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1.
Nat Commun ; 12(1): 1707, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731708

RESUMO

Invasive pulmonary aspergillosis (IPA) is a life-threatening lung disease of immunocompromised humans, caused by the opportunistic fungal pathogen Aspergillus fumigatus. Inadequacies in current diagnostic procedures mean that early diagnosis of the disease, critical to patient survival, remains a major clinical challenge, and is leading to the empiric use of antifungal drugs and emergence of azole resistance. A non-invasive procedure that allows both unambiguous detection of IPA and its response to azole treatment is therefore needed. Here, we show that a humanised Aspergillus-specific monoclonal antibody, dual labelled with a radionuclide and fluorophore, can be used in immunoPET/MRI in vivo in a neutropenic mouse model and 3D light sheet fluorescence microscopy ex vivo in the infected mouse lungs to quantify early A. fumigatus lung infections and to monitor the efficacy of azole therapy. Our antibody-guided approach reveals that early drug intervention is critical to prevent complete invasion of the lungs by the fungus, and demonstrates the power of molecular imaging as a non-invasive procedure for tracking IPA in vivo.


Assuntos
Anticorpos Monoclonais Humanizados/imunologia , Antifúngicos/uso terapêutico , Aspergillus fumigatus/imunologia , Pulmão/efeitos dos fármacos , Pulmão/diagnóstico por imagem , Compostos Radiofarmacêuticos/imunologia , Animais , Anticorpos Antifúngicos/química , Anticorpos Antifúngicos/imunologia , Anticorpos Monoclonais Humanizados/química , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/patogenicidade , Azóis/uso terapêutico , Radioisótopos de Cobre/química , Monitoramento de Medicamentos , Corantes Fluorescentes/química , Humanos , Aspergilose Pulmonar Invasiva/diagnóstico por imagem , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Aspergilose Pulmonar Invasiva/microbiologia , Pulmão/microbiologia , Imagem por Ressonância Magnética , Camundongos , Microscopia de Fluorescência , Tomografia por Emissão de Pósitrons , Radioimunodetecção , Compostos Radiofarmacêuticos/química
3.
PLoS One ; 15(9): e0238855, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32976540

RESUMO

BACKGROUND: Early recognition and diagnosis of allergic bronchopulmonary aspergillosis (ABPA) is critical to improve patient symptoms, and antifungal therapy may prevent or delay progression of bronchiectasis and development of chronic pulmonary aspergillosis. OBJECTIVE: A recently commercialized lateral flow assay (Aspergillus ICT) (LDBio Diagnostics, Lyons, France) detects Aspergillus-specific antibodies in <30 minutes, requiring minimal laboratory equipment. We evaluated this assay for diagnosis of ABPA compared to diseased (asthma and/or bronchiectasis) controls. METHODS: ABPA and control sera collected at the National Aspergillosis Centre (Manchester, UK) and/or from the Manchester Allergy, Respiratory and Thoracic Surgery research biobank were evaluated using the Aspergillus ICT assay. Results were read both visually and digitally (using a lateral flow reader). Serological Aspergillus-specific IgG and IgE, and total IgE titres were measured by ImmunoCAP. RESULTS: For 106 cases of ABPA versus all diseased controls, sensitivity and specificity for the Aspergillus ICT were 90.6% and 87.2%, respectively. Sensitivity for 'proven' ABPA alone (n = 96) was 89.8%, and 94.4% for 'presumed' ABPA (n = 18). 'Asthma only' controls (no bronchiectasis) and 'bronchiectasis controls' exhibited 91.4% and 81.7% specificity, respectively. Comparison of Aspergillus ICT result with Aspergillus-specific IgG and IgE titres showed no evident immunoglobulin isotype bias. Digital measurements displayed no correlation between ImmunoCAP Aspergillus-specific IgE level and ICT test line intensity. CONCLUSIONS: The Aspergillus ICT assay exhibits good sensitivity for ABPA serological screening. It is easy to perform and interpret, using minimal equipment and resources; and provides a valuable simple screening resource to rapidly distinguish more serious respiratory conditions from Aspergillus sensitization alone.


