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1.
Front Immunol ; 12: 670574, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995406

RESUMO

Neutrophils are critical as the first-line defense against fungal pathogens. Yet, previous studies indicate that neutrophil function is complex during Cryptococcus neoformans (Cn) infection. To better understand the role of neutrophils in acute pulmonary cryptococcosis, we analyzed neutrophil heterogeneity by single-cell transcriptional analysis of immune cells in the lung of Cn-infected mice from a published dataset. We identified neutrophils by reference-based annotation and identified two distinct neutrophil subsets generated during acute Cn infection: A subset with an oxidative stress signature (Ox-PMN) and another with enhanced cytokine gene expression (Cyt-PMN). Based on gene regulatory network and ligand-receptor analysis, we hypothesize that Ox-PMNs interact with the fungus and generate ROS, while Cyt-PMNs are longer-lived neutrophils that indirectly respond to Cn-derived ligands and cytokines to modulate cell-cell communication with dendritic cells and alveolar macrophages. Based on the data, we hypothesized that, during in vivo fungal infection, there is a division of labor in which each activated neutrophil becomes either Ox-PMN or Cyt-PMN.


Assuntos
Criptococose/imunologia , Pneumopatias Fúngicas/imunologia , Ativação de Neutrófilo/imunologia , Neutrófilos/imunologia , Animais , Criptococose/metabolismo , Cryptococcus neoformans/imunologia , Citocinas/imunologia , Citocinas/metabolismo , Pneumopatias Fúngicas/metabolismo , Camundongos , Estresse Oxidativo/imunologia , Espécies Reativas de Oxigênio/imunologia , Análise de Célula Única
2.
Am J Pathol ; 191(1): 108-130, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33069717

RESUMO

Pulmonary mycoses are difficult to treat and detrimental to patients. Fungal infections modulate the lung immune response, induce goblet cell hyperplasia and metaplasia, and mucus hypersecretion in the airways. Excessive mucus clogs small airways and reduces pulmonary function by decreasing oxygen exchange, leading to respiratory distress. The forkhead box protein A2 (FOXA2) is a transcription factor that regulates mucus homeostasis in the airways. However, little is known whether pulmonary mycosis modulates FOXA2 function. Herein, we investigated whether Blastomyces dermatitidis and Histoplasma capsulatum-infected canine and feline lungs and airway epithelial cells could serve as higher animal models to examine the relationships between fungal pneumonia and FOXA2-regulated airway mucus homeostasis. The results indicate that fungal infection down-regulated FOXA2 expression in airway epithelial cells, with concomitant overexpression of mucin 5AC (MUC5AC) and mucin 5B (MUC5B) mucins. Mechanistic studies reveal that B. dermatitidis infection, as well as ß-glucan exposure, activated the Dectin-1-SYK-epidermal growth factor receptor-AKT/extracellular signal-regulated kinase 1/2 signaling pathway that inhibits the expression of FOXA2, resulting in overexpression of MUC5AC and MUC5B in canine airway cells. Further understanding of the role of FOXA2 in mucus hypersecretion may lead to novel therapeutics against excessive mucus in both human and veterinary patients with pulmonary mycosis.


Assuntos
Blastomicose/metabolismo , Histoplasmose/metabolismo , Pneumopatias Fúngicas/metabolismo , Muco/metabolismo , Transdução de Sinais/fisiologia , Animais , Blastomicose/patologia , Gatos , Modelos Animais de Doenças , Cães , Receptores ErbB/metabolismo , Fator 3-beta Nuclear de Hepatócito/metabolismo , Histoplasma , Histoplasmose/patologia , Pneumopatias Fúngicas/patologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinase Syk/metabolismo
3.
mBio ; 11(1)2020 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911495

