RESUMO
This study aimed to assess whether genetic variants of dendritic cell-associated C-type lectine-1 (Dectin-1), Toll-like receptor 2 (TLR2), Toll-like receptor 4 (TLR4), and myeloid differentiation primary response 88 (MyD88) influence the susceptibility to pulmonary invasive fungal disease (IFD) in patients with acute myeloid leukemia (AML) from a Chinese Han population. Eight single nucleotide polymorphisms (SNPs) of Dectin-1 (rs16910526, rs3901533, and rs7309123), TLR2 (rs5743708), TLR4 (rs4986790 and rs4986791) and MyD88 (rs4988453 and rs4988457) in the genomic DNA of 172 adult AML patients were genotyped. Pulmonary IFD was diagnosed as proven or probable according to the 2008 European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) consensus guidelines. SNPs that were significant in the univariate analysis were further analyzed using the multiple logistic regression analysis to determine their association with the occurrence of pulmonary IFD. The mRNA expression of Dectin-1 was detected according to the genotype by quantitative realtime PCR (qRT-PCR), and the correlation of this expression with the occurrence of pulmonary IFD in AML patients was analyzed. Two Dectin-1 intron SNPs (rs3901533 and rs7309123) were found to be significantly associated with the susceptibility to pulmonary IFD in AML patients in a Chinese Han population. Significant associations were noted between pulmonary IFD and Dectin-1 rs3901533 dominant model (G/T+G/G vs. T/T, OR: 2.158; 95% CI: 1.109-4.2, P=0.02), Dectin-1 rs3901533 G allele (OR: 2.201; 95% CI: 1.206-4.019, P=0.01), or Dectin-1 rs7309123 C allele (OR: 1.919; 95% CI: 1.047-3.518, P=0.03). There were no significant associations between pulmonary IFD and the remaining Dectin-1 SNPs (rs16910526), TLR2 (rs5743708), TLR4 (rs4986790 and rs4986791) or MyD88 (rs4988453 and rs4988457). In conclusion, two Dectin-1 SNPs (rs3901533 and rs7309123) are associated with increased susceptibility to pulmonary IFD in AML patients in a Chinese Han population.
Assuntos
Povo Asiático/etnologia , Infecções Fúngicas Invasivas/genética , Lectinas Tipo C/genética , Leucemia Mieloide Aguda/microbiologia , Pneumopatias Fúngicas/genética , Povo Asiático/genética , China/etnologia , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Infecções Fúngicas Invasivas/etnologia , Leucemia Mieloide Aguda/etnologia , Leucemia Mieloide Aguda/genética , Pneumopatias Fúngicas/etnologia , Masculino , Fator 88 de Diferenciação Mieloide/genética , Polimorfismo de Nucleotídeo Único , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genéticaRESUMO
CD40 ligand (CD40L) deficiency is a rare but life-threatening primary immunodeficiency caused by mutations in the CD40L gene. Here, we investigated a cohort of 40 genetically diagnosed CD40L-deficient patients from the Chinese mainland, analysed their clinical and genetic data, and examined CD40L expression, the proportion of T cell subsets, B cell subsets and T follicular helper (Tfh) cells. The aim was to provide a complete picture of CD40L deficiency. Initial presentations of the patient cohort mainly involved recurrent fever (47.5%) and sinopulmonary infection (42.5%). Life-threatening infections (42.5%), caused by various pathogens, were the most serious threats faced by CD40L-deficient patients, while neutropenia (57.5%) remained the most common complication. Opportunistic infections, including Pneumocystis carinii pneumonia and invasive fungal disease associated with Talaromyces marneffei, were also common in the cohort. In addition, seven patients (17.5%) suffered BCGitis/BCGosis, which is a major problem facing a planned immunization programme in China. It was intriguing that reduced IgM levels were observed in 12.5% of patients, while normal or elevated IgA levels were shown in 47.5% of patients. Thirty-seven unique mutations were identified in 40 patients; of these, 10 were novel. Furthermore, we observed a lower percentage of NK cells, Tfh cells, and central memory CD4+ T cells, and an extremely small class-switched memory B cell population, in CD40L-deficient patients. Patients who underwent hematopoietic stem cell transplantation experienced better disease remission. Taken together, our data establish the largest database about CD40L deficiency in China and provide genetic, immunologic and clinical information about Chinese CD40L-deficient patients.
