systemically. Temporary immunosuppression during Aspergillus-exposure showed a drastic reduction in the lung-infiltrating antifungal T-cell responses more than 2 weeks after abrogation of the suppressive treatment. This was reflected in blood, but to a much lesser extent. In conclusion, by using the human-relevant large animal model the pig, this study highlights that the blood clearly reflects the mucosal fungal-specific T-cell reactivity in environmentally exposed as well as experimentally exposed healthy pigs. But, immunosuppression significantly impacts the mucosal site in contrast to the initial systemic immune response.


Asunto(s)
Antifúngicos/inmunología , Aspergillus fumigatus/inmunología , Aspergillus/inmunología , Sus scrofa/inmunología , Animales , Modelos Animales de Enfermedad , Interacciones Huésped-Patógeno/inmunología , Humanos , Pulmón/inmunología , Esporas Fúngicas/inmunología , Porcinos , Células TH1/inmunología
5.
Cell Host Microbe ; 27(6): 859-862, 2020 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-32526182

RESUMEN

Nosocomial fungal infections require a robust scientific response to complement antifungal development and the implementation of infection control measures. This Commentary discusses how a parallel effort to address fungal pathogenesis and antifungal immunity, the mycobiota and colonization resistance, and risk factors is essential to reduce the toll of these infections.


Asunto(s)
Antifúngicos/inmunología , Infección Hospitalaria/microbiología , Hongos/patogenicidad , Inmunidad , Antifúngicos/uso terapéutico , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/inmunología , Humanos , Micobioma/efectos de los fármacos , Micobioma/inmunología , Micosis/microbiología , Factores de Riesgo
6.
Nat Commun ; 11(1): 1913, 2020 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-32312989

RESUMEN

The TAGAP gene locus has been linked to several infectious diseases or autoimmune diseases, including candidemia and multiple sclerosis. While previous studies have described a role of TAGAP in T cells, much less is known about its function in other cell types. Here we report that TAGAP is required for Dectin-induced anti-fungal signaling and proinflammatory cytokine production in myeloid cells. Following stimulation with Dectin ligands, TAGAP is phosphorylated by EPHB2 at tyrosine 310, which bridges proximal Dectin-induced EPHB2 activity to downstream CARD9-mediated signaling pathways. During Candida albicans infection, mice lacking TAGAP mount defective immune responses, impaired Th17 cell differentiation, and higher fungal burden. Similarly, in experimental autoimmune encephalomyelitis model of multiple sclerosis, TAGAP deficient mice develop significantly attenuated disease. In summary, we report that TAGAP plays an important role in linking Dectin-induced signaling to the promotion of effective T helper cell immune responses, during both anti-fungal host defense and autoimmunity.


Asunto(s)
Antifúngicos/inmunología , Candidiasis/inmunología , Diferenciación Celular , Proteínas Activadoras de GTPasa/química , Proteínas Activadoras de GTPasa/metabolismo , Receptor EphB2/metabolismo , Transducción de Señal/efectos de los fármacos , Células Th17/metabolismo , Animales , Antifúngicos/farmacología , Proteínas Adaptadoras de Señalización CARD/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/microbiología , Femenino , Proteínas Activadoras de GTPasa/genética , Humanos , Lectinas Tipo C/metabolismo , Masculino , Ratones Noqueados , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/inmunología , Fosforilación , Receptor EphB2/inmunología , Receptores Inmunológicos , Receptores de Reconocimiento de Patrones/metabolismo , Células Th17/inmunología
7.
PLoS One ; 14(4): e0215535, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31022215