RESUMO

Caspase recruitment domain-containing protein 9 (CARD9) is a critical adaptor molecule triggered by the interaction of C-type lectin receptors (CLRs) with carbohydrate motifs found in fungi. Consequently, clinical and animal studies indicate that CARD9 is an important regulator of protective immunity against fungal pathogens. Previous studies suggest that CARD9 is important for the induction of protection against Cryptococcus neoformans, an opportunistic fungal pathogen that causes life-threatening infections of the central nervous system in immunocompromised patients. However, the effect of CARD9 deficiency on the induction of protective immune responses against C. neoformans is unknown. Immunization with a C. neoformans mutant that overexpresses the transcription factor zinc finger 2, denoted LW10, results in protection against an otherwise lethal challenge with wild-type (WT) C. neoformans Our results showed that CARD9 is essential for the induction of vaccine-mediated immunity against C. neoformans infection. We observed significant decreases in interleukin-17 (IL-17) production and significant increases in Th2-type cytokine (IL-4, IL-5, and IL-13) production in CARD9-deficient mice after inoculation with strain LW10. While leukocyte infiltration to the lungs of CARD9-deficient mice was similar in LW10 and WT C. neoformans-infected mice, macrophages derived from CARD9-deficient mice inherently skewed toward an M2 activation phenotype, were unable to contain the growth of LW10, and failed to produce nitric oxide in response to infection with LW10 or stimulation with lipopolysaccharide. These results suggest that CARD9-mediated signaling is required for M1 macrophage activation and fungicidal activity necessary for the induction of vaccine-mediated immunity against C. neoformansIMPORTANCECryptococcus neoformans is a fungal pathogen that is found throughout the environment and can cause life-threatening infections of the lung and central nervous system in severely immunocompromised individuals. Caspase recruitment domain-containing protein 9 (CARD9) is a critical molecule that is activated after interactions of C-type lectin receptors (CLRs) found on the surfaces of specific immune cells, with carbohydrate structures associated with fungi. Patients with defects in CARD9 are significantly more susceptible to a multitude of fungal infections. C. neoformans contains several carbohydrate structures that interact with CLRs on immune cells and activate CARD9. Consequently, these studies evaluated the necessity of CARD9 for the induction of protective immunity against C. neoformans infection. These results are important, as they advance our understanding of cryptococcal pathogenesis and host factors necessary for the induction of protective immunity against C. neoformans.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/genética , Criptococose/imunologia , Criptococose/microbiologia , Cryptococcus neoformans/imunologia , Pneumopatias Fúngicas/imunologia , Pneumopatias Fúngicas/microbiologia , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Animais , Biomarcadores , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Criptococose/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Resistência à Doença/imunologia , Feminino , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Imunofenotipagem , Leucócitos/imunologia , Leucócitos/metabolismo , Leucócitos/patologia , Pneumopatias Fúngicas/metabolismo , Masculino , Camundongos , Receptores de Reconhecimento de Padrão/metabolismo
4.
Immunology ; 155(2): 155-163, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29781185

RESUMO

The mucosal surface of the respiratory tract encounters microbes, such as fungal particles, with every inhaled breath. When pathogenic fungi breach the physical barrier and innate immune system within the lung to establish an infection, adaptive immunity is engaged, often in the form of helper CD4 T-cell responses. Type 1 responses, characterized by interferon-γ production from CD4 cells, promote clearance of Histoplasma capsulatum and Cryptococcus neoformans infection. Likewise, interleukin-17A (IL-17A) production from Th17 cells promotes immunity to Blastomyces dermatitidis and Coccidioides species infection by recruiting neutrophils. In contrast the development of T helper type 2 responses, characterized by IL-5 production from T cells and eosinophil influx into the lungs, drives allergic bronchopulmonary aspergillosis and poor outcomes during C. neoformans infection. Experimental vaccines against several endemic mycoses, including Histoplasma capsulatum, Coccidioides, Cryptococcus and Blastomyces dermatitidis, induce protective T-cell responses and foreshadow the development of vaccines against pulmonary fungal infections for use in humans. Additionally, recent work using antifungal T cells as immunotherapy to protect immune-compromised patients from opportunist fungal infections also shows great promise. This review covers the role of T-cell responses in driving protection and pathology in response to pulmonary fungal infections, and highlights promising therapeutic applications of antifungal T cells.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Pneumopatias Fúngicas/etiologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Animais , Humanos , Pneumopatias Fúngicas/metabolismo , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
5.
Respir Res ; 17(1): 66, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27250970

RESUMO

Pulmonary surfactant is a complex fluid that comprises phospholipids and four proteins (SP-A, SP-B, SP-C, and SP-D) with different biological functions. SP-B, SP-C, and SP-D are essential for the lungs' surface tension function and for the organization, stability and metabolism of lung parenchyma. SP-A and SP-D, which are also known as pulmonary collectins, have an important function in the host's lung immune response; they act as opsonins for different pathogens via a C-terminal carbohydrate recognition domain and enhance the attachment to phagocytic cells or show their own microbicidal activity by increasing the cellular membrane permeability. Interactions between the pulmonary collectins and bacteria or viruses have been extensively studied, but this is not the same for fungal pathogens. SP-A and SP-D bind glucan and mannose residues from fungal cell wall, but there is still a lack of information on their binding to other fungal carbohydrate residues. In addition, both their relation with immune cells for the clearance of these pathogens and the role of surfactant proteins' regulation during respiratory fungal infections remain unknown. Here we highlight the relevant findings associated with SP-A and SP-D in those respiratory mycoses where the fungal infective propagules reach the lungs by the airways.