Assuntos
Anticorpos Antifúngicos/sangue , Aspergilose Broncopulmonar Alérgica/diagnóstico , Aspergillus/imunologia , Imunoensaio/métodos , Testes Sorológicos/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antifúngicos/imunologia , Aspergilose Broncopulmonar Alérgica/epidemiologia , Aspergilose Broncopulmonar Alérgica/microbiologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Reino Unido/epidemiologia , Adulto Jovem
4.
Rhinology ; 58(2): 136-144, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31904030

RESUMO

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous disease, and its pathogenesis remains controversial. This study aimed to examine the involvement of fungi in CRSwNP pathogenesis. METHODS: We enrolled 29 controls and 111 CRSwNP patients. We analyzed fungi in the nasal secretions, serum fungus-specific immunoglobulin E (IgE) levels, and nasal polyp (NP) IgE levels. Moreover, we evaluated the correlation between patients' IgE levels and computed tomography (CT) scores. RESULTS: There was no difference in fungal detection rate between CRSwNP patients with and without asthma. Specific IgEs against various antigens were highly detectable in NPs of CRSwNP patients. In CRSwNP patients, fungus-specific IgE levels in NPs were correlated with CT scores. Serum fungus-specific IgEs became undetectable after operation in more than half of the CRSwNP patients without asthma but not in those with asthma. Other serum airborne antigen-specific IgEs did not become undetectable after operation. CONCLUSIONS: Fungus-specific IgEs were highly detectable in NPs of CRSwNP patients, and NPs comprised a major region of specific IgE production. Fungi may therefore play an important role in CRSwNP pathogenesis by inducing Th2 immune responses, including IgE synthesis.


Assuntos
Anticorpos Antifúngicos/imunologia , Imunoglobulina E/imunologia , Micoses/imunologia , Pólipos Nasais/imunologia , Rinite/imunologia , Sinusite/imunologia , Estudos de Casos e Controles , Doença Crônica , Fungos , Humanos , Micoses/complicações , Pólipos Nasais/microbiologia , Rinite/microbiologia , Sinusite/microbiologia
5.
J Pediatr Gastroenterol Nutr ; 69(6): 696-703, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31764438

RESUMO

OBJECTIVES: Crohn disease (CD) is a chronic relapsing condition possibly caused by a dysbiotic microbiome. Approximately 30% to 60% of patients with CD have anti-Saccharomyces cerevisiae antibody (ASCA), but any association with gut microbiota is unexplored. We hypothesized that ASCA positivity would predict a signature microbial status and clinical phenotype. METHODS: Ileocolonic mucosal biopsies were obtained from children with CD (n = 135), and controls without inflammatory bowel disease (n = 45). Comparison was made between ASCA status, microbial diversity, and clinical characteristics. RESULTS: ASCA was highly specific but poorly sensitive for the diagnosis of CD. In patients with CD, ASCA positivity was associated with older age (≥10 years), ileocolonic disease, and long-term risk of surgery. Microbial alpha and beta diversity were similar in patients with CD with or without ASCA, but significantly less when compared to noninflammatory bowel disease controls. Microbial richness was similar across all 3 groups. Fourteen bacterial species were associated with ASCA-positive patients with CD and 14 species with ASCA-negative patients (P < 0.05). After using a false discovery rate correction Ruminococcus torques and bacterium Yersinia enterocolitica 61 remained significantly associated with CD ASCA positivity (P = 0.0178), whereas Enterobacter cloacae and Faecalibacterium prausnitzii were significantly associated with CD ASCA negativity (P = 0.0178 and 0.0342). CONCLUSION: ASCA-positive and ASCA-negative patients with CD have significant differences in gut microbiome composition, which could possibly be influencing the phenotype of the disease.


Assuntos
Anticorpos Antifúngicos/imunologia , Doença de Crohn/microbiologia , Microbioma Gastrointestinal/imunologia , Proteínas de Saccharomyces cerevisiae/imunologia , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino
6.
Zhonghua Nei Ke Za Zhi ; 58(11): 826-828, 2019 Nov 01.
Artigo em Chinês | MEDLINE | ID: mdl-31665859

RESUMO

This study aims to explore the diagnostic value of specific immunoglobulin E (sIgE) and specific immunoglobulin G (sIgG) of Aspergillus fumigatus in the diagnosis of allergic broncho-pulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS). A total of 17 ABPA patients and 14 SAFS patients were enrolled. The levels of sIgG [2 294.00 (1 527.00, 14 170.00) U/ml vs. 972.60 (650.90, 1 792.00) U/ml] and sIgE [8.77 (1.64, 16.85) kU/L vs. 1.04 (0.70, 2.05) kU/L] in ABPA patients were significantly higher than those in SAFS patients (P<0.05). Aspergillus fumigatus sIgG was strongly correlated with Aspergillus fumigatus sIgE (r(s)=0.797, P<0.001) in ABPA patients. When combined with Aspergillus fumigatus sIgG (>1 000.00 U/mL) and Aspergillus fumigatus sIgE (>1.00 kU/L), the sensitivity was 82.3% and specificity 78.6% for the differential diagnosis of ABPA and SAFS. It demonstrates the diagnostic value of Aspergillus fumigatus sIgG and sIgE.