Assuntos
Ligante de CD40/genética , Síndromes de Imunodeficiência/imunologia , Células Matadoras Naturais/imunologia , Pneumopatias Fúngicas/imunologia , Pneumocystis carinii/fisiologia , Pneumonia por Pneumocystis/imunologia , Linfócitos T/imunologia , Talaromyces/fisiologia , China , Estudos de Coortes , Febre , Humanos , Imunoglobulina M/sangue , Síndromes de Imunodeficiência/genética , Memória Imunológica , Pneumopatias Fúngicas/genética , Masculino , Mycobacterium bovis , Pneumonia por Pneumocystis/genética , Adulto JovemRESUMO
Fungal infections in CD4+ T cell immunocompromised patients have risen sharply in recent years. Although vaccines offer a rational avenue to prevent infections, there are no licensed fungal vaccines available. Inactivated vaccines are safer but less efficacious and require adjuvants that may undesirably bias toward poor protective immune responses. We hypothesized that reducing the TCR signaling threshold could potentiate antifungal CD8+ T cell responses and immunity to inactivated vaccine in the absence of CD4+ T cells. In this study, we show that CBLB, a negative regulator of TCR signaling, suppresses CD8+ T cells in response to inactivated fungal vaccination in a mouse model of CD4+ T cell lymphopenia. Conversely, Cblb deficiency enhanced both the type 1 (e.g., IFN-γ) and type 17 (IL-17A) CD8+ T cell responses to inactivated fungal vaccines and augmented vaccine immunity to lethal fungal pneumonia. Furthermore, we show that immunization with live or inactivated vaccine yeast did not cause detectable pathologic condition in Cblb-/- mice. Augmented CD8+ T cell responses in the absence of CBLB also did not lead to terminal differentiation or adversely affect the expression of transcription factors T-bet, Eomes, and RORγt. Additionally, our adoptive transfer experiments showed that CBLB impedes the effector CD8+ T cell responses in a cell-intrinsic manner. Finally, we showed that ablation of Cblb overcomes the requirement of HIF-1α for expansion of CD8+ T cells upon vaccination. Thus, adjuvants that target CBLB may augment inactivated vaccines and immunity against systemic fungal infections in vulnerable patients.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Fúngicas/imunologia , Imunidade Celular , Pneumopatias Fúngicas/imunologia , Pneumonia/imunologia , Proteínas Proto-Oncogênicas c-cbl/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Linfócitos T CD8-Positivos/patologia , Vacinas Fúngicas/farmacologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Pneumopatias Fúngicas/genética , Pneumopatias Fúngicas/patologia , Pneumopatias Fúngicas/prevenção & controle , Camundongos , Camundongos Knockout , Pneumonia/genética , Pneumonia/patologia , Pneumonia/prevenção & controle , Proteínas Proto-Oncogênicas c-cbl/genética , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Vacinas de Produtos Inativados/imunologia , Vacinas de Produtos Inativados/farmacologiaRESUMO
Cryptococcus neoformans is an opportunistic fungal pathogen that is inhaled into the lungs and can lead to life-threatening meningoencephalitis in immunocompromised patients. Currently, the molecular mechanisms that regulate the mammalian immune response to respiratory cryptococcal challenge remain poorly defined. DAP12, a signaling adapter for multiple pattern recognition receptors in myeloid and natural killer (NK) cells, has been shown to play both activating and inhibitory roles during lung infections by different bacteria and fungi. In this study, we demonstrate that DAP12 plays an important inhibitory role in the immune response to C. neoformans Infectious outcomes in DAP12(-/-) mice, including survival and lung fungal burden, are significantly improved compared to those in C57BL/6 wild-type (WT) mice. We find that eosinophils and macrophages are decreased while NK cells are increased in the lungs of infected DAP12(-/-) mice. In contrast to WT NK cells, DAP12(-/-) NK cells are able to repress C. neoformans growth in vitro Additionally, DAP12(-/-) macrophages are more highly activated than WT macrophages, with increased production of tumor necrosis factor (TNF) and CCL5/RANTES and more efficient uptake and killing of C. neoformans These findings suggest that DAP12 acts as a brake on the pulmonary immune response to C. neoformans by promoting pulmonary eosinophilia and by inhibiting the activation and antifungal activities of effector cells, including NK cells and macrophages.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/imunologia , Criptococose/imunologia , Cryptococcus neoformans/patogenicidade , Regulação Fúngica da Expressão Gênica , Interações Hospedeiro-Patógeno , Pneumopatias Fúngicas/imunologia , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Quimiocina CCL5/genética , Quimiocina CCL5/imunologia , Criptococose/genética , Criptococose/microbiologia , Criptococose/patologia , Cryptococcus neoformans/crescimento & desenvolvimento , Cryptococcus neoformans/imunologia , Modelos Animais de Doenças , Eosinófilos/imunologia , Eosinófilos/microbiologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/microbiologia , Pulmão/imunologia , Pulmão/microbiologia , Pneumopatias Fúngicas/genética , Pneumopatias Fúngicas/microbiologia , Pneumopatias Fúngicas/patologia , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