Assuntos
Pneumopatias Fúngicas/metabolismo , Pulmão/metabolismo , Pneumonia/metabolismo , Proteína A Associada a Surfactante Pulmonar/metabolismo , Proteína D Associada a Surfactante Pulmonar/metabolismo , Animais , Citocinas/imunologia , Citocinas/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Imunidade Inata , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Pulmão/imunologia , Pulmão/microbiologia , Pneumopatias Fúngicas/imunologia , Pneumopatias Fúngicas/microbiologia , Pneumonia/imunologia , Pneumonia/microbiologia , Proteína A Associada a Surfactante Pulmonar/imunologia , Proteína D Associada a Surfactante Pulmonar/imunologia
6.
PLoS One ; 11(3): e0150632, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26963509

RESUMO

BACKGROUND: Patients with acute myeloid leukemia (AML) who undergo induction chemotherapy are at high risk for invasive fungal disease (IFD). Dectin-1, a C-type lectin family member represents one of the most important pattern recognition receptors of the innate immune system and single nucleotide polymorphisms (SNPs) in the Dectin-1 gene have been associated with an increased risk of infectious complications. We sought to investigate the impact of three different Dectin-1 SNPs and one TLR2 SNP on developing IFD in 186 adult patients with newly diagnosed AML following anthracycline-based induction chemotherapy. PATIENTS AND METHODS: Genotyping of Dectin-1 SNPs (rs16910526, rs3901533 and rs7309123) and TLR2 SNP (rs5743708) was performed by TaqMan method and pyrosequencing. IFD was defined according to the EORTC/MSG consensus guidelines. Multiple logistic regression analyses were applied to evaluate the association between the polymorphisms and the occurrence of pulmonary infections. Dectin-1 expression studies with SNP genotyped human monocytes were performed to elucidate susceptibility to IFD following chemotherapy. RESULTS: We could demonstrate that patients carrying the Dectin-1 SNP rs7309123 G/G (n = 47) or G/G and C/G (n = 133) genotype revealed a significant higher risk for developing both pneumonia in general (adjusted odds ratio (OR): 2.5; p = 0.014 and OR: 3.0, p = 0.004) and pulmonary IFD (OR: 2.6; p = 0.012 and OR: 2.4, p = 0.041, respectively). Patients carrying the TLR2 SNP rs5743708 (R753Q, GA/AA genotype, n = 12) also revealed a significantly higher susceptibility to pneumonia including IFD. Furthermore, Dectin-1 mRNA expression in human monocytes was lower following chemotherapy. CONCLUSION: To our best knowledge, this study represents the first analysis demonstrating that harbouring polymorphisms of Dectin-1 (rs7309123) or TLR2 (rs5743708) represents an independent risk factor of developing IFD in patients with AML undergoing induction chemotherapy.


Assuntos
Predisposição Genética para Doença , Lectinas Tipo C/genética , Leucemia Mieloide Aguda/genética , Pneumopatias Fúngicas/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Receptor 2 Toll-Like/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Lectinas Tipo C/biossíntese , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Pneumopatias Fúngicas/metabolismo , Pneumopatias Fúngicas/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/patologia , Proteínas de Neoplasias/biossíntese , Receptor 2 Toll-Like/biossíntese
7.
J Aerosol Med Pulm Drug Deliv ; 29(4): 362-77, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26859446

RESUMO

BACKGROUND: Understanding the relationship between dose, lung exposure, and drug efficacy continues to be a challenging aspect of inhaled drug development. An experimental inhalation platform was developed using mometasone furoate to link rodent lung exposure to its in vivo pharmacodynamic (PD) effects. METHODS: We assessed the effect of mometasone delivered directly to the lung in two different rodent PD models of lung inflammation. The data obtained were used to develop and evaluate a mathematical model to estimate drug dissolution, transport, distribution, and efficacy, following inhaled delivery in rodents and humans. RESULTS: Mometasone directly delivered to the lung, in both LPS and Alternaria alternata rat models, resulted in dose dependent inhibition of BALf cellular inflammation. The parameters for our mathematical model were calibrated to describe the observed lung and systemic exposure profiles of mometasone in humans and in animal models. We found that physicochemical properties, such as lung fluid solubility and lipophilicity, strongly influenced compound distribution and lung retention. CONCLUSIONS: Presently, we report on a novel and sophisticated mathematical model leading to improvements in a current inhaled drug development practices by providing a quantitative understanding of the relationship between PD effects and drug concentration in lungs.