Assuntos
Aspergilose Broncopulmonar Alérgica/diagnóstico , Aspergillus fumigatus/isolamento & purificação , Asma/complicações , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Anticorpos Antifúngicos/imunologia , Aspergilose Broncopulmonar Alérgica/sangue , Aspergilose Broncopulmonar Alérgica/imunologia , Aspergilose Broncopulmonar Alérgica/microbiologia , Aspergillus fumigatus/imunologia , Asma/sangue , Asma/diagnóstico , Humanos , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Índice de Gravidade de Doença
7.
Sci Rep ; 9(1): 17179, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748544

RESUMO

In recent years, research has focused on the immunoreactive components of the Sporothrix schenckii cell wall that can be relevant targets for preventive and therapeutic vaccines against sporotrichosis, an emergent worldwide mycosis. In a previous study, we identified a 47-kDa enolase as an immunodominant antigen in mice vaccinated with an adjuvanted mixture of S. schenckii cell wall proteins. Here, we sought to assess the protective potential of a Sporothrix spp. recombinant enolase (rSsEno) formulated with or without the adjuvant Montanide Pet-GelA (PGA) against the S. brasiliensis infection in mice. Mice that were immunized with rSsEno plus PGA showed increased antibody titters against rSsEno and increased median survival time when challenged with S. brasiliensis as compared with mice that had not been immunized or that were immunized with rSsEno alone. Immunization with rSsEno plus PGA induced a predominantly T-helper 1 cytokine pattern after in vitro stimulation of splenic cells with rSsEno: elevated levels of IFN-γ and IL-2, as well as of other cytokines involved in host defense against sporotrichosis, such as TNF-alpha, IL-6, and IL-4. Furthermore, we show for the first time the presence of enolase in the cell wall of both S. schenckii and S. brasiliensis. As a whole, our results suggest that enolase could be used as a potential antigenic target for vaccinal purposes against sporotrichosis.


Assuntos
Anticorpos Antifúngicos/imunologia , Proteínas Fúngicas/imunologia , Imunidade Celular/imunologia , Fosfopiruvato Hidratase/imunologia , Sporothrix/enzimologia , Sporothrix/imunologia , Esporotricose/prevenção & controle , Sequência de Aminoácidos , Animais , Citocinas/metabolismo , Proteínas Fúngicas/administração & dosagem , Imunização , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosfopiruvato Hidratase/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Homologia de Sequência , Esporotricose/imunologia , Esporotricose/microbiologia
8.
Immunol Rev ; 292(1): 24-36, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31559648

RESUMO

B lymphocytes must respond to vast numbers of foreign antigens, including those of microbial pathogens. To do so, developing B cells use combinatorial joining of V-, D-, and J-gene segments to generate an extraordinarily diverse repertoire of B-cell antigen receptors (BCRs). Unsurprisingly, a large fraction of this initial BCR repertoire reacts to self-antigens, and these "forbidden" B cells are culled by immunological tolerance from mature B-cell populations. While culling of autoreactive BCRs mitigates the risk of autoimmunity, it also opens gaps in the BCR repertoire, which are exploited by pathogens that mimic the forbidden self-epitopes. Consequently, immunological tolerance, necessary for averting autoimmune disease, also acts to limit effective microbial immunity. In this brief review, we recount the evidence for the linkage of tolerance and impaired microbial immunity, consider the implications of this linkage for vaccine development, and discuss modulating tolerance as a potential strategy for strengthening humoral immune responses.


Assuntos
Anticorpos Antibacterianos/imunologia , Anticorpos Antifúngicos/imunologia , Linfócitos B/imunologia , Tolerância Imunológica/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Animais , Linfócitos B/metabolismo , Linfócitos B/microbiologia , Humanos , Imunidade Humoral/imunologia , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/imunologia
9.
Artigo em Inglês | MEDLINE | ID: mdl-31380292