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/biossínteseRESUMO
Viruses use Tyro3, Axl, and Mertk (TAM) receptor tyrosine kinases to infect and modulate the immune properties of various cell types, which led us to investigate whether TAM receptor activation affected primary viral infection and viral exacerbation of asthma in experimental models. In these lung-specific models, we observed that Axl was the most abundantly induced TAM receptor protein. During primary respiratory syncytial virus (RSV) infection, anti-Axl mAb treatment significantly increased the number of IFN-γ-producing T cells and NK cells and significantly suppressed RSV replication and whole lung levels of IL-4 and IL-13. Intrapulmonary H1N1 infection induced lethal pulmonary inflammation, but anti-Axl mAb treatment of infected mice significantly increased the number of IFN-ß-producing macrophages and dendritic cells and significantly suppressed neutrophil infiltration. Consequently, the lethal effect of H1N1 infection in this model was significantly reduced in the mAb-treated group compared with the IgG control-treated group. Targeting Axl also inhibited airway hyperresponsiveness, IL-4 and IL-13 production, and goblet cell metaplasia in an Aspergillus fumigatus-induced asthma model. Finally, infection of mice with RSV during fungal asthma significantly exacerbated airway inflammation, goblet cell metaplasia, and airway remodeling, but all of these features in this viral exacerbation model were ameliorated by anti-Axl mAb treatment. Taken together, these results demonstrate that Axl modulates the pulmonary immune response during viral and/or allergic pathology, and they also suggest that targeting this TAM receptor might provide a novel therapeutic approach in these infectious diseases.
Assuntos
Asma/metabolismo , Asma/patologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Asma/complicações , Asma/imunologia , Feminino , Expressão Gênica , Humanos , Vírus da Influenza A Subtipo H1N1 , Pulmão/metabolismo , Pulmão/patologia , Pulmão/virologia , Pneumopatias Fúngicas/complicações , Pneumopatias Fúngicas/genética , Pneumopatias Fúngicas/patologia , Camundongos , Infecções por Orthomyxoviridae/complicações , Infecções por Orthomyxoviridae/genética , Infecções por Orthomyxoviridae/mortalidade , Infecções por Orthomyxoviridae/patologia , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Receptores Virais/genética , Receptores Virais/metabolismo , Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/patologia , Viroses/complicações , Viroses/genética , c-Mer Tirosina Quinase , Receptor Tirosina Quinase AxlRESUMO
Genetic factors that regulate the pathogenesis of pneumonia caused by the fungus Cryptococcus neoformans are poorly understood. Through a phenotypic strain survey we observed that inbred C3H/HeN mice develop a significantly greater lung fungal burden than mice of the resistant CBA/J strain 4 weeks following intratracheal infection with C. neoformans ATCC 24067. The aim of the present study was to characterize the inflammatory response of C3H/HeN mice following C. neoformans pulmonary infection and to identify genetic loci that regulate host defense. Following cryptococcal infection, C3H/HeN mice demonstrated a Th2 immune response with heightened airway and tissue eosinophilia, goblet cell metaplasia, and significantly higher lung interleukin-5 (IL-5) and IL-13 protein expression relative to CBA/J mice. Conversely, CBA/J mice exhibited greater airway and tissue neutrophilia that was associated with significantly higher pulmonary expression of gamma interferon, CXCL10, and IL-17 proteins than C3H/HeN mice. Using the fungal burden at 4 weeks postinfection as a phenotype, genome-wide quantitative trait locus (QTL) analysis among 435 segregating (C3H/HeN × CBA/J)F2 (C3HCBAF2) hybrids identified two significant QTLs on chromosomes 1 (Cnes4) and 9 (Cnes5) that control susceptibility to cryptococcal pneumonia in an additive manner. Susceptible C3H/HeN mice carry a resistance allele at Cnes4 and a susceptibility allele at Cnes5. These studies reveal additional genetic complexity of the host response to C. neoformans that is associated with divergent patterns of pulmonary inflammation.