RESUMEN

ß-(1→3)-D-Glucan is an essential component of the fungal cell wall. Mouse monoclonal antibodies (mAbs) against synthetic nona-ß-(1→3)-D-glucoside conjugated with bovine serum albumin (BSA) were generated using hybridoma technology. The affinity constants of two selected mAbs, 3G11 and 5H5, measured by a surface plasmon resonance biosensor assay using biotinylated nona-ß-(1→3)-D-glucan as the ligand, were approximately 11 nM and 1.9 nM, respectively. The glycoarray, which included a series of synthetic oligosaccharide derivatives representing ß-glucans with different lengths of oligo-ß-(1→3)-D-glucoside chains, demonstrated that linear tri-, penta- and nonaglucoside, as well as a ß-(1→6)-branched octasaccharide, were recognized by mAb 5H5. By contrast, only linear oligo-ß-(1→3)-D-glucoside chains that were not shorter than pentaglucosides (but not the branched octaglucoside) were ligands for mAb 3G11. Immunolabelling indicated that 3G11 and 5H5 interact with both yeasts and filamentous fungi, including species from Aspergillus, Candida, Penicillium genera and Saccharomyces cerevisiae, but not bacteria. Both mAbs could inhibit the germination of Aspergillus fumigatus conidia during the initial hours and demonstrated synergy with the antifungal fluconazole in killing C. albicans in vitro. In addition, mAbs 3G11 and 5H5 demonstrated protective activity in in vivo experiments, suggesting that these ß-glucan-specific mAbs could be useful in combinatorial antifungal therapy.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Antifúngicos/farmacología , Antígenos Fúngicos/inmunología , Candidiasis/tratamiento farmacológico , beta-Glucanos/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Antifúngicos/inmunología , Aspergillus fumigatus/efectos de los fármacos , Aspergillus fumigatus/inmunología , Candida albicans/efectos de los fármacos , Candida albicans/inmunología , Candidiasis/inmunología , Candidiasis/microbiología , Pared Celular/efectos de los fármacos , Pared Celular/inmunología , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Fluconazol/farmacología , Humanos , Ratones , Pruebas de Sensibilidad Microbiana , Resultado del Tratamiento
8.
Mol Immunol ; 105: 260-269, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30562646

RESUMEN

At the lung lining innate defenses protect our lungs against inhaled fungal cells that could pose a threat to our health. These defenses are comprised of mucociliary clearance, soluble effector molecules and roaming phagocytic cells, such as macrophages and neutrophils. How important each of these defenses is during fungal clearance depends on the specific fungal pathogen in question and on the stage of infection. In this study the localization and antifungal activity of the lung surfactant protein D (SP-D) was studied in an environment mimicking the lung lining. To this end Calu-3 cells were grown on an air-liquid interface allowing them to polarize and to produce mucus at their apical surface. Additionally, neutrophils were added to study their role in fungal clearance. Two fungal pathogens were used for these experiments: Candida albicans and Aspergillus fumigatus, both of clinical relevance. During fungal infection SP-D localized strongly to both fungal surfaces and stayed bound through the different stages of infection. Furthermore, SP-D decreased fungal adhesion to the epithelium and increased fungal clearance by neutrophils from the epithelial surface. These findings suggest that SP-D plays an important role at the different stages of pulmonary defense against fungal intruders.


Asunto(s)
Antifúngicos/inmunología , Aspergilosis/inmunología , Aspergillus fumigatus/inmunología , Candida albicans/inmunología , Candidiasis/inmunología , Pulmón/inmunología , Proteína D Asociada a Surfactante Pulmonar/inmunología , Mucosa Respiratoria/inmunología , Antifúngicos/química , Aspergilosis/patología , Candidiasis/patología , Línea Celular , Humanos , Pulmón/microbiología , Proteína D Asociada a Surfactante Pulmonar/química , Mucosa Respiratoria/microbiología
9.
Semin Cell Dev Biol ; 89: 78-90, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-29366628

RESUMEN

Fungal infections remain a significant global health problem in humans. Fungi infect millions of people worldwide and cause from acute superficial infections to life-threatening systemic disease to chronic illnesses. Trying to decipher the complex innate and adaptive immune mechanisms that protect humans from pathogenic fungi is therefore a key research goal that may lead to immune-based therapeutic strategies and improved patient outcomes. In this review, we summarize how the cells and molecules of the innate immune system activate the adaptive immune system to elicit long-term immunity to fungi. We present current knowledge and exciting new advances in the context of organ-specific immunity, outlining the tissue-specific tropisms for the major pathogenic fungi of humans, the antifungal functions of tissue-resident myeloid cells, and the adaptive immune responses required to protect specific organs from fungal challenge.


