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Biomed Pharmacother ; 137: 111341, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33561646


Mycobacterium bovis (M. bovis) is a member of mycobacterium tuberculosis complex (MTBC), and a causative agent of chronic respiratory disease in a wide range of hosts. Bacillus Calmette-Guerin (BCG) vaccine is mostly used for the prevention of childhood tuberculosis. Further substantial implications are required for the development and evaluation of new tuberculosis (TB) vaccines as well as improving the role of BCG in TB control strategies. In this study, we prepared PLGA nanoparticles encapsulated with argF antigen (argF-NPs). We hypothesized, that argF nanoparticles mediate immune responses of BCG vaccine in mice models of M. bovis infection. We observed that mice vaccinated with argF-NPs exhibited a significant increase in secretory IFN-γ, CD4+ T cells response and mucosal secretory IgA against M. bovis infection. In addition, a marked increase was observed in the level of secretory IL-1ß, TNF-α and IL-10 both in vitro and in vivo upon argF-NPs vaccination. Furthermore, argF-NPs vaccination resulted in a significant reduction in the inflammatory lesions in the lung's tissues, minimized the losses in total body weight and reduced M. bovis burden in infected mice. Our results indicate that BCG prime-boost strategy might be a promising measure for the prevention against M. bovis infection by induction of CD4+ T cells responses and mucosal antibodies.

Vacina BCG/administração & dosagem , Vacina BCG/imunologia , Mycobacterium bovis , Nanopartículas/administração & dosagem , Ornitina Carbamoiltransferase/imunologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/imunologia , Tuberculose Bovina/prevenção & controle , Administração Intranasal , Animais , Formação de Anticorpos/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Bovinos , Linhagem Celular , Modelos Animais de Doenças , Feminino , Imunoglobulina A Secretora/metabolismo , Imunoglobulina G/sangue , Interferon gama/metabolismo , Interleucina-10/sangue , Interleucina-1beta/sangue , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos Endogâmicos BALB C , Mycobacterium bovis/crescimento & desenvolvimento , Mycobacterium bovis/patogenicidade , Nanopartículas/química , Ornitina Carbamoiltransferase/administração & dosagem , Ornitina Carbamoiltransferase/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Baço/microbiologia , Baço/patologia , Fator de Necrose Tumoral alfa/sangue
Pharmaceutics ; 12(12)2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33271900


Mycobacterium bovis (M. bovis) is a member of the Mycobacterium tuberculosis complex imposing a high zoonotic threat to human health. The limited efficacy of BCG (Bacillus Calmette-Guérin) and upsurges of drug-resistant tuberculosis require new effective vaccination approaches and anti-TB drugs. Poly (lactic-co-glycolic acid) (PLGA) is a preferential drug delivery system candidate. In this study, we formulated PLGA nanoparticles (NPs) encapsulating the recombinant protein bovine neutrophil ß-defensin-5 (B5), and investigated its role in immunomodulation and antimicrobial activity against M. bovis challenge. Using the classical water-oil-water solvent-evaporation method, B5-NPs were prepared, with encapsulation efficiency of 85.5% ± 2.5%. These spherical NPs were 206.6 ± 26.6 nm in diameter, with a negatively charged surface (ζ-potential -27.1 ± 1.5 mV). The encapsulated B5 protein from B5-NPs was released slowly under physiological conditions. B5 or B5-NPs efficiently enhanced the secretion of tumor necrosis factor α (TNF-α), interleukin (IL)-1ß and IL-10 in J774A.1 macrophages. B5-NPs-immunized mice showed significant increases in the production of TNF-α and immunoglobulin A (IgA) in serum, and the proportion of CD4+ T cells in spleen compared with B5 alone. In immunoprotection studies, B5-NPs-immunized mice displayed significant reductions in pulmonary inflammatory area, bacterial burden in the lungs and spleen at 4-week after M. bovis challenge. In treatment studies, B5, but not B5-NPs, assisted rifampicin (RIF) with inhibition of bacterial replication in the lungs and spleen. Moreover, B5 alone also significantly reduced the bacterial load in the lungs and spleen. Altogether, our findings highlight the significance of the B5-PLGA NPs in terms of promoting the immune effect of BCG and the B5 in enhancing the therapeutic effect of RIF against M. bovis.

BMC Infect Dis ; 19(1): 1031, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801478


BACKGROUND: Mycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice. METHODS: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 h before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and the role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR were performed to detect the expression of Type I IFNs and related genes. Lung lesions induced by M. bovis were assessed by histopathological examination. Viable bacterial count was determined by CFU assay. RESULTS: We observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell activation and recruitment in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice. CONCLUSIONS: Altogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.

Interferon Tipo I/metabolismo , Mycobacterium bovis/patogenicidade , Tuberculose/tratamento farmacológico , Tuberculose/metabolismo , Animais , Anticorpos/farmacologia , Citocinas/metabolismo , Feminino , Humanos , Interferon Tipo I/antagonistas & inibidores , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Mycobacterium bovis/imunologia , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/imunologia , Transdução de Sinais/efeitos dos fármacos
Int J Mol Sci ; 20(1)2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30577452


It is widely accepted that different strains of Mycobacterium tuberculosis have variable degrees of pathogenicity and induce different immune responses in infected hosts. Similarly, different strains of Mycobacterium bovis have been identified but there is a lack of information regarding the degree of pathogenicity of these strains and their ability to provoke host immune responses. Therefore, in the current study, we used a mouse model to evaluate various factors involved in the severity of disease progression and the induction of immune responses by two strains of M. bovis isolated from cattle. Mice were infected with both strains of M. bovis at different colony-forming unit (CFU) via inhalation. Gross and histological findings revealed more severe lesions in the lung and spleen of mice infected with M. bovis N strain than those infected with M. bovis C68004 strain. In addition, high levels of interferon-γ (IFN-γ), interleukin-17 (IL-17), and IL-22 production were observed in the serum samples of mice infected with M. bovis N strain. Comparative genomic analysis showed the existence of 750 single nucleotide polymorphisms and 145 small insertions/deletions between the two strains. After matching with the Virulence Factors Database, mutations were found in 29 genes, which relate to 17 virulence factors. Moreover, we found an increased number of virulent factors in M. bovis N strain as compared to M. bovis C68004 strain. Taken together, our data reveal that variation in the level of pathogenicity is due to the mutation in the virulence factors of M. bovis N strain. Therefore, a better understanding of the mechanisms of mutation in the virulence factors will ultimately contribute to the development of new strategies for the control of M. bovis infection.

Interações Hospedeiro-Patógeno/imunologia , Mycobacterium bovis , Tuberculose Bovina/genética , Tuberculose Bovina/microbiologia , Animais , Biópsia , Bovinos , Citocinas/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Patógeno/genética , Pulmão/patologia , Camundongos , Tipagem de Sequências Multilocus , Mutação , Mycobacterium bovis/classificação , Mycobacterium bovis/genética , Mycobacterium bovis/imunologia , Mycobacterium bovis/patogenicidade , Polimorfismo de Nucleotídeo Único , Baço/patologia , Tuberculose Bovina/imunologia , Virulência/genética , Fatores de Virulência