Assuntos
Cromossomos de Mamíferos/genética , Criptococose/genética , Cryptococcus neoformans/patogenicidade , Predisposição Genética para Doença , Pneumopatias Fúngicas/genética , Locos de Características Quantitativas/genética , Animais , Criptococose/imunologia , Criptococose/microbiologia , Criptococose/patologia , Citocinas/metabolismo , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Pneumopatias Fúngicas/imunologia , Pneumopatias Fúngicas/microbiologia , Pneumopatias Fúngicas/patologia , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos CBA , Células Th1/imunologia , Células Th2/imunologiaRESUMO
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/terapiaRESUMO
Sterol regulatory element binding proteins (SREBPs) are a class of basic helix-loop-helix transcription factors that regulate diverse cellular responses in eukaryotes. Adding to the recognized importance of SREBPs in human health, SREBPs in the human fungal pathogens Cryptococcus neoformans and Aspergillus fumigatus are required for fungal virulence and susceptibility to triazole antifungal drugs. To date, the exact mechanism(s) behind the role of SREBP in these observed phenotypes is not clear. Here, we report that A. fumigatus SREBP, SrbA, mediates regulation of iron acquisition in response to hypoxia and low iron conditions. To further define SrbA's role in iron acquisition in relation to previously studied fungal regulators of iron metabolism, SreA and HapX, a series of mutants were generated in the ΔsrbA background. These data suggest that SrbA is activated independently of SreA and HapX in response to iron limitation, but that HapX mRNA induction is partially dependent on SrbA. Intriguingly, exogenous addition of high iron or genetic deletion of sreA in the ΔsrbA background was able to partially rescue the hypoxia growth, triazole drug susceptibility, and decrease in ergosterol content phenotypes of ΔsrbA. Thus, we conclude that the fungal SREBP, SrbA, is critical for coordinating genes involved in iron acquisition and ergosterol biosynthesis under hypoxia and low iron conditions found at sites of human fungal infections. These results support a role for SREBP-mediated iron regulation in fungal virulence, and they lay a foundation for further exploration of SREBP's role in iron homeostasis in other eukaryotes.
Assuntos
Antifúngicos/farmacologia , Aspergillus fumigatus/efeitos dos fármacos , Ergosterol/metabolismo , Ferro/metabolismo , Proteínas de Ligação a Elemento Regulador de Esterol/metabolismo , Animais , Aspergillus fumigatus/patogenicidade , Farmacorresistência Fúngica/genética , Regulação Fúngica da Expressão Gênica/genética , Homeostase , Humanos , Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/genética , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Sideróforos/metabolismo , Proteínas de Ligação a Elemento Regulador de Esterol/genética , Triazóis/farmacologiaRESUMO
Tumour necrosis factor (TNF) is primarily secreted by monocytes/macrophages and activated T lymphocytes in response to fungal infections. TNF acts through TNF receptor 1 (TNFR1) triggering a pro-inflammatory response, and therefore plays a pivotal role in immune regulation and host immune responses. We hypothesized that single nucleotide polymorphisms (SNPs) in TNFR1 gene may influence the innate immune response against Aspergillus. Three SNPs were genotyped in 275 individuals (144 immunocompromised haematological patients with high-risk of developing IPA and 131 healthy controls): TNFR1(-383(A/C)) (rs2234649) and TNFR1(-609(G/T)) (rs4149570) in the 5 prime UTR region, and TNFR1(+36(A/G)) SNP (rs767455) in the first exon of the gene. Of the 144 haematological patients, 77 patients developed Invasive Pulmonary Aspergillosis (IPA) infection and the remaining 67 patients were not infected. TNFR1(+36(A/G)) and TNFR1(-609(G/T)) were associated with IPA susceptibility (p=0.033 and p=0.018, respectively). A role of TNFR1 genetic variants in the susceptibility of patients to develop IPA was also supported by the significantly lower TNFR1 mRNA expression level in IPA than in IPA-resistant patients and the strong correlation between the TNFR1(-609) genetic variant and the expression levels of TNFR1. There was also a tendency for a higher frequency of galactomannan (GM) positivity in patients with TNFR1(-609G/G) genotype than in patients with TNFR1(-609G/T) (p=0.0909) or TNFR1(-609T/T) (p=0.0913) genotype. Predictive sequence analysis of the effects of TNFR1(-609) promoter polymorphism revealed that this SNP might play a critical role in modifying the affinity of ICSBP/IRF-8, a transcription factor that is involved in the TNFR1-mediated activation of NFkappaB signalling pathway. Taken together, these data suggest that TNFR1 polymorphisms influence the risk of IPA disease and might be useful for risk stratification strategies. These findings need to be confirmed in validation studies with larger samples of haematological patients.