Asunto(s)
Inmunidad Adaptativa/inmunología , Antifúngicos/uso terapéutico , Inmunidad Innata/inmunología , Micosis/inmunología , Inmunidad Adaptativa/efectos de los fármacos , Antifúngicos/inmunología , Hongos/efectos de los fármacos , Hongos/patogenicidad , Humanos , Inmunidad Innata/efectos de los fármacos , Micosis/tratamiento farmacológico , Micosis/microbiología
10.
Nat Commun ; 8(1): 1968, 2017 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-29213074

RESUMEN

Cryptococcus neoformans is an encapsulated fungal pathogen that causes cryptococcosis, which is a major opportunistic infection in immunosuppressed individuals. Mammalian ß-galactoside-binding protein Galectin-3 (Gal-3) modulates the host innate and adaptive immunity, and plays significant roles during microbial infections including some fungal diseases. Here we show that this protein plays a role also in C. neoformans infection. We find augmented Gal-3 serum levels in human and experimental infections, as well as in spleen, lung, and brain tissues of infected mice. Gal-3-deficient mice are more susceptible to cryptococcosis than WT animals, as demonstrated by the higher fungal burden and lower animal survival. In vitro experiments show that Gal-3 inhibits fungal growth and exerts a direct lytic effect on C. neoformans extracellular vesicles (EVs). Our results indicate a direct role for Gal-3 in antifungal immunity whereby this molecule affects the outcome of C. neoformans infection by inhibiting fungal growth and reducing EV stability, which in turn could benefit the host.


Asunto(s)
Antifúngicos/inmunología , Antifúngicos/farmacología , Criptococosis/tratamiento farmacológico , Criptococosis/inmunología , Cryptococcus neoformans/efectos de los fármacos , Galectina 3/inmunología , Galectina 3/farmacología , Inmunidad Adaptativa , Animales , Cápsulas Bacterianas/efectos de los fármacos , Proteínas Sanguíneas , Encéfalo/inmunología , Criptococosis/microbiología , Cryptococcus neoformans/crecimiento & desarrollo , Cryptococcus neoformans/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Galectina 3/sangre , Galectina 3/genética , Galectinas , Expresión Génica , Humanos , Pulmón/inmunología , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Bazo/inmunología
11.
J Agric Food Chem ; 65(38): 8340-8347, 2017 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-28871788

RESUMEN

The highly conserved SGT1 (suppressor of the G2 alleles of skp1) proteins from Arabidopsis are known to contribute to plant resistance to pathogens. While SGT1 proteins respond to fungal pathogens, their antifungal activity is not reported and the mechanism for this inhibition is not well understood. Therefore, recombinant Arabidopsis SGT1 proteins were cloned, expressed, and purified to evaluate their antifungal activity, resulting in their potent inhibition of pathogen growth. Dye-labeled proteins are localized to the cytosol of Candida albicans cells without the disruption of the cell membrane. Moreover, we showed that entry of the proteins into C. albicans cells resulted in the accumulation of reactive oxygen species (ROS) and cell death via altered mitochondrial potential. Morphological changes of C. albicans cells in the presence of proteins were visualized by scanning electron microscopy. Our data suggest that AtSGT1 proteins play a critical role in plant resistance to pathogenic fungal infection and they can be classified to a new plant antifungal protein.