Assuntos
Alternariose/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Cálculos da Dosagem de Medicamento , Pneumopatias Fúngicas/tratamento farmacológico , Pulmão/efeitos dos fármacos , Modelos Biológicos , Furoato de Mometasona/administração & dosagem , Pneumonia/tratamento farmacológico , Administração por Inalação , Aerossóis , Alternaria , Alternariose/metabolismo , Alternariose/microbiologia , Alternariose/fisiopatologia , Animais , Anti-Inflamatórios/farmacocinética , Modelos Animais de Doenças , Humanos , Lipopolissacarídeos , Pulmão/metabolismo , Pulmão/fisiopatologia , Pneumopatias Fúngicas/metabolismo , Pneumopatias Fúngicas/microbiologia , Pneumopatias Fúngicas/fisiopatologia , Masculino , Furoato de Mometasona/farmacocinética , Pneumonia/induzido quimicamente , Pneumonia/metabolismo , Pneumonia/fisiopatologia , Ratos Endogâmicos BN , Ratos Sprague-Dawley , Especificidade da Espécie , Distribuição Tecidual
8.
Am J Respir Cell Mol Biol ; 54(1): 25-33, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26039320

RESUMO

Lipoxins (LX) are proresolving mediators that augment host defense against bacterial infection. Here, we investigated roles for LX in lung clearance of the fungal pathogen Cryptococcus neoformans (Cne). After intranasal inoculation of 5,000 CFU Cne, C57BL/6 and C.B-17 mice exhibited strain-dependent differences in Cne clearance, immunologic responses, and lipoxin A4 (LXA4) formation and receptor (ALX/FPR2) expression. Compared with C.B-17 mice, C57BL/6 lungs had increased and persistent Cne infection 14 days after inoculation, increased eosinophils, and distinct profiles of inflammatory cytokines. Relative to C.B-17 mice, bronchoalveolar lavage fluid levels of LXA4 were increased before and after infection in C57BL/6. The kinetics for 15-epi-LXA4 production were similar in both strains. Lung basal expression of the LX biosynthetic enzyme Alox12/15 (12/15-lipoxygenase) was increased in C57BL/6 mice and further increased after Cne infection. In contrast, lung basal expression of the LXA4 receptor Alx/Fpr2 was higher in C.B-17 relative to C57BL/6 mice, and after Cne infection, Alx/Fpr2 expression was significantly increased in only C.B-17 mice. Heat-killed Cne initiated lung cell generation of IFN-γ and IL-17 and was further increased in C.B-17 mice by 15-epi-LXA4. A trend toward reduced Cne clearance and IFN-γ production was observed upon in vivo administration of an ALX/FPR2 antagonist. Together, these findings provide the first evidence that alterations in cellular immunity against Cne are associated with differences in LXA4 production and receptor expression, suggesting an important role for ALX/FPR2 signaling in the regulation of pathogen-mediated inflammation and antifungal lung host defense.


Assuntos
Criptococose/metabolismo , Cryptococcus neoformans/patogenicidade , Lipoxinas/metabolismo , Pneumopatias Fúngicas/metabolismo , Pulmão/metabolismo , Transdução de Sinais , Animais , Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/metabolismo , Líquido da Lavagem Broncoalveolar/química , Quimiotaxia de Leucócito , Criptococose/imunologia , Criptococose/microbiologia , Cryptococcus neoformans/imunologia , Interações Hospedeiro-Patógeno , Imunidade Celular , Interferon gama/metabolismo , Interleucina-17/metabolismo , Cinética , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/microbiologia , Pneumopatias Fúngicas/imunologia , Pneumopatias Fúngicas/microbiologia , Camundongos Endogâmicos C57BL , Oligopeptídeos/farmacologia , Receptores de Formil Peptídeo/antagonistas & inibidores , Receptores de Formil Peptídeo/metabolismo , Transdução de Sinais/efeitos dos fármacos , Especificidade da Espécie
9.
Mol Pharm ; 12(8): 2651-64, 2015 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-25941882

RESUMO

Current therapies are insufficient to prevent recurrent fungal infection especially in the lower part of the lung. A careful and systematic understanding of the properties of nanoparticles plays a significant role in the design, development, optimization, and in vivo performances of the nanoparticles. In the present study, PLGA nanoparticles containing the antifungal drug voriconazole was prepared and two best formulations were selected for further characterization and in vivo studies. The nanoparticles and the free drug were radiolabeled with technetium-99m with 90% labeling efficiency, and the radiolabeled particles were administered to investigate the effect on their blood clearance, biodistribution, and in vivo gamma imaging. In vivo deposition of the drug in the lobes of the lung was studied by LC-MS/MS study. The particles were found to be spherical and had an average hydrodynamic diameter of 300 nm with a smooth surface. The radiolabeled particles and the free drug were found to accumulate in various major organs. Drug accumulation was more pronounced in the lung in the case of administration of the nanoparticles than that of the free drug. The free drug was found to be excreted more rapidly than the nanoparticle containing drug following the inhalation route as assessed by gamma scintigraphy study. Thus, the study reveals that pulmonary administration of nanoparticles containing voriconazole could be a better therapeutic choice even as compared to the iv route of administration of the free drug and/or the drug loaded nanoparticles.


Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Pneumopatias Fúngicas/tratamento farmacológico , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Voriconazol/administração & dosagem , Voriconazol/farmacocinética , Administração por Inalação , Animais , Disponibilidade Biológica , Portadores de Fármacos , Feminino , Meia-Vida , Pneumopatias Fúngicas/metabolismo , Masculino , Camundongos , Nanopartículas/química , Ácido Poliglicólico/química , Ratos , Ratos Sprague-Dawley
10.
Eukaryot Cell ; 14(8): 728-44, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25911225

RESUMO

Aspergillus fumigatus is an opportunistic pathogenic fungus able to infect immunocompromised patients, eventually causing disseminated infections that are difficult to control and lead to high mortality rates. It is important to understand how the signaling pathways that regulate these factors involved in virulence are orchestrated. Protein phosphatases are central to numerous signal transduction pathways. Here, we characterize the A. fumigatus protein phosphatase 2A SitA, the Saccharomyces cerevisiae Sit4p homologue. The sitA gene is not an essential gene, and we were able to construct an A. fumigatus null mutant. The ΔsitA strain had decreased MpkA phosphorylation levels, was more sensitive to cell wall-damaging agents, had increased ß-(1,3)-glucan and chitin, was impaired in biofilm formation, and had decreased protein kinase C activity. The ΔsitA strain is more sensitive to several metals and ions, such as MnCl2, CaCl2, and LiCl, but it is more resistant to ZnSO4. The ΔsitA strain was avirulent in a murine model of invasive pulmonary aspergillosis and induces an augmented tumor necrosis factor alpha (TNF-α) response in mouse macrophages. These results stress the importance of A. fumigatus SitA as a possible modulator of PkcA/MpkA activity and its involvement in the cell wall integrity pathway.


Assuntos
Aspergillus fumigatus/metabolismo , Biofilmes/crescimento & desenvolvimento , Proteínas de Transporte de Cátions/metabolismo , Adesão Celular/fisiologia , Parede Celular/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Virulência/fisiologia , Animais , Quitina/metabolismo , Modelos Animais de Doenças , Feminino , Proteínas Fúngicas/metabolismo , Aspergilose Pulmonar Invasiva/metabolismo , Aspergilose Pulmonar Invasiva/microbiologia , Pneumopatias Fúngicas/metabolismo , Pneumopatias Fúngicas/microbiologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/metabolismo
12.
J Immunol ; 194(9): 4507-17, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25825440

RESUMO

Pathogens are sensed by innate immune receptors that initiate an efficient adaptive immune response upon activation. The elements of the innate immune recognition process for Paracoccidioides brasiliensis include TLR-2, TLR-4, and dectin-1. However, there are additional receptors necessary for the host immune responses to P. brasiliensis. The nucleotide-binding oligomerization domain-like receptor (NLRs), which activate inflammasomes, are candidate receptors that deserve renewed investigation. After pathogen infection, the NLRs form large signaling platforms called inflammasomes, which lead to caspase-1 activation and maturation of proinflammatory cytokines (IL-18 and IL-1ß). In this study, we showed that NLR family pyrin domain-containing 3 (Nlrp3) is required to induce caspase-1 activation and further secretion of IL-1ß and IL-18 by P. brasiliensis-infected macrophages. Additionally, potassium efflux and lysosomal acidification induced by the fungus were important steps in the caspase-1 activation mechanism. Notably, Nlrp3 and caspase-1 knockout mice were more susceptible to infection than were the wild-type animals, suggesting that the Nlrp3-dependent inflammasomes contribute to host protection against P. brasiliensis. This protective effect occurred owing to the inflammatory response mediated by IL-18, as shown by an augmented fungus burden in IL-18 knockout mice. Taken together, our results show that the Nlrp3 inflammasome is essential for resistance against P. brasiliensis because it orchestrates robust caspase-1 activation and triggers an IL-18-dependent proinflammatory response.


Assuntos
Proteínas de Transporte/metabolismo , Imunidade Inata , Inflamassomos/metabolismo , Interleucina-18/metabolismo , Pneumopatias Fúngicas/imunologia , Pneumopatias Fúngicas/metabolismo , Animais , Caspase 1/metabolismo , Modelos Animais de Doenças , Resistência à Doença/genética , Resistência à Doença/imunologia , Granuloma/genética , Granuloma/imunologia , Granuloma/metabolismo , Inflamassomos/genética , Interleucina-18/genética , Interleucina-1beta/biossíntese , Pneumopatias Fúngicas/mortalidade , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Masculino , Camundongos , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Paracoccidioides/imunologia
13.
Transplantation ; 99(9): e140-4, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25710608