Assuntos
Aspergilose/genética , Predisposição Genética para Doença , Pneumopatias Fúngicas/genética , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/análise , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Aspergilose/etiologia , Biomarcadores , Feminino , Galactose/análogos & derivados , Humanos , Fatores Reguladores de Interferon/metabolismo , Pneumopatias Fúngicas/etiologia , Masculino , Mananas/análiseRESUMO
Invasive aspergillosis (IA) is a common and life-threatening infection in immunocompromised individuals. A number of environmental and epidemiologic risk factors for developing IA have been identified. However, genetic factors that affect risk for developing IA have not been clearly identified. We report that host genetic differences influence outcome following establishment of pulmonary aspergillosis in an exogenously immune suppressed mouse model. Computational haplotype-based genetic analysis indicated that genetic variation within the biologically plausible positional candidate gene plasminogen (Plg; Gene ID 18855) correlated with murine outcome. There was a single nonsynonymous coding change (Gly110Ser) where the minor allele was found in all of the susceptible strains, but not in the resistant strains. A nonsynonymous single nucleotide polymorphism (Asp472Asn) was also identified in the human homolog (PLG; Gene ID 5340). An association study within a cohort of 236 allogeneic hematopoietic stem cell transplant (HSCT) recipients revealed that alleles at this SNP significantly affected the risk of developing IA after HSCT. Furthermore, we demonstrated that plasminogen directly binds to Aspergillus fumigatus. We propose that genetic variation within the plasminogen pathway influences the pathogenesis of this invasive fungal infection.
Assuntos
Alelos , Aspergilose/genética , Aspergilose/microbiologia , Predisposição Genética para Doença , Pneumopatias Fúngicas/genética , Pneumopatias Fúngicas/microbiologia , Plasminogênio/genética , Transdução de Sinais/genética , Animais , Aspergilose/mortalidade , Aspergilose/patologia , Aspergillus fumigatus/imunologia , Aspergillus fumigatus/patogenicidade , Feminino , Humanos , Pneumopatias Fúngicas/imunologia , Pneumopatias Fúngicas/mortalidade , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos AKR , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Endogâmicos MRL lpr , Camundongos Endogâmicos NZB , Camundongos Knockout , Plasminogênio/fisiologiaRESUMO
OBJECTIVE: The aim of this study was to determine whether interleukin-1 alpha (IL1alpha), interleukin-1 beta (IL1beta), and IL1 receptor antagonist (IL1Ra) polymorphisms are implicated in invasive pulmonary aspergillosis (IPA) pathogenesis. MATERIALS AND METHODS: Subjects comprised 110 hematological patients and 148 healthy controls. Genotypic and allelic frequencies were similar between hematological patients and controls. IPA was diagnosed in 59 of the 110 patients according to consensus criteria published by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC/IFICG). RESULTS AND DISCUSSIONS: Individual locus analysis showed that IL1alpha and IL1Ra polymorphisms were not associated with the presence of IPA (p = 0.560 and p = 0.680, respectively). However, a trend towards a higher presence of IL1beta( - ) (511TT) genotype (or IL1beta(-511T) allele) in the IPA group than in the non-IPA patient group (p = 0.092 and p = 0.095, respectively) was found. Haplotype analysis revealed that VNTR2/-889C/-511T haplotype was strongly associated with susceptibility to develop IPA infection (p = 0.020). Haplotype analysis also showed an association between VNTR2/-889C/-511C haplotype and resistance to IPA infection (p = 0.028). Furthermore, patients with IL1Ra VNTR2/2 and IL1beta(-511)T/T genotypes had a higher positive serum galactomannan percentage versus patients with other genotypes. Finally, C-reactive protein (CRP) production was significantly associated with IL1 gene cluster polymorphisms, although CRP values were similar between IPA and non-IPA groups. CONCLUSION: These findings indicate a critical role of IL1 gene cluster polymorphisms in the susceptibility to IPA infection and CRP production.