Asunto(s)
Antifúngicos/farmacología , Proteínas de Arabidopsis/farmacología , Arabidopsis/enzimología , Candida albicans/efectos de los fármacos , Glucosiltransferasas/farmacología , Mitocondrias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Antifúngicos/inmunología , Antifúngicos/aislamiento & purificación , Arabidopsis/genética , Arabidopsis/inmunología , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/inmunología , Proteínas de Arabidopsis/aislamiento & purificación , Candida albicans/metabolismo , Glucosiltransferasas/genética , Glucosiltransferasas/inmunología , Glucosiltransferasas/aislamiento & purificación , Mitocondrias/efectos de los fármacos , Enfermedades de las Plantas/inmunología , Enfermedades de las Plantas/microbiología
12.
J Immunol ; 199(2): 624-632, 2017 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-28566368

RESUMEN

The polysaccharide-rich fungal cell wall provides pathogen-specific targets for antifungal therapy and distinct molecular patterns that stimulate protective or detrimental host immunity. The echinocandin antifungal caspofungin inhibits synthesis of cell wall ß-1,3-glucan and is used for prophylactic therapy in immune-suppressed individuals. However, breakthrough infections with fungal pathogen Aspergillus fumigatus are associated with caspofungin prophylaxis. In this study, we report in vitro and in vivo increases in fungal surface chitin in A. fumigatus induced by caspofungin that was associated with airway eosinophil recruitment in neutropenic mice with invasive pulmonary aspergillosis (IA). More importantly, caspofungin treatment of mice with IA resulted in a pattern of increased fungal burden and severity of disease that was reversed in eosinophil-deficient mice. Additionally, the eosinophil granule proteins major basic protein and eosinophil peroxidase were more frequently detected in the bronchoalveolar lavage fluid of lung transplant patients diagnosed with IA that received caspofungin therapy when compared with azole-treated patients. Eosinophil recruitment and inhibition of fungal clearance in caspofungin-treated mice with IA required RAG1 expression and γδ T cells. These results identify an eosinophil-mediated mechanism for paradoxical caspofungin activity and support the future investigation of the potential of eosinophil or fungal chitin-targeted inhibition in the treatment of IA.


Asunto(s)
Antifúngicos/efectos adversos , Antifúngicos/farmacología , Aspergillus fumigatus/efectos de los fármacos , Quitina/metabolismo , Equinocandinas/farmacología , Eosinófilos/inmunología , Aspergilosis Pulmonar Invasiva/inmunología , Aspergilosis Pulmonar Invasiva/fisiopatología , Lipopéptidos/farmacología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Animales , Antifúngicos/inmunología , Antifúngicos/uso terapéutico , Aspergillus fumigatus/química , Aspergillus fumigatus/inmunología , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/microbiología , Caspofungina , Quitina/química , Quitina/inmunología , Equinocandinas/efectos adversos , Equinocandinas/inmunología , Equinocandinas/uso terapéutico , Eosinófilos/fisiología , Humanos , Aspergilosis Pulmonar Invasiva/tratamiento farmacológico , Aspergilosis Pulmonar Invasiva/microbiología , Lipopéptidos/efectos adversos , Lipopéptidos/inmunología , Lipopéptidos/uso terapéutico , Ratones , Linfocitos T/inmunología
13.
Biochem Biophys Res Commun ; 490(3): 746-752, 2017 08 26.
Artículo en Inglés | MEDLINE | ID: mdl-28645609

RESUMEN

Antimicrobial peptides/proteins are immune-related molecules that are widely distributed in bacteria, fungi, plants, invertebrates and higher animals. They have exhibited great potential to be developed into antimicrobial drugs. The housefly, Musca domestica, lives in a highly contaminated environment and has adapted a robust immune system against various pathogens. As an effort to search for new antimicrobial molecules in the housefly, we investigated the function of an uncharacterized gene firstly by confirming that its expression was induced by infection in M. domestica. The corresponding protein was then shown to have potent antimicrobial activity. Scanning Electron Microscopy data showed that treatment of C. albicans cells with the protein caused cell size decreasing and cell elongation. The results here suggest the protein a novel class of antimicrobial protein and provide new insights into the immunological mechanisms by which M. domestica combats invading C. albicans.