RESUMO

BACKGROUND: Prompt diagnosis of invasive fungal infections (IFI) remains a challenge. (1,3)ß-D-glucan detection in bronchoalveolar lavage (BAL) fluid by Fungitell assay aims to further improve upon the test's utility by directly applying it to specimens from the target organ. METHODS: A prospective multicenter analysis of the Fungitell assay was performed on BAL and serum samples obtained from nonselected solid-organ transplantation patients suffering from probable, proven or no IFI according to the revised criteria of the European Organisation for Research and Treatment of Cancer / Mycosis Study Group. RESULTS: Two hundred thirty-three BAL and 109 serum specimens from 135 patients with proven, probable, or no IFI were tested. Based on a 100 pg/mL: cutoff per test sensitivity, specificity, positive and negative predictive values were 79.2%, 38.5%, 27.6%, and 86.3% in BALs and 79.2%, 81.8%, 69.2%, and 83.1% in sera investigated. CONCLUSIONS: The accuracy of the (1,3)ß-D-glucan test is marginal so that its utility as a clinical test for early diagnosis of IFI is questionable in the lung transplant population. Although the high negative predictive value of the Fungitell assay in both, BALs and sera, may support exclusion of pulmonary IFI in solid-organ transplantation patients, the low positive predictive value limits its utility as a screening tool for early diagnosis of IFI.


Assuntos
Líquido da Lavagem Broncoalveolar/química , Pneumopatias Fúngicas/diagnóstico , Transplante de Órgãos/efeitos adversos , beta-Glucanas/análise , Adulto , Áustria , Biomarcadores/análise , Estudos de Casos e Controles , Estudos Cross-Over , Feminino , Humanos , Pneumopatias Fúngicas/metabolismo , Pneumopatias Fúngicas/microbiologia , Transplante de Pulmão/efeitos adversos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Proteoglicanas , Reprodutibilidade dos Testes , Resultado do Tratamento , beta-Glucanas/sangue
14.
Korean J Radiol ; 14(3): 540-3, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23690726

RESUMO

The radiologic appearance of multiple discrete pulmonary nodules in immunocompetent patients, with cryptococcal infection, has been rarely described. We describe a case of pulmonary cryptococcosis, presenting with bilaterally and randomly distributed nodules on a computed tomography, mimicking hematogeneous metastases. Positron emission tomography does not demonstrate 18F-fluorodeoxyglucose (FDG) uptake, suggesting a low probability for malignancy, which is a crucial piece of information for clinicians when making a management decision. We find the absence of FDG uptake correlates with the pathologic finding of an infectious nodule, composed of fibrosis and necrosis.


Assuntos
Criptococose/diagnóstico por imagem , Fluordesoxiglucose F18 , Pneumopatias Fúngicas/diagnóstico por imagem , Imagem Multimodal/métodos , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X/métodos , Criptococose/metabolismo , Fluordesoxiglucose F18/farmacocinética , Humanos , Imunocompetência , Pneumopatias Fúngicas/metabolismo , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Nódulos Pulmonares Múltiplos/diagnóstico por imagem , Compostos Radiofarmacêuticos/farmacocinética
15.
J Allergy Clin Immunol ; 129(2): 280-91; quiz 292-3, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22284927

RESUMO

Asthma is a common disorder that in 2009 afflicted 8.2% of adults and children, 24.6 million persons, in the United States. In patients with moderate and severe persistent asthma, there is significantly increased morbidity, use of health care support, and health care costs. Epidemiologic studies in the United States and Europe have associated mold sensitivity, particularly to Alternaria alternata and Cladosporium herbarum, with the development, persistence, and severity of asthma. In addition, sensitivity to Aspergillus fumigatus has been associated with severe persistent asthma in adults. Allergic bronchopulmonary aspergillosis (ABPA) is caused by A fumigatus and is characterized by exacerbations of asthma, recurrent transient chest radiographic infiltrates, coughing up thick mucus plugs, peripheral and pulmonary eosinophilia, and increased total serum IgE and fungus-specific IgE levels, especially during exacerbation. The airways appear to be chronically or intermittently colonized by A fumigatus in patients with ABPA. ABPA is the most common form of allergic bronchopulmonary mycosis (ABPM); other fungi, including Candida, Penicillium, and Curvularia species, are implicated. The characteristics of ABPM include severe asthma, eosinophilia, markedly increased total IgE and specific IgE levels, bronchiectasis, and mold colonization of the airways. The term severe asthma associated with fungal sensitization (SAFS) has been coined to illustrate the high rate of fungal sensitivity in patients with persistent severe asthma and improvement with antifungal treatment. The immunopathology of ABPA, ABPM, and SAFS is incompletely understood. Genetic risks identified in patients with ABPA include HLA association and certain T(H)2-prominent and cystic fibrosis variants, but these have not been studied in patients with ABPM and SAFS. Oral corticosteroid and antifungal therapies appear to be partially successful in patients with ABPA. However, the role of antifungal and immunomodulating therapies in patients with ABPA, ABPM, and SAFS requires additional larger studies.