Assuntos
Aspergilose/genética , Interleucina-1alfa/genética , Interleucina-1beta/genética , Pneumopatias Fúngicas/genética , Receptores Tipo I de Interleucina-1/genética , Aspergilose/sangue , Aspergilose/etiologia , Aspergillus/imunologia , Proteína C-Reativa/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Galactose/análogos & derivados , Predisposição Genética para Doença , Haplótipos , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Hospedeiro Imunocomprometido , Interleucina-1alfa/sangue , Interleucina-1alfa/imunologia , Interleucina-1beta/sangue , Interleucina-1beta/imunologia , Pneumopatias Fúngicas/sangue , Pneumopatias Fúngicas/etiologia , Masculino , Mananas/sangue , Família Multigênica , Polimorfismo de Nucleotídeo Único , Receptores Tipo I de Interleucina-1/sangue , Receptores Tipo I de Interleucina-1/imunologia , Estatística como AssuntoRESUMO
Several lines of evidence indicate that IL6 plays a major role in the pathogenesis of a number of infectious diseases. The purpose of this study was to determine whether IL6 promoter polymorphisms were genetic markers of susceptibility to invasive pulmonary aspergillosis (IPA). To clarify the relationship between IL6 variants and IPA susceptibility, the IL6-174(G/C) and IL6-634(G/C) promoter single nucleotide polymorphisms (SNPs) were defined and plasma concentrations of IL6 and C-reactive protein (CRP) were measured. The study included 130 patients with haematological malignancies and 145 unrelated healthy individuals. No significant genotypic and allelic differences were found between patients and healthy controls. IPA was diagnosed in 71 of 130 patients according to the consensus criteria. CRP values were significantly associated with both IL6-174(G/C) and IL6-634(G/C) polymorphisms. However, IL6 and CRP values were similar between IPA and non-IPA groups. Neither IL6-174(G/C) nor IL6-634(G/C) polymorphisms were associated with IPA infection (p=0.414 and p=0.184, respectively). No evidence of association was found between allelic frequencies of IL6 promoter polymorphisms and IPA infection (p=0.864 and p=0.104, respectively). Further, no association was detected between IL6 genotypes and clinical profiles in IPA patients. Haplotype analysis also revealed that IL6 gene was not associated with IPA susceptibility in a Spanish population (Global haplotype association p value: 0.31). These findings suggest that IL6 polymorphisms influence on CRP circulating levels but are not associated with IPA susceptibility. Because the sample size is relatively small in our series, larger investigations of IL6-174(G/C)/IL6-634(G/C) genotypes and haplotypes are needed to clarify the potential role of this gene in the pathophysiology of IPA infection.
Assuntos
Aspergilose/genética , Proteína C-Reativa/análise , Predisposição Genética para Doença , Interleucina-6/genética , Pneumopatias Fúngicas/genética , Polimorfismo de Nucleotídeo Único , Feminino , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Regiões Promotoras GenéticasRESUMO
The murine model of paracoccidioidomycosis, the most important South American endemic mycosis, mimics the human disease: resistance is associated with preserved cellular immunity while T-cell anergy is related with susceptibility. In the present study we asked whether a previous s.c. infection which induces strong cellular immunity would protect mice against a lethal pulmonary challenge. It was found that susceptible but not resistant mice developed immunoprotection and aseptic cure of infection. Immunoprotection led to reversal of DTH anergy, increased levels of antibodies and pulmonary IL-12, IL-2 and IL-4 indicating a balanced type 1/type 2 response. On the contrary, no marked differences in A/Sn infection and immunity were observed. Depletion experiments showed that immunoprotection required the cooperative action of CD4(+) and CD8(+) T cells in association with IFN-gamma and IL-12. Altogether, these observations demonstrated that susceptible hosts can develop sterilizing immunity and defined the main immunological requirements to control secondary paracoccidioidomycosis.
Assuntos
Vacinas Fúngicas/administração & dosagem , Imunização , Pneumopatias Fúngicas/genética , Pneumopatias Fúngicas/prevenção & controle , Paracoccidioides/imunologia , Paracoccidioidomicose/genética , Paracoccidioidomicose/prevenção & controle , Animais , Anticorpos Antifúngicos/sangue , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Suscetibilidade a Doenças/imunologia , Predisposição Genética para Doença , Hipersensibilidade Tardia , Injeções Subcutâneas , Interferon gama/imunologia , Interleucinas/imunologia , Pulmão/imunologia , Pneumopatias Fúngicas/sangue , Pneumopatias Fúngicas/imunologia , Masculino , Camundongos , Paracoccidioidomicose/sangue , Paracoccidioidomicose/imunologia , Subpopulações de Linfócitos TRESUMO
This present study was undertaken to examine the role of the host response to Aspergillus fumigatus in the development of clinical symptoms of invasive pulmonary aspergillosis (IPA). The natural outcome and response to IPA infection varies between individuals. Whereas some variation may be attributable to fungi and environmental variables, it is probable that host genetic background also plays a significant role. Interleukin (IL)-10 has a key function in the regulation of cellular immune responses and is involved in various inflammatory diseases. IL-10 promoter carries a polymorphism that has been associated to production levels. Our aim was to investigate the role of this polymorphism in susceptibility to develop IPA infection. The study included 120 haematological patients and 124 age and sex-matched controls and bi-allelic IL-10 -1082(G/A) polymorphism was examined. Genotypic (p=0.385) and allelic frequencies (p=0.527, OR=0.89, 95% CI=0.78-1.60) were similar between patients and healthy controls. IPA was diagnosed in 59 of the 120 patients according to consensus criteria published by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC/IFICG). Our results provide evidence that IL-10 -1082(AA) genotype is associated with resistance to develop IPA (p=0.001). Allele frequency of IL-10 -1082A allele was weakly associated with susceptibility to develop IPA infection (p=0.052). In conclusion, these results suggest that differential production of IL-10 may alter the risk for IPA in haematological patients.