Asunto(s)
Antifúngicos/farmacología , Candida albicans/efectos de los fármacos , Moscas Domésticas/microbiología , Proteínas de Insectos/farmacología , Secuencia de Aminoácidos , Animales , Antifúngicos/química , Antifúngicos/inmunología , Antifúngicos/metabolismo , Candida albicans/inmunología , Candidiasis/tratamiento farmacológico , Candidiasis/inmunología , Clonación Molecular , Genes de Insecto , Moscas Domésticas/química , Moscas Domésticas/genética , Moscas Domésticas/inmunología , Humanos , Proteínas de Insectos/química , Proteínas de Insectos/genética , Proteínas de Insectos/inmunología
14.
Methods Mol Biol ; 1625: 113-128, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28584987

RESUMEN

The chapter reviews methods utilized for the isolation and characterization of a promising immunogen candidate, aiming at a human vaccine against paracoccidioidomycosis. Peptide P10 carries a T-CD4+ epitope and was identified as an internal sequence of the major diagnostic antigen known as gp43 glycoprotein. It successfully treated massive intratracheal infections by virulent Paracoccidioides brasiliensis in combination with chemotherapy.An introduction about the systemic mycosis was found essential to understand the various options that were considered to design prophylactic and therapeutic vaccine protocols using peptide P10.


Asunto(s)
Blastomyces/inmunología , Vacunas Fúngicas/inmunología , Paracoccidioidomicosis/inmunología , Paracoccidioidomicosis/prevención & control , Vacunas de Subunidad/inmunología , Animales , Antifúngicos/inmunología , Antígenos Fúngicos/química , Antígenos Fúngicos/inmunología , Antígenos Fúngicos/aislamiento & purificación , Citocinas/metabolismo , Modelos Animales de Enfermedad , Proteínas Fúngicas , Humanos , Inmunización , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Ratones , Paracoccidioidomicosis/tratamiento farmacológico , Péptidos/química , Péptidos/inmunología , Péptidos/aislamiento & purificación , Proteómica/métodos
15.
Biosci Biotechnol Biochem ; 81(6): 1090-1098, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28485206

RESUMEN

The inducible metabolites were analyzed in barley leaves inoculated with Bipolaris sorokiniana, the causal agent of spot blotch of barley. HPLC analysis revealed that B. sorokiniana-infected leaves accumulated 4 hydrophilic compounds. They were purified by ODS column chromatography and preparative HPLC. Spectroscopic analyses revealed that they were tyramine (1), 3-(2-aminoethyl)-3-hydroxyindolin-2-one (2), serotonin (3), and 5,5'-dihydroxy-2,4'-bitryptamine (4). Among these, 2 and 4 have not been reported as natural products. They showed antifungal activity in an assay of inhibition of B. sorokiniana conidia germination, suggesting that they play a role in the chemical defense of barley as phytoalexins. The accumulation of 1-4 was examined also in the leaves of rice and foxtail millet. Rice leaves accumulated 2, 3, and 4, whereas foxtail millet leaves accumulated 3 and 4 in response to pathogen attack, suggesting the generality of accumulation of 3 and 4 in the Poaceae species.