RESUMO

Aspergillus fumigatus and A. flavus are the fungal pathogens responsible for most cases of invasive aspergillosis (IA). Early detection of the circulating antigen galactomannan (GM) in serum allows the prompt application of effective antifungal therapy, thus improving the survival rate of IA patients. However, the use of monoclonal antibodies (mAbs) for the diagnosis of IA is often associated with false positives due to cross-reaction with bacterial polysaccharides. More specific antibodies are therefore needed. Here we describe the characterization of the Aspergillus-specific mAb AP3 (IgG1κ), including the precise identification of its corresponding antigen. The antibody was generated using A. parasiticus cell wall fragments and was shown to bind several Aspergillus species. Immunofluorescence microscopy revealed that AP3 binds a cell wall antigen, but immunoprecipitation and enzyme-linked immunosorbent assays showed that the antigen is also secreted into the culture medium. The inability of AP3 to bind the A. fumigatus galactofuranose (Galf )-deficient mutant ΔglfA confirmed that Galf residues are part of the epitope. Several lines of evidence strongly indicated that AP3 recognizes the Galf residues of O-linked glycans on Aspergillus proteins. Glycoarray analysis revealed that AP3 recognizes oligo-[ß-D-Galf-1,5] sequences containing four or more residues with longer chains more efficiently. We also showed that AP3 captures GM in serum, suggesting it may be useful as a diagnostic tool for patients with IA.


Assuntos
Anticorpos Antifúngicos/imunologia , Anticorpos Monoclonais/imunologia , Antígenos de Fungos/imunologia , Aspergilose/imunologia , Aspergillus/imunologia , Mananas/imunologia , Animais , Antígenos de Fungos/genética , Aspergillus/genética , Aspergillus flavus/genética , Aspergillus flavus/imunologia , Aspergillus fumigatus/imunologia , Parede Celular/química , Reações Cruzadas , Modelos Animais de Doenças , Epitopos/isolamento & purificação , Feminino , Testes Imunológicos , Mananas/genética , Camundongos , Camundongos Endogâmicos BALB C , Polissacarídeos Bacterianos/imunologia , Proteínas Recombinantes
10.
Mycoses ; 62(12): 1108-1115, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31408547

RESUMO

BACKGROUND: An early diagnosis of chronic pulmonary aspergillosis (CPA) at the stage of simple aspergilloma (SA) remains a challenge in low- and middle-income countries, where imaging may not be routinely available. OBJECTIVE: We investigate the role of Aspergillus fumigatus-specific IgG in serum, and galactomannan (GM) in bronchoalveolar lavage fluid (BALF) and serum for the diagnosis of SA. METHODS: We included 46 consecutive treatment-naïve subjects with SA. The 81 controls were subjects of treated pulmonary tuberculosis with residual radiological abnormality and minimal symptoms; and subjects with pulmonary disorders other than CPA who underwent bronchoscopy. The diagnosis of SA was based on consistent clinical features along with radiological manifestations (cavity with fungal ball). RESULTS: Using receiver operating characteristic (ROC) curve analysis, the best cut-off value for A fumigatus-specific IgG was 27.3 mgA/L (AUROC, 0.839; sensitivity, 63.5%; specificity, 98.3%). The best cut-off value for serum and BALF-GM was 0.7 (AUROC, 0.636; sensitivity, 32%; specificity, 96.2%) and 2.5 (AUROC, 0.833; sensitivity, 63.7%; specificity, 97.1%), respectively. A combination of A fumigatus-specific IgG (>27 mgA/L) or serum GM (≥0.7) or BALF-GM (≥2.5) had a sensitivity and specificity of 82.6% and 96%, respectively. CONCLUSIONS: A combination of serological tests has the best sensitivity in diagnosing SA. More studies are needed to confirm our findings.


Assuntos
Anticorpos Antifúngicos/sangue , Imunoglobulina G/sangue , Mananas/imunologia , Aspergilose Pulmonar/diagnóstico , Adulto , Anticorpos Antifúngicos/imunologia , Aspergillus fumigatus , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/microbiologia , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Aspergilose Pulmonar/imunologia , Curva ROC , Sensibilidade e Especificidade , Testes Sorológicos , Tomografia Computadorizada por Raios X
11.
PLoS One ; 14(8): e0221228, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31412087

