RESUMO
Given the impossibility to study the lung immune response during Mycobacterium tuberculosis-latent infection, and consequently, the mechanisms that control the bacterial load, it is reasonable to determine the activation of local immunity in the early phase of the infection. The phosphatidylinositol-3-kinase gamma enzyme (PI3Kγ) is involved in the leukocyte recruitment, phagocytosis and cellular differentiation, and therefore, it is considered a promising target for the development of immunotherapies for chronic inflammatory diseases. Mice genetically deficient in PI3Kγ (PI3Kγ-/-) or WT (Wild Type) were evaluated 15 days post-infection. The enzyme deficiency improved the resistance against infection, increased the frequency of CD4+IL-17+ cells, the production of IL-17 as well as the gene and protein expression of molecules associated with Th17â¯cell differentiation and neutrophil recruitment. Our findings show, for the first time, the participation of the PI3Kγ in vivo in the M. tuberculosis-infection, and suggest an association of Th17â¯cells with protection in the early phase of tuberculosis.
Assuntos
Classe Ib de Fosfatidilinositol 3-Quinase/deficiência , Pulmão/enzimologia , Mycobacterium tuberculosis/patogenicidade , Neutrófilos/enzimologia , Células Th17/enzimologia , Tuberculose Pulmonar/enzimologia , Tuberculose Pulmonar/imunologia , Animais , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Pulmão/imunologia , Pulmão/microbiologia , Ativação Linfocitária , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/imunologia , Infiltração de Neutrófilos , Neutrófilos/imunologia , Neutrófilos/microbiologia , Pneumonia/enzimologia , Pneumonia/imunologia , Pneumonia/microbiologia , Transdução de Sinais , Células Th17/imunologia , Células Th17/microbiologia , Fatores de Tempo , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/prevenção & controleRESUMO
Leukotrienes are reported to be potent proinflammatory mediators that play a role in the development of several inflammatory diseases such as asthma, rheumatoid arthritis and periodontal disease. Leukotrienes have also been associated with protection against infectious diseases. However, the role of leukotrienes in Mycobacterium tuberculosis infection is not understood. To answer this question, we studied the role of leukotrienes in the protective immune response conferred by prime-boost heterologous immunization against tuberculosis. We immunized BALB/c mice (4-11/group) with subcutaneous BCG vaccine (1 x 10(5) M. bovis BCG) (prime) followed by intramuscular DNA-HSP65 vaccine (100 µg) (boost). During the 30 days following the challenge, the animals were treated by gavage daily with MK-886 (5 mg·kg-1·day-1) to inhibit leukotriene synthesis. We showed that MK-886-treated mice were more susceptible to M. tuberculosis infection by counting the number of M. tuberculosis colony-forming units in lungs. The histopathological analysis showed an impaired influx of leukocytes to the lungs of MK-886-treated mice after infection, confirming the involvement of leukotrienes in the protective immune response against experimental tuberculosis. However, prime-boost-immunized mice treated with MK-886 remained protected after challenge with M. tuberculosis, suggesting that leukotrienes are not required for the protective effect elicited by immunization. Protection against M. tuberculosis challenge achieved by prime-boost immunization in the absence of leukotrienes was accompanied by an increase in IL-17 production in the lungs of these animals, as measured by ELISA. Therefore, these data suggest that the production of IL-17 in MK-886-treated, immunized mice could contribute to the generation of a protective immune response after infection with M. tuberculosis.
Assuntos
Animais , Feminino , Camundongos , Proteínas de Bactérias/imunologia , /imunologia , Leucócitos/imunologia , Leucotrienos/biossíntese , Tuberculose Pulmonar/prevenção & controle , Vacinas de DNA/imunologia , Vacina BCG/administração & dosagem , Vacina BCG/imunologia , Proteínas de Bactérias/administração & dosagem , Movimento Celular , /administração & dosagem , Citocinas/biossíntese , Imunização Secundária , Indóis/farmacologia , Antagonistas de Leucotrienos/farmacologia , Leucotrienos/agonistas , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Camundongos Endogâmicos BALB C , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia , Vacinas de DNA/administração & dosagemRESUMO
Leukotrienes are reported to be potent proinflammatory mediators that play a role in the development of several inflammatory diseases such as asthma, rheumatoid arthritis and periodontal disease. Leukotrienes have also been associated with protection against infectious diseases. However, the role of leukotrienes in Mycobacterium tuberculosis infection is not understood. To answer this question, we studied the role of leukotrienes in the protective immune response conferred by prime-boost heterologous immunization against tuberculosis. We immunized BALB/c mice (4-11/group) with subcutaneous BCG vaccine (1 x 10(5) M. bovis BCG) (prime) followed by intramuscular DNA-HSP65 vaccine (100 microg) (boost). During the 30 days following the challenge, the animals were treated by gavage daily with MK-886 (5 mg x kg(-1) x day(-1)) to inhibit leukotriene synthesis. We showed that MK-886-treated mice were more susceptible to M. tuberculosis infection by counting the number of M. tuberculosis colony-forming units in lungs. The histopathological analysis showed an impaired influx of leukocytes to the lungs of MK-886-treated mice after infection, confirming the involvement of leukotrienes in the protective immune response against experimental tuberculosis. However, prime-boost-immunized mice treated with MK-886 remained protected after challenge with M. tuberculosis, suggesting that leukotrienes are not required for the protective effect elicited by immunization. Protection against M. tuberculosis challenge achieved by prime-boost immunization in the absence of leukotrienes was accompanied by an increase in IL-17 production in the lungs of these animals, as measured by ELISA. Therefore, these data suggest that the production of IL-17 in MK-886-treated, immunized mice could contribute to the generation of a protective immune response after infection with M. tuberculosis.