Asunto(s)
Antifúngicos/inmunología , Hordeum/inmunología , Enfermedades de las Plantas/inmunología , Saccharomycetales/efectos de los fármacos , Sesquiterpenos/inmunología , Esporas Fúngicas/efectos de los fármacos , Antifúngicos/metabolismo , Antifúngicos/farmacología , Cromatografía Líquida de Alta Presión , Hordeum/metabolismo , Hordeum/microbiología , Interacciones Hidrofóbicas e Hidrofílicas , Indoles/inmunología , Indoles/metabolismo , Indoles/farmacología , Oryza/inmunología , Oryza/metabolismo , Oryza/microbiología , Enfermedades de las Plantas/microbiología , Inmunidad de la Planta , Hojas de la Planta/inmunología , Hojas de la Planta/metabolismo , Hojas de la Planta/microbiología , Saccharomycetales/patogenicidad , Saccharomycetales/fisiología , Serotonina/biosíntesis , Serotonina/inmunología , Serotonina/farmacología , Sesquiterpenos/metabolismo , Sesquiterpenos/farmacología , Setaria (Planta)/inmunología , Setaria (Planta)/metabolismo , Setaria (Planta)/microbiología , Especificidad de la Especie , Esporas Fúngicas/patogenicidad , Esporas Fúngicas/fisiología , Triptaminas/biosíntesis , Triptaminas/inmunología , Triptaminas/farmacología , Tiramina/biosíntesis , Tiramina/inmunología , Tiramina/farmacología , Fitoalexinas
17.
Cell Host Microbe ; 20(6): 695-697, 2016 Dec 14.
Artículo en Inglés | MEDLINE | ID: mdl-27978429

RESUMEN

Unabated inflammation and impaired antifungal immunity underlie genetic defects in NOX-2-dependent activation of LC3-associated phagocytosis (LAP). In this issue of Cell Host & Microbe, Oikonomou et al. (2016) identify a molecular link between IFN-γ/DAPK1 signaling, the proteosomal degradation pathway, and LAP that is critical for dampening Aspergillus-triggered immunopathology.


Asunto(s)
Antifúngicos/inmunología , Aspergilosis/inmunología , Proteínas Quinasas Asociadas a Muerte Celular/metabolismo , Proteínas Quinasas Asociadas a Muerte Celular/farmacología , Inflamación/inmunología , Antiinflamatorios , Antifúngicos/efectos adversos , Aspergilosis/tratamiento farmacológico , Aspergillus/efectos de los fármacos , Aspergillus/patogenicidad , Aspergillus fumigatus/efectos de los fármacos , Aspergillus fumigatus/patogenicidad , Proteína 7 Relacionada con la Autofagia , Beclina-1 , Interferón gamma/metabolismo , Interferón gamma/farmacología , Macrófagos/microbiología , Fagocitosis/inmunología , Transducción de Señal/inmunología
18.
Infect Immun ; 84(9): 2493-504, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27324480

RESUMEN

Conventional dendritic cells (cDCs) are critical for protection against pulmonary infection with the opportunistic fungal pathogen Cryptococcus neoformans; however, the role of plasmacytoid dendritic cells (pDCs) is unknown. We show for the first time that murine pDCs have direct activity against C. neoformans via reactive oxygen species (ROS), a mechanism different from that employed to control Aspergillus fumigatus infections. The anticryptococcal activity of murine pDCs is independent of opsonization but appears to require the C-type lectin receptor Dectin-3, a receptor not previously evaluated during cryptococcal infections. Human pDCs can also inhibit cryptococcal growth by a mechanism similar to that of murine pDCs. Experimental pulmonary infection of mice with a C. neoformans strain that induces protective immunity demonstrated that recruitment of pDCs to the lungs is CXCR3 dependent. Taken together, our results show that pDCs inhibit C. neoformans growth in vitro via the production of ROS and that Dectin-3 is required for optimal growth-inhibitory activity.


Asunto(s)
Antifúngicos/inmunología , Antifúngicos/metabolismo , Cryptococcus neoformans/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Lectinas Tipo C/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Aspergilosis/inmunología , Aspergillus fumigatus/inmunología , Criptococosis/inmunología , Femenino , Humanos , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/microbiología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL
19.
J Infect Dis ; 213(8): 1289-98, 2016 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-26908736

