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1.
Microbes Infect ; 17(5): 337-44, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25817335

RESUMO

Nucleotide-binding oligomerization domain-2 (NOD2) is an innate immune receptor that recognizes peptidoglycan-derived muramyl dipeptide from intracellular bacteria and triggers proinflammatory signals. In this study, we sought to evaluate the role played by this receptor during early and late stages of infection with Mycobacterium avium in mice. We demonstrated that NOD2 knockout (KO) animals were able to control M. avium infection similarly to wild-type mice at all time points studied, even though IL-12 and TNF-α production was impaired in NOD2-deficient macrophages. At 100 days following infection with this bacterium, but not at 30 days post-infection, NOD2-deficient mice showed significantly diminished production of IFN-γ, as confirmed by reduced accumulation of IFN-γ and IL-12 mRNA in the spleens of KO mice. Additionally, a reduction in the size and in the number of lymphocytes/granulocytes of hepatic granulomas from NOD2 KO animals was observed only during late time points of M. avium infection. Taken together, these data demonstrate that NOD2 regulates type-1 cytokine responses to M. avium but is not required for the control of infection with this bacterium in vivo.


Assuntos
Citocinas/metabolismo , Mycobacterium avium/fisiologia , Proteína Adaptadora de Sinalização NOD2/metabolismo , Receptores Imunológicos/metabolismo , Animais , Citocinas/imunologia , Infecções/imunologia , Camundongos , Camundongos Knockout , Mycobacterium avium/citologia , Proteína Adaptadora de Sinalização NOD2/imunologia , Receptores Imunológicos/imunologia
2.
Infect Immun ; 83(3): 1210-6, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25583526

RESUMO

Brucella abortus is a Gram-negative bacterium that infects humans and cattle, causing a chronic inflammatory disease known as brucellosis. A Th1-mediated immune response plays a critical role in host control of this pathogen. Recent findings indicate contrasting roles for lipid mediators in host responses against infections. 5-Lipoxygenase (5-LO) is an enzyme required for the production of the lipid mediators leukotrienes and lipoxins. To determine the involvement of 5-LO in host responses to B. abortus infection, we intraperitoneally infected wild-type and 5-LO-deficient mice and evaluated the progression of infection and concomitant expression of immune mediators. Here, we demonstrate that B. abortus induced the upregulation of 5-LO mRNA in wild-type mice. Moreover, this pathogen upregulated the production of the lipid mediators leukotriene B4 and lipoxin A4 in a 5-LO-dependent manner. 5-LO-deficient mice displayed lower bacterial burdens in the spleen and liver and less severe liver pathology, demonstrating an enhanced resistance to infection. Host resistance paralleled an increased expression of the proinflammatory mediators interleukin-12 (IL-12), gamma interferon (IFN-γ), and inducible nitric oxide synthase (iNOS) during the course of infection. Moreover, we demonstrated that 5-LO downregulated the expression of IL-12 in macrophages during B. abortus infection. Our results suggest that 5-LO has a major involvement in B. abortus infection, by functioning as a negative regulator of the protective Th1 immune responses against this pathogen.


Assuntos
Araquidonato 5-Lipoxigenase/imunologia , Brucella abortus/imunologia , Brucelose/enzimologia , Brucelose/imunologia , Células Th1/imunologia , Animais , Araquidonato 5-Lipoxigenase/deficiência , Araquidonato 5-Lipoxigenase/genética , Carga Bacteriana , Brucelose/microbiologia , Brucelose/patologia , Progressão da Doença , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Imunidade Inata , Injeções Intraperitoneais , Interferon gama/genética , Interferon gama/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Leucotrieno B4/biossíntese , Lipoxinas/biossíntese , Fígado/imunologia , Fígado/microbiologia , Fígado/patologia , Macrófagos/imunologia , Macrófagos/microbiologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Baço/imunologia , Baço/microbiologia , Baço/patologia , Células Th1/microbiologia , Células Th1/patologia
3.
Eur J Immunol ; 43(9): 2373-85, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23716075

RESUMO

Mycobacterium avium has been reported to signal through both Toll-like receptor (TLR2) and TLR9. To investigate the role of TLR6 in innate immune responses to M. avium, TLR6, MyD88, TLR2, and TLR2/6 KO mice were infected with this pathogen. Bacterial burdens were higher in the lungs and livers of infected TLR6, TLR2, TLR2/6, and MyD88 KO mice compared with those in C57BL/6 mice, which indicates that TLR6 is required for the efficient control of M. avium infection. However, TLR6 KO spleen cells presented with normal M. avium induced IFN-γ responses as measured by ELISA and flow cytometry. In contrast, the production of IFN-γ in lung tissue was diminished in all studied KO mice. Furthermore, only MyD88 deficiency reduced granuloma areas in mouse livers. Moreover, we determined that TLR6 plays an important role in controlling bacterial growth within macrophages and in the production of TNF-α, IL-12, and IL-6 by M. avium infected DCs. Finally, the lack of TLR6 reduced activation of MAPKs and NF-κB in DCs. In summary, TLR6 is required for full resistance to M. avium and for the activation of DCs to produce proinflammatory cytokines.