Assuntos
Pneumopatias Fúngicas , Hipersensibilidade Respiratória , Antígenos de Fungos/imunologia , Mudança Climática , Humanos , Imunoterapia , Pneumopatias Fúngicas/genética , Pneumopatias Fúngicas/metabolismo , Pneumopatias Fúngicas/terapia , Hipersensibilidade Respiratória/genética , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/terapia
16.
Am J Respir Cell Mol Biol ; 46(3): 290-8, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21960549

RESUMO

It is widely held that exposure to pathogens such as fungi can be an agent of comorbidity, such as exacerbation of asthma or chronic obstructive pulmonary disease. Although many studies have examined allergic responses to fungi and their effects on pulmonary function, the possible pathologic implications of the early innate responses to fungal pathogens have not been explored. We examined early responses to the atypical fungus Pneumocystis in two common strains of mice in terms of overall immunological response and related pathology, such as cell damage and airway hyperresponsiveness (AHR). We found a strong strain-specific response in BALB/c mice that included recruitment of neutrophils, NK, NKT, and CD4 T cells. This response was accompanied by elevated indicators of lung damage (bronchoalveolar lavage fluid albumin and LDH) and profound AHR. This early response was absent in C57BL/6 mice, although both strains exhibited a later response associated with the clearance of Pneumocystis. We found that this AHR could not be attributed exclusively to the presence of recruited neutrophils, NKT, NK, or CD4 cells or to the actions of IFN-γ or IL-4. However, in the absence of STAT6 signaling, AHR and inflammatory cell recruitment were virtually absent. Gene expression analysis indicated that this early response included activation of several transcription factors that could be involved in pulmonary remodeling. These results show that exposure to a fungus such as Pneumocystis can elicit pulmonary responses that may contribute to morbidity, even without prior sensitization, in the context of certain genetic backgrounds.


Assuntos
Hiper-Reatividade Brônquica/metabolismo , Imunidade Inata , Pneumopatias Fúngicas/metabolismo , Pulmão/metabolismo , Infecções por Pneumocystis/metabolismo , Fator de Transcrição STAT6/metabolismo , Albuminas/metabolismo , Animais , Antígenos CD1/genética , Antígenos CD1/metabolismo , Hiper-Reatividade Brônquica/genética , Hiper-Reatividade Brônquica/imunologia , Hiper-Reatividade Brônquica/microbiologia , Hiper-Reatividade Brônquica/fisiopatologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/microbiologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Interferon gama/deficiência , Interferon gama/genética , Interleucina-4/metabolismo , L-Lactato Desidrogenase/metabolismo , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/fisiopatologia , Pneumopatias Fúngicas/genética , Pneumopatias Fúngicas/imunologia , Pneumopatias Fúngicas/microbiologia , Pneumopatias Fúngicas/fisiopatologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Células T Matadoras Naturais/microbiologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Neutrófilos/microbiologia , Infecções por Pneumocystis/genética , Infecções por Pneumocystis/imunologia , Infecções por Pneumocystis/microbiologia , Infecções por Pneumocystis/fisiopatologia , Receptores de Interleucina-4/deficiência , Receptores de Interleucina-4/genética , Receptores de Interleucina-8B/deficiência , Receptores de Interleucina-8B/genética , Fator de Transcrição STAT6/deficiência , Fator de Transcrição STAT6/genética , Transdução de Sinais , Especificidade da Espécie , Fatores de Tempo
17.
Eur J Nucl Med Mol Imaging ; 39(1): 120-8, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21947022

RESUMO

PURPOSE: Between 30 and 50% of febrile neutropenic episodes are accounted for by infection. C-reactive protein (CRP) is a nonspecific parameter for infection and inflammation but might be employed as a trigger for diagnosis. The aim of the study was to evaluate whether (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT can be used to detect inflammatory foci in neutropenic patients with elevated CRP and whether it helps to direct treatment. METHODS: Twenty-eight consecutive patients with neutropenia as a result of intensive chemotherapy for haematological malignancies or myeloablative therapy for haematopoietic stem cell transplantation were prospectively included. (18)F-FDG PET/CT was added to the regular diagnostic workup once the CRP level rose above 50 mg/l. RESULTS: Pathological FDG uptake was found in 26 of 28 cases despite peripheral neutrophil counts less than 0.1 × 10(-9)/l in 26 patients: in the digestive tract in 18 cases, around the tract of the central venous catheter (CVC) in 9 and in the lungs in 7 cases. FDG uptake in the CVC tract was associated with coagulase-negative staphylococcal bacteraemia (p < 0.001) and deep venous thrombosis (p = 0.002). The number of patients having Streptococcus mitis bacteraemia appeared to be higher in patients with grade 3 oesophageal FDG uptake (p = 0.08). Pulmonary FDG uptake was associated with the presence of invasive fungal disease (p = 0.04). CONCLUSION: (18)F-FDG PET/CT scanning during chemotherapy-induced febrile neutropenia and increased CRP is able to detect localized foci of infection and inflammation despite the absence of circulating neutrophils. Besides its potential role in detecting CVC-related infection during febrile neutropenia, the high negative predictive value of (18)F-FDG PET/CT is important for avoiding unnecessary diagnostic tests and therapy.