RESUMO

Early and accurate diagnosis of coccidioidomycosis, also known as Valley fever, is critical for appropriate disease treatment and management. Current serodiagnosis is based on the detection of patient serum antibodies that react with tube precipitin (TP) and complement fixation (CF) antigens of Coccidioides. IgM is the first class of antibodies produced by hosts in response to coccidioidal insults. The highly glycosylated ß-glucosidase 2 (BGL2) is a major active component of the TP antigen that stimulates IgM antibody responses during early Coccidioides infection. The predominant IgM epitope on BGL2 is a unique 3-O-methyl-mannose moiety that is not produced by commonly used protein expression systems. We genetically engineered and expressed a recombinant BGL2 (rBGL2ur), derived from Coccidioides, in non-pathogenic Uncinocarpus reesii, a fungus phylogenetically related to the Coccidioides pathogen. The rBGL2ur protein was purified from the culture medium of transformed U. reesii by nickel affinity chromatography, and the presence of 3-O-methyl mannose was demonstrated by gas chromatography. Seroreactivity of the purified rBGL2ur protein was tested by enzyme-linked immunosorbent assays using sera from 90 patients with coccidioidomycosis and 134 control individuals. The sensitivity and specificity of the assay with rBGL2ur were 78.8% and 87.3%, respectively. These results were comparable to those obtained using a proprietary MiraVista Diagnostic (MVD) IgM (63.3% sensitivity; 96.3% specificity), but significantly better than the ID-TP assay using non-concentrated patient sera (33.3% sensitivity; 100% specificity). Expression of rBGL2ur in U. reesii retains its antigenicity for coccidioidomycosis serodiagnosis and greatly reduces biosafety concerns for antigen production, as Coccidioides spp. are biological safety level 3 agents.


Assuntos
Anticorpos Antifúngicos , Antígenos de Fungos/imunologia , Coccidioides , Coccidioidomicose , Precipitinas , Saccharomycetales , Testes Sorológicos , Anticorpos Antifúngicos/química , Anticorpos Antifúngicos/imunologia , Coccidioides/química , Coccidioides/genética , Coccidioides/imunologia , Coccidioidomicose/diagnóstico , Coccidioidomicose/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Precipitinas/química , Precipitinas/imunologia , Saccharomycetales/química , Saccharomycetales/genética
12.
Future Microbiol ; 14: 867-884, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31340660

RESUMO

Aim: Cryptococcus neoformans is the major agent of cryptococcosis. The main virulence factor is the polysaccharide (PS) capsule. Changes in cryptococcal PS properties have been poorly elucidated. Materials & methods: We analyzed the mechanical properties of secreted PS and intact capsules, using dynamic light scattering and optical tweezers. Results: Storage and loss moduli showed that secreted PS behaves as a viscoelastic liquid, while capsular PS behaves as a viscoelastic solid. The secreted PS remains as a viscoelastic fluid at different temperatures with thermal hysteresis after 85°C. Antibody binding altered the viscoelastic behavior of both secreted and capsular PS. Conclusion: Deciphering the mechanical aspects of these structures could reveal features that may have consequences in novel therapies against cryptococcosis.


Assuntos
Anticorpos Antifúngicos/metabolismo , Cryptococcus neoformans/química , Polissacarídeos/fisiologia , Temperatura , Fatores de Virulência/fisiologia , Anticorpos Antifúngicos/imunologia , Cápsulas Fúngicas/química , Cápsulas Fúngicas/imunologia , Cápsulas Fúngicas/fisiologia , Pinças Ópticas , Tamanho da Partícula , Polissacarídeos/química , Polissacarídeos/imunologia , Polissacarídeos/metabolismo , Reologia , Fatores de Virulência/química , Fatores de Virulência/imunologia , Fatores de Virulência/metabolismo , Substâncias Viscoelásticas
13.
mSphere ; 4(3)2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31167944

RESUMO

Rhodotorula yeasts are pink, encapsulated basidiomycetes isolated from a variety of environments and clinical settings. They are increasingly linked with disease, particularly central venous catheter infections and meningitis, in immunocompromised patients. Eight clinical and eight environmental strains molecularly typed as Rhodotorula mucilaginosa were compared to six Cryptococcus neoformans strains for phenotypic variability. Growth on cell integrity-challenging media suggested that R. mucilaginosa cells possess differences in signaling pathways, cell wall composition, or assembly and that their membranes are more susceptible to perturbations than those of C. neoformans All 16 R. mucilaginosa strains produced urease, while none produced melanin with l-3,4-dihydroxyphenylalanine (l-DOPA) as a substrate. India ink staining reveals that clinical R. mucilaginosa capsules are larger than environmental capsules but that both are generally smaller than C. neoformans capsules. All R. mucilaginosa strains were resistant to fluconazole. Only two clinical strains were susceptible to voriconazole; all of the environmental strains were resistant. We generated an anticapsular antibody (Rh1) to R. mucilaginosa; Rh1 did not bind C. neoformans control strains, was specific to Rhodotorula species, and bound to all tested Rhodotorula strains. Binding assays performed with wheat germ agglutinin (WGA), concanavalin A (ConA), calcofluor white (CFW), and eosin Y dye (EY) cell surface probes suggested that chitin may be more accessible in R. mucilaginosa but that the total abundance of chitooligomers is less than in C. neoformans This report describes a novel reagent that can be used to identify Rhodotorula species and lays the foundation for future cell envelope composition analysis.IMPORTANCE Currently, there is very little known about the phenotypic variability within species of Rhodotorula strains and the role of their capsule. Cryptococcus neoformans has been considered the only encapsulated human fungal pathogen, but as more individuals come to live in states of immunocompromised health, they are more susceptible to fungal infections, including those by Rhodotorula R. mucilaginosa species are some of those most commonly associated with clinical infections. We wanted to know if clinical and environmental strains of R. mucilaginosa demonstrated disparate capsule phenotypes. With limited antifungal options available and clinical Rhodotorula spp. often resistant to common antifungal drugs such as fluconazole, caspofungin (1, 2), and voriconazole (2), a better understanding of the fungal biology could inform the design and use of future antifungal drugs. The generation of an antibody specific to Rhodotorula fungi could be a useful diagnostic tool, and this work presents the first mention of such in the literature.