Assuntos
Aspergilose/genética , Interleucina-10/genética , Pneumopatias Fúngicas/genética , Adulto , Aspergilose/imunologia , Feminino , Galactose/análogos & derivados , Predisposição Genética para Doença , Humanos , Interleucina-10/imunologia , Pneumopatias Fúngicas/imunologia , Masculino , Mananas/imunologia , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas , Estudos ProspectivosRESUMO
Tumor necrosis factor alpha (TNF-alpha) and lymphotoxin alpha (LT-alpha) are pivotal mediators of inflammatory responses in fungal infection diseases. We hypothesized that polymorphisms in genes of these cytokines or their receptors might increase the susceptibility of hematologic patients to develop invasive pulmonary aspergillosis (IPA). One hundred two hematologic patients and 124 age-matched controls were enrolled in the study, and the following standard single nucleotide polymorphisms were investigated: TNF-alpha -308 and +489, LT-alpha +252 and Tumor Necrosis Factor Receptor 2 (TNFR2) +676. Variable number of tandem repeats (VNTRs) at position -322 of the TNFR2 gene were also studied. Genotypic and allelic frequencies were similar between patients and controls. IPA was diagnosed in 54 of the 102 patients according to consensus criteria published by the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group. TNF-alpha and LT-alpha polymorphisms were not associated with presence of IPA. Susceptibility to IPA was strongly associated with VNTR at position -322 in the promoter region of the TNR2 gene (p = 0.029) but was not associated with the presence of TNFR2 +676 polymorphism. A genetic difference in TNFR2 promoter VNTR may play a major role in susceptibility to IPA infection.
Assuntos
Aspergilose/genética , Aspergilose/metabolismo , Predisposição Genética para Doença , Pneumopatias Fúngicas/genética , Pneumopatias Fúngicas/metabolismo , Repetições Minissatélites/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Aspergilose/terapia , Feminino , Marcadores Genéticos , Humanos , Pneumopatias Fúngicas/terapia , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Estudos ProspectivosRESUMO
Aspergillus fumigatus is ubiquitous and yet causes invasive, chronic and allergic disease of the lung. Chronic cavitary pulmonary aspergillosis (CCPA) is a slowly destructive form of pulmonary aspergillosis, without immunocompromise. We hypothesized that CCPA cytokine gene polymorphisms would differ from patients with allergic bronchopulmonary aspergillosis (ABPA) and uninfected controls. We have profiled functional cytokine gene polymorphisms for interleukin (IL)-10, IL-15, transforming growth factors (TGF)-beta1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma in patients with CCPA (n = 24) who were compared with other forms of aspergillosis (mostly ABPA) (n = 15) and with ethnically matched controls (n = 65-330). Results are described with reference to the high-producing genotype in each case. Susceptibility to aspergillosis (all patients compared with normal controls) was associated with higher frequency of the IL-15 +13689*A allele (OR = 2.37, P = 0.0028) and A/A genotype (chi(2) = 10.31, P < 0.001), with a lower frequency of the TNF-alpha-308*A/A genotype (chi(2) = 11.05, P < 0.01). Within the aspergillosis patients, CCPA is associated with lower frequency of the IL-10 -1082*G allele (OR = 0.38, P = 0.0006) and G/G genotype (chi(2) = 22.45, P < 0.001) and with a lower frequency of the TGF-beta1 +869 *T allele (OR +0.42, P < 0.0029) and T/T genotype (chi(2) = 17.82, P < 0.001) compared with non-CCPA patients and normal controls. Patients infected with Aspergillus appear to be higher producers of IL-15, a Th2-promoting cytokine, and lower producers of TNF-alpha, a cytokine central in protective responses. CCPA occurs in patients who are genetically lower producers of both IL-10 and TGF-beta1. As these cytokines are regulatory and anti-inflammatory, CCPA may be a consequence of poor inflammatory response control in the lung.