Assuntos
Fluordesoxiglucose F18 , Neoplasias Hematológicas/tratamento farmacológico , Pneumopatias Fúngicas/diagnóstico por imagem , Imagem Multimodal , Neutropenia/complicações , Tomografia por Emissão de Pósitrons , Transplante de Células-Tronco/efeitos adversos , Infecções Estreptocócicas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Idoso , Antineoplásicos/efeitos adversos , Bacteriemia/complicações , Bacteriemia/diagnóstico por imagem , Bacteriemia/metabolismo , Transporte Biológico , Proteína C-Reativa/metabolismo , Cateterismo Venoso Central/efeitos adversos , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Pneumopatias Fúngicas/complicações , Pneumopatias Fúngicas/metabolismo , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Neutropenia/patologia , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/metabolismo , Streptococcus mitis/patogenicidade
19.
PLoS One ; 6(2): e17204, 2011 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-21359196

RESUMO

The current studies evaluated the role of interleukin (IL)-17A in the induction of protective immunity against pulmonary cryptococcosis in mice. Protection against pulmonary infection with C. neoformans strain H99γ was associated with increased IL-17A production. Signaling through the IFN-γ receptor (R) was required for increased IL-17A production, however, a Th17-type cytokine profile was not observed. Neutrophils were found to be the predominant leukocytic source of IL-17A, rather than T cells, suggesting that the IL-17A produced was not part of a T cell-mediated Th17-type immune response. Depletion of IL-17A in mice during pulmonary infection with C. neoformans strain H99γ resulted in an initial increase in pulmonary fungal burden, but had no effect on cryptococcal burden at later time points. Also, depletion of IL-17A did not affect the local production of other cytokines. IL-17RA⁻/⁻ mice infected with C. neoformans strain H99γ survived the primary infection as well as a secondary challenge with wild-type cryptococci. However, dissemination of the wild-type strain to the brain was noted in the surviving IL-17RA⁻/⁻ mice. Altogether, our results suggested that IL-17A may be important for optimal protective immune responsiveness during pulmonary C. neoformans infection, but protective Th1-type immune responses are sufficient for protection against cryptococcal infection.


Assuntos
Criptococose/imunologia , Cryptococcus neoformans/imunologia , Imunidade Celular/genética , Interleucina-17/fisiologia , Pneumopatias Fúngicas/imunologia , Animais , Quimiotaxia de Leucócito/genética , Criptococose/genética , Criptococose/mortalidade , Cryptococcus neoformans/metabolismo , Cryptococcus neoformans/fisiologia , Citoproteção/genética , Citoproteção/imunologia , Feminino , Interleucina-17/genética , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Pneumopatias Fúngicas/genética , Pneumopatias Fúngicas/metabolismo , Pneumopatias Fúngicas/mortalidade , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/fisiologia , Células Th17/imunologia , Células Th17/metabolismo , Células Th17/fisiologia
20.
PLoS Pathog ; 6(6): e1000953, 2010 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-20585559

RESUMO

Cryptococcus neoformans is a common life-threatening human fungal pathogen. The size of cryptococcal cells is typically 5 to 10 microm. Cell enlargement was observed in vivo, producing cells up to 100 microm. These morphological changes in cell size affected pathogenicity via reducing phagocytosis by host mononuclear cells, increasing resistance to oxidative and nitrosative stress, and correlated with reduced penetration of the central nervous system. Cell enlargement was stimulated by coinfection with strains of opposite mating type, and ste3aDelta pheromone receptor mutant strains had reduced cell enlargement. Finally, analysis of DNA content in this novel cell type revealed that these enlarged cells were polyploid, uninucleate, and produced daughter cells in vivo. These results describe a novel mechanism by which C. neoformans evades host phagocytosis to allow survival of a subset of the population at early stages of infection. Thus, morphological changes play unique and specialized roles during infection.


Assuntos
Encéfalo/microbiologia , Criptococose/metabolismo , Criptococose/patologia , Cryptococcus neoformans/fisiologia , Pneumopatias Fúngicas/patologia , Animais , Barreira Hematoencefálica , Western Blotting , Encéfalo/metabolismo , Lavagem Broncoalveolar , Adesão Celular , Proliferação de Células , Feminino , Citometria de Fluxo , Humanos , Pneumopatias Fúngicas/metabolismo , Pneumopatias Fúngicas/microbiologia , Camundongos , Camundongos Endogâmicos A , Estresse Oxidativo , Fagocitose , Ploidias , RNA Mensageiro/genética , Receptores de Feromônios/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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