Assuntos
Parede Celular/química , Cápsulas Fúngicas/química , Rhodotorula/química , Animais , Anticorpos Antifúngicos/imunologia , Antifúngicos/farmacologia , Parede Celular/efeitos dos fármacos , Cryptococcus neoformans/química , Cryptococcus neoformans/efeitos dos fármacos , Cápsulas Fúngicas/efeitos dos fármacos , Humanos , Melaninas , Fenótipo , Coelhos , Rhodotorula/efeitos dos fármacos , Transdução de Sinais , Urease/biossíntese
14.
Mycopathologia ; 184(3): 393-402, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31201650

RESUMO

Recently, we have reported serological cross-reactivity between paracoccidioidomycosis ceti and paracoccidioidomycosis, histoplasmosis, and coccidioidomycosis. However, data on the interaction of Arthrographis kalrae with the above pathogenic fungal infections are lacking. A. kalrae is a widely occurring ascomycetous fungus; causes superficial and deep mycoses; shows thermally dependent dimorphism; and has a genomic profile related to the above-mentioned fungal species. Our study aims to investigate cross-reactivity using eight murine sera, obtained from experimental infection with two A. kalrae isolates. The murine sera were incubated with fungal cells of A. kalrae, Coccidioides posadasii, Histoplasma capsulatum, Paracoccidioides sp., and P. brasiliensis. Thirty murine sera, obtained from experimental infection with six isolates of H. capsulatum, sera from three cases of dolphin paracoccidioidomycosis ceti, two human sera from patients with paracoccidioidomycosis, and a serum sample from a healthy person with a history of coccidioidomycosis, were also incubated with A. kalrae fungal cells and the respective fungal cells that caused the infection as positive controls. Sera derived from the mice infected with A. kalrae reacted strongly when incubated with the Paracoccidioides sp., P. brasiliensis, and C. posadasii, but no positive reaction was observed against the fungal cells of H. capsulatum. The murine sera infected with three out of six isolates of H. capsulatum, and all cetacean and human serum samples reacted positively with the fungal cells of A. kalrae. The present study demonstrated serological cross-reactions among A. kalrae infection, coccidioidomycosis, paracoccidioidomycosis, paracoccidioidomycosis ceti, and histoplasmosis.


Assuntos
Anticorpos Antifúngicos/sangue , Anticorpos Antifúngicos/imunologia , Antígenos de Fungos/imunologia , Ascomicetos/imunologia , Reações Cruzadas , Animais , Golfinhos , Humanos , Camundongos
15.
Intern Med ; 58(19): 2835-2838, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31243216

RESUMO

Allergic bronchopulmonary aspergillosis (ABPA) is an eosinophilic inflammatory condition characterized by exaggerated immune responses to the fungal genus Aspergillus. Pulmonary manifestations in patients with Crohn's disease (CD) are frequent comorbidities. A 66-year-old man with CD treated with an anti-tumor necrosis factor-α antibody presented with dyspnea. Laboratory findings of elevated blood eosinophils and total serum IgE and positive aspergillus-specific antibodies as well as imaging findings of central bronchiectasis and mucoid impaction indicated a diagnosis of ABPA. To our knowledge, this is the first report of ABPA arising in a patient with CD. We discuss the pathophysiological mechanism of this rare complication.