Assuntos
Complexo Mycobacterium avium/imunologia , Infecção por Mycobacterium avium-intracellulare/imunologia , Receptor 6 Toll-Like/imunologia , Animais , Carga Bacteriana/imunologia , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Ativação Enzimática , Granuloma/imunologia , Humanos , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-12/biossíntese , Interleucina-6/biossíntese , Fígado/imunologia , Pulmão/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator 88 de Diferenciação Mieloide/deficiência , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , NF-kappa B/metabolismo , Transdução de Sinais/imunologia , Baço/imunologia , Receptor 2 Toll-Like/deficiência , Receptor 2 Toll-Like/genética , Receptor 2 Toll-Like/imunologia , Receptor 6 Toll-Like/deficiência , Receptor 6 Toll-Like/genética , Fator de Necrose Tumoral alfa/biossíntese
4.
Infect Immun ; 81(5): 1654-62, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23460520

RESUMO

Brucella abortus is recognized by several Toll-like receptor (TLR)-associated pathways triggering proinflammatory responses that affect both the nature and intensity of the immune response. Previously, we demonstrated that B. abortus-mediated dendritic cell (DC) maturation and control of infection are dependent on the adaptor molecule MyD88. However, the involvement of all TLRs in response to B. abortus infection is not completely understood. Therefore, we decided to evaluate the requirement for TLR6 in host resistance to B. abortus. Here, we demonstrated that TLR6 is an important component for triggering an innate immune response against B. abortus. An in vitro luciferase assay indicated that TLR6 cooperates with TLR2 to sense Brucella and further activates NF-κB signaling. However, in vivo analysis showed that TLR6, not TLR2, is required for the efficient control of B. abortus infection. Additionally, B. abortus-infected dendritic cells require TLR6 to induce tumor necrosis factor alpha (TNF-α) and interleukin-12 (IL-12). Furthermore, our findings demonstrated that the mitogen-activated protein kinase (MAPK) signaling pathway is impaired in TLR2, TLR6, and TLR2/6 knockout (KO) DCs when infected with B. abortus, which may account for the lower proinflammatory cytokine production observed in TLR6 KO mouse dendritic cells. In summary, the results presented here indicate that TLR6 is required to trigger innate immune responses against B. abortus in vivo and is required for the full activation of DCs to induce robust proinflammatory cytokine production.


Assuntos
Brucella abortus/imunologia , Brucelose/imunologia , Imunidade Inata/fisiologia , Receptor 6 Toll-Like/fisiologia , Análise de Variância , Animais , Citocinas/metabolismo , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Quinases de Proteína Quinase Ativadas por Mitógeno/fisiologia , NF-kappa B/metabolismo , Transdução de Sinais/imunologia , Baço/microbiologia , Receptor 2 Toll-Like/fisiologia , Receptor 6 Toll-Like/deficiência
5.
Infect Immun ; 77(1): 98-107, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18824533

RESUMO

In areas where schistosomiasis is endemic, a negative correlation is observed between atopy and helminth infection, associated with a low prevalence of asthma. We investigated whether Schistosoma mansoni infection or injection of parasite eggs can modulate airway allergic inflammation in mice, examining the mechanisms of such regulation. We infected BALB/c mice with 30 S. mansoni cercariae or intraperitoneally injected 2,500 schistosome eggs, and experimental asthma was induced by ovalbumin (OVA). The number of eosinophils in bronchoalveolar lavage fluid was higher in the asthmatic group than in asthmatic mice infected with S. mansoni or treated with parasite eggs. Reduced Th2 cytokine production, characterized by lower levels of interleukin-4 (IL-4), IL-5, and immunoglobulin E, was observed in both S. mansoni-treated groups compared to the asthmatic group. There was a reduction in the number of inflammatory cells in lungs of S. mansoni-infected and egg-treated mice, demonstrating that both S. mansoni infection and the egg treatment modulated the lung inflammatory response to OVA. Only allergic animals that were treated with parasite eggs had increased numbers of CD4(+) CD25(+) Foxp3(+) T cells and increased levels of IL-10 and decreased production of CCL2, CCL3, and CCL5 in the lungs compared to the asthmatic group. Neutralization of IL-10 receptor or depletion of CD25(+) T cells in vivo confirmed the critical role of CD4(+) CD25(+) Foxp3(+) regulatory T cells in experimental asthma modulation independent of IL-10.


Assuntos
Antígenos de Protozoários/imunologia , Asma/imunologia , Linfócitos T CD4-Positivos/imunologia , Schistosoma mansoni/imunologia , Esquistossomose/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Asma/prevenção & controle , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Linfócitos T CD4-Positivos/química , Citocinas/análise , Eosinófilos/imunologia , Feminino , Citometria de Fluxo , Imunoglobulina E/análise , Subunidade alfa de Receptor de Interleucina-2/análise , Contagem de Leucócitos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Esquistossomose/complicações , Subpopulações de Linfócitos T/química
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