RESUMEN

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine that plays a critical role in regulating myeloid cell host defense. In this study, we demonstrated that GM-CSF signaling plays an essential role in antifungal defense against Aspergillus fumigatus. Mice that lack the GM-CSF receptor ß chain (GM-CSFRß) developed invasive hyphal growth and exhibited impaired survival after pulmonary challenge with A. fumigatus conidia. GM-CSFRß signaling regulated the recruitment of inflammatory monocytes to infected lungs, but not the recruitment of effector neutrophils. Cell-intrinsic GM-CSFRß signaling mediated neutrophil and inflammatory monocyte antifungal activity, because lung GM-CSFRß(-/-) leukocytes exhibited impaired conidial killing compared with GM-CSFRß(+/+) counterparts in mixed bone marrow chimeric mice. GM-CSFRß(-/-) neutrophils exhibited reduced (hydrogenated) nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in vivo. Conversely, administration of recombinant GM-CSF enhanced neutrophil NADPH oxidase function, conidiacidal activity, and lung fungal clearance in A. fumigatus-challenged mice. Thus, our study illustrates the functional role of GM-CSFRß signaling on lung myeloid cell responses against inhaled A. fumigatus conidia and demonstrates a benefit for systemic GM-CSF administration.


Asunto(s)
Antifúngicos/inmunología , Aspergilosis/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Neutrófilos/inmunología , Estallido Respiratorio/inmunología , Transducción de Señal/inmunología , Animales , Aspergilosis/metabolismo , Aspergillus fumigatus/inmunología , Células Cultivadas , Citometría de Flujo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Ratones , Monocitos/inmunología , Monocitos/metabolismo , Activación Neutrófila , Neutrófilos/metabolismo , Especies Reactivas de Oxígeno/inmunología
20.
J Allergy Clin Immunol ; 136(5): 1295-301.e1-5, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26037551

RESUMEN

BACKGROUND: Peanut is one of the most hazardous sources of food allergens. Unknown allergens are still hidden in the complex lipophilic matrix. These allergens need to be discovered to allow estimation of the allergenic risk for patients with peanut allergy and to further improve diagnostic measures. OBJECTIVE: We performed detection, isolation, and characterization of novel peanut allergens from lipophilic peanut extract. METHODS: Extraction of roasted peanuts were performed under defined extraction conditions and examined by means of 2-dimensional PAGE. Subsequently, chromatographic methods were adapted to isolate low-molecular-weight components. Proteins were studied by using SDS-PAGE and immunoblotting with sera from patients with peanut allergy. For allergen identification protein sequencing, homology search and mass spectrometry were applied. Functional characterization for allergenicity was performed by using the basophil activation assay and for antimicrobial activity by using inhibition assays of different bacteria and fungi. RESULTS: IgE-reactive proteins of 12, 11, and 10 kDa were first detected after chloroform/methanol extraction in the flow through of hydrophobic interaction chromatography. The proteins were able to activate basophils of patients with peanut allergy. N-terminal sequencing and homology search in the expressed sequence tag database identified the allergens as peanut defensins, which was confirmed by using mass spectrometry. On microbial cell cultures, the peanut defensins showed inhibitory effects on the mold strains of the genera Cladosporium and Alternaria but none on bacteria. CONCLUSIONS: We identified defensins as novel peanut allergens (Ara h 12 and Ara h 13) that react in particular with IgE of patients with severe peanut allergy. Their antimicrobial activity is solely antifungal.


Asunto(s)
Alérgenos/inmunología , Arachis/inmunología , Basófilos/inmunología , Defensinas/inmunología , Hipersensibilidad al Cacahuete/inmunología , Extractos Vegetales/inmunología , Alérgenos/aislamiento & purificación , Alternaria/efectos de los fármacos , Antifúngicos/inmunología , Antifúngicos/aislamiento & purificación , Antifúngicos/farmacología , Defensinas/aislamiento & purificación , Defensinas/farmacología , Electroforesis en Gel de Poliacrilamida , Humanos , Immunoblotting , Inmunoglobulina E/metabolismo , Espectrometría de Masas , Hipersensibilidad al Cacahuete/diagnóstico , Extractos Vegetales/aislamiento & purificación , Homología de Secuencia de Aminoácido
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