Assuntos
Aspergilose Broncopulmonar Alérgica/etiologia , Doença de Crohn/complicações , Pulmão/diagnóstico por imagem , Idoso , Anticorpos Antifúngicos/imunologia , Aspergilose Broncopulmonar Alérgica/diagnóstico , Aspergilose Broncopulmonar Alérgica/microbiologia , Aspergillus/imunologia , Eosinófilos/patologia , Humanos , Imunoglobulina E/imunologia , Pulmão/fisiopatologia , Masculino , Radiografia Torácica , Tomografia Computadorizada por Raios X
16.
J Immunol ; 202(10): 2945-2956, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988115

RESUMO

Imprime PGG (Imprime) is an i.v. administered, yeast ß-1,3/1,6 glucan in clinical development with checkpoint inhibitors. Imprime-mediated innate immune activation requires immune complex formation with naturally occurring IgG anti-ß glucan Abs (ABA). We administered Imprime to healthy human volunteers to assess the necessity of ABA for Imprime-mediated immunopharmacodynamic (IPD) changes. Imprime (4 mg/kg) was administered i.v. in single and multiple infusions. Subsets of subjects were premedicated with antihistamine and corticosteroid. Peripheral blood was measured before, during and after Imprime administration for IPD changes (e.g., ABA, circulating immune complexes, complement activation, complete blood counts, cytokine/chemokine, and gene expression changes). IPD changes were analyzed based on pretreatment serum ABA levels: low-ABA (<20 µg/ml), mid-ABA (≥20-50 µg/ml), and high-ABA (≥50 µg/ml). At the end of infusion, free serum ABA levels decreased, circulating immune complex levels increased, and complement activation was observed. At ∼1-4 h after end of infusion, increased expression of cytokines/chemokines, a 1.5-4-fold increase in neutrophil and monocyte counts and a broad activation of innate immune genes were observed. Low-ABA subjects typically showed minimal IPD changes except when ABA levels rose above 20 µg/ml after repeated Imprime dosing. Mild-to-moderate infusion-related reactions occurred in subjects with ABA ≥20 µg/ml. Premedications alleviated some of the infusion-related reactions, but also inhibited cytokine responses. In conclusion, ABA levels, being critical for Imprime-mediated immune activation may provide a plausible, mechanism-based biomarker to identify patients most likely to respond to Imprime-based anticancer immunotherapy.


Assuntos
Adjuvantes Imunológicos , Polissacarídeos Fúngicos , Imunoterapia , Neoplasias , Saccharomyces cerevisiae/química , beta-Glucanas , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacocinética , Anticorpos Antifúngicos/sangue , Anticorpos Antifúngicos/imunologia , Quimiocinas/sangue , Quimiocinas/imunologia , Feminino , Polissacarídeos Fúngicos/administração & dosagem , Polissacarídeos Fúngicos/química , Polissacarídeos Fúngicos/farmacocinética , Humanos , Masculino , Neoplasias/sangue , Neoplasias/imunologia , Neoplasias/terapia , beta-Glucanas/administração & dosagem , beta-Glucanas/química , beta-Glucanas/farmacocinética
17.
Br J Dermatol ; 181(4): 866-869, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30980721
18.
Sci Rep ; 9(1): 6194, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30996274

RESUMO

NDV-3A, a novel fungal vaccine undergoing clinical trials, contains a recombinant version of the Candida albicans rAls3 N-terminus protein (rAls3p-N) in aluminum hydroxide. In a Phase 1b/2a clinical trial, NDV-3A protected women from recurrent vulvovaginal candidiasis. Here, we reveal that active immunization in mice with NDV-3A induces high titers of anti-rAls3p-N antibodies that interfere with C. albicans ability to adhere to and invade endothelial cells, and form biofilm in vitro. Anti-rAls3p-N antibodies also significantly inhibit yeast dispersal from the hyphal layers of biofilms. Compared to placebo, NDV-3A vaccination inhibited C. albicans dissemination to kidneys and prevented colonization of central venous catheters in mice. Overall, these preclinical studies suggest that NDV-3A may serve as an immunotherapeutic strategy for prevention of infections on indwelling medical devices.