Assuntos
Aspergilose Broncopulmonar Alérgica/genética , Aspergilose/genética , Aspergillus fumigatus/imunologia , Citocinas/genética , Citocinas/imunologia , Pneumopatias Fúngicas/genética , Adulto , Aspergilose/imunologia , Aspergilose Broncopulmonar Alérgica/imunologia , Estudos de Casos e Controles , Inglaterra , Predisposição Genética para Doença , Genótipo , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-15/genética , Pneumopatias Fúngicas/imunologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Sinusite/microbiologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta1 , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
The immunoprotective and immunomodulatory role of neutrophils during pulmonary infection of resistant (A/J) and susceptible (B10.A) mice to Paracoccidioides brasiliensis was investigated. First, comparative studies about early cellular influx to the lungs demonstrated higher numbers of neutrophils in susceptible rather than in resistant mice. Neutrophil depletion resulted in decreased survival times of susceptible but not resistant mice. In both mouse strains, depletion led to increased fungal burdens at Week 1 of infection; however, only susceptible mice remained with increased pulmonary fungal loads and presented a dramatic fungal dissemination to liver and spleen. At Week 1 of infection, treated and untreated B10.A and A/J mice were negative for delayed-type hypersensitivity (DTH) reactions, which remained negative for the susceptible strain. In contrast, from the second week onward, control and neutrophil-depleted, resistant mice became positive for DTH reactions. In B10.A mice, neutrophil depletion resulted in increased levels of interleukin (IL)-12 and IL-4 in the lungs, high levels of hepatic cytokines, and increased synthesis of T helper cell type 1 (Th1)- and Th2-regulated antibodies [immunoglobulin G1 (IgG1), IgA, and IgG3]. In neutrophil-depleted A/J mice, high levels of pulmonary IL-12 and granulocyte macrophage-colony stimulating factor were concomitant to diminished levels of hepatic cytokines and increased amounts of Th1-regulated isotypes (IgG2a, IgG2b, and IgG3). Differently from primary infection, neutrophil depletion did not alter immunoprotection in secondary paracoccidioidomycosis. As a whole, our data showed that the genetic patterns of hosts exert an important influence on the immunoprotective and immunoregulatory functions of neutrophils, which appear to be essential in situations devoid of cell-mediated immunity.
Assuntos
Imunidade Inata , Pneumopatias Fúngicas/imunologia , Neutrófilos/imunologia , Paracoccidioides/imunologia , Paracoccidioidomicose/imunologia , Animais , Anticorpos Antifúngicos/biossíntese , Anticorpos Antifúngicos/sangue , Anticorpos Antifúngicos/imunologia , Anticorpos Monoclonais/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Cruzamentos Genéticos , Citocinas/biossíntese , Citocinas/genética , Vacinas Fúngicas/imunologia , Hipersensibilidade Tardia/imunologia , Imunidade Inata/genética , Isotipos de Imunoglobulinas/biossíntese , Isotipos de Imunoglobulinas/imunologia , Procedimentos de Redução de Leucócitos , Fígado/metabolismo , Fígado/microbiologia , Fígado/patologia , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Pneumopatias Fúngicas/genética , Pneumopatias Fúngicas/patologia , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos , Paracoccidioidomicose/genética , Paracoccidioidomicose/patologia , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/imunologia , Baço/microbiologia , Baço/patologia , Células Th1/imunologia , Células Th2/imunologia , VacinaçãoRESUMO
Herein, we report that the intrapulmonary delivery of an adenovirus vector expressing KARAP/DAP12, an adaptor protein expressed in granulocytes and mononuclear cells, enhanced fungal clearance during experimental invasive pulmonary aspergillosis in neutropenic mice.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Adenoviridae/genética , Aspergilose/imunologia , Aspergillus fumigatus , Pneumopatias Fúngicas/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Aspergilose/genética , Aspergillus fumigatus/imunologia , Imunidade Inata/genética , Pulmão/microbiologia , Pulmão/patologia , Pneumopatias Fúngicas/genética , Camundongos , Camundongos Mutantes , Neutropenia/genética , Ativação TranscricionalRESUMO
Chronic granulomatous disease (CGD) is characterized by life-threatening bacterial and fungal infections. Treatment with posaconazole led to a complete response in 7 of 8 patients with CGD with invasive mold infections (7 proven cases and 1 possible case) after failure or intolerance of treatment with standard antifungal agents. In this preliminary study, salvage treatment with posaconazole was safe and effective.