Assuntos
Anticorpos Antifúngicos/farmacologia , Proteínas Fúngicas/imunologia , Vacinas Fúngicas/uso terapêutico , Vacinação/métodos , Animais , Anticorpos Antifúngicos/imunologia , Biofilmes/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Candida albicans/imunologia , Adesão Celular/efeitos dos fármacos , Cateteres Venosos Centrais/microbiologia , Vacinas Fúngicas/farmacologia , Humanos , Controle de Infecções , Camundongos , Proteínas Recombinantes
19.
Autoimmunity ; 52(1): 37-47, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30884988

RESUMO

A clear correlation exists between microbiota and the dysregulation of the immune response in Inflammatory Bowel Diseases (IBD), which comprise Crohn's disease (CD) and ulcerative colitis (UC). These unbalanced reactions also involve humoral responses, with antibodies against Saccharomyces cerevisiae. Thus, here we aimed to quantify IgA and IgG specific to S. cerevisiae (ASCA) in quiescent CD and UC, to correlate the production of these antibodies with patient's inflammatory response and disease clinical presentation. Twenty-nine subjects (16 CD and 13 UC) and 45 healthy controls were enrolled in this study and had plasma samples tested for ASCA and cytokines (IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α), besides clinical evaluation. IBD patients had increase IgA and IgG ASCA, especially those with colonic (L2) and fistulizing (B3) CD. Similarly, patients who dropped out the treatment had augmented ASCA, while IgG was reduced in those receiving sulfasalazine treatment. Furthermore, the quiescent CD patients had elevated IL-6 on plasma, especially in the absence of treatment, together with increased counter regulatory response of IL-10. There was a positive correlation between IgA and IgG on CD but not UC, as well as between IgA and TNF in total IBD patients. In addition, the levels of IgG x TNF, IgA x IL-10 and IgG x IL-10 were also correlated in CD, indicating that ASCA production may be influenced by the inflammatory response. Finally, we concluded that ASCA could be pointed as relevant biomarker of CD presentation and residual inflammation, even in clinical remission patients.


Assuntos
Anticorpos Antifúngicos , Doença de Crohn , Imunoglobulina A , Imunoglobulina G , Saccharomyces cerevisiae/imunologia , Adulto , Idoso , Anticorpos Antifúngicos/sangue , Anticorpos Antifúngicos/imunologia , Doença de Crohn/sangue , Doença de Crohn/imunologia , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade
20.
Eur Ann Allergy Clin Immunol ; 51(2): 75-79, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30832470

RESUMO

Summary: Allergic bronchopulmonary mycosis (ABPM) is a clinical syndrome associated with immune sensitivity to various fungi that colonize the airways. Early diagnosis and treatment with systemic corticosteroids is the key in preventing the progression of the disease to irreversible lung fibrosis. Although Aspergillus has progressively gained recognition as a causative agent in past few decades, other fungi, that have been reported to cause ABPM, are not yet widely evaluated. We studied hundred and two patients with asthma for occurrence of ABPM. Patients were tested for cutaneous hypersensitivity and serum precipitin to 12 common fungal antigens. The positive cases were further evaluated for ABPM using standard criteria. Out of 102 asthma patients screened, 18 patients had either skin prick test (SPT) and/or serum precipitin positive. While 14 patients were SPT positive for one or more fungal antigen, two patients were serum precipitin positive for one or more fungi. Two patients had both serum precipitin positive as well as SPT positive. Six (5.8%) patients were diagnosed as ABPM as they fulfilled the criteria. Three of these were because of Aspergillus sp. Two were because of fungi other than Aspergillus namely Schizophyllum and Curvularia. One patient had ABPM because of both Aspergillus and Curvularia. In our study absolute eosinophil count (AEC), total IgE, serum precipitin and SPT had sensitivity of 100%, 100% 50% and 83.3% respectively for diagnosing ABPM. The specificity of these tests was 44.79%, 64.58% 98.96% and 88.54% respectively. Specfic IgE was positive in 50% of patients with either serum precipitin or SPT positivity. SPT or serum precipitin followed by specific IgE had sensitivity of 100% and specificity of 96.88% for diagnosing ABPM. SPT alone followed by Specific IgE had a sensitivity of 83.33% and specificity of 96.88% for diagnosing ABPM. We found that fungi other than Aspergillus such as schizophyllum, and curvularia, can be implicated in ABPM. Multiple fungal agents may be responsible for ABPM in an individual. There is a subset of patients of BA who have fungal sensitization but do not fulfil the criteria for ABPM. SPT was the single most sensitive and specific test, AEC >350 and total IgE more than 417IU were most sensitive tests and SPT followed by specific IgE was most effective strategy for diagnosing ABPM.


Assuntos
Anticorpos Antifúngicos/imunologia , Testes de Precipitina/métodos , Aspergilose Pulmonar/diagnóstico , Aspergilose Pulmonar/etiologia , Testes Cutâneos/métodos , Anticorpos Antifúngicos/sangue , Estudos Transversais , Fungos/imunologia , Humanos , Aspergilose Pulmonar/imunologia , Reprodutibilidade dos Testes , Schizophyllum/imunologia , Sensibilidade e Especificidade
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