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Therapeutic Administration of Recombinant Paracoccin Confers Protection against Paracoccidioides brasiliensis Infection: Involvement of TLRs

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Paiva Alegre-Maller, Ana Claudia [1] ; Mendonca, Flavia Costa [1] ; da Silva, Thiago Aparecido [1] ; Oliveira, Aline Ferreira [1] ; Freitas, Mateus Silveira [1] ; Hanna, Ebert Seixas [1] ; Almeida, Igor C. [2] ; Gay, Nicholas J. [3] ; Roque-Barreira, Maria Cristina [1]
Número total de Autores: 9
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Biol Celular & Mol Bioagentes Patogen, Sao Paulo - Brazil
[2] Univ Texas El Paso, Dept Biol Sci, BBRC, El Paso, TX 79968 - USA
[3] Univ Cambridge, Dept Biochem, Cambridge CB2 1QW - England
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: PLoS Neglected Tropical Diseases; v. 8, n. 12 DEC 2014.
Citações Web of Science: 17

Background: Paracoccin (PCN) is an N-acetylglucosamine-binding lectin from the human pathogenic fungus Paracoccidioides brasiliensis. Recombinant PCN (rPCN) induces a T helper (Th) 1 immune response when prophylactically administered to BALB/c mice, protecting them against subsequent challenge with P. brasiliensis. In this study, we investigated the therapeutic effect of rPCN in experimental paracoccidioidomycosis (PCM) and the mechanism accounting for its beneficial action. Methodology/Principal Findings: Four distinct regimens of rPCN administration were assayed to identify which was the most protective, relative to vehicle administration. In all rPCN-treated mice, pulmonary granulomas were less numerous and more compact. Moreover, fewer colony-forming units were recovered from the lungs of rPCN-treated mice. Although all therapeutic regimens of rPCN were protective, maximal efficacy was obtained with two subcutaneous injections of 0.5 mg rPCN at 3 and 10 days after infection. The rPCN treatment was also associated with higher pulmonary levels of IL-12, IFN-gamma, TNF-alpha, nitric oxide (NO), and IL-10, without IL-4 augmentation. Encouraged by the pulmonary cytokine profile of treated mice and by the fact that in vitro rPCN-stimulated macrophages released high levels of IL-12, we investigated the interaction of rPCN with Toll-like receptors (TLRs). Using a reporter assay in transfected HEK293T cells, we verified that rPCN activated TLR2 and TLR4. The activation occurred independently of TLR2 heterodimerization with TLR1 or TLR6 and did not require the presence of the CD14 or CD36 co-receptors. The interaction between rPCN and TLR2 depended on carbohydrate recognition because it was affected by mutation of the receptor's N-glycosylation sites. The fourth TLR2 N-glycan was especially critical for the rPCN-TLR2 interaction. Conclusions/Significance: Based on our results, we propose that PCN acts as a TLR agonist. PCN binds to N-glycans on TLRs, triggers regulated Th1 immunity, and exerts a therapeutic effect against P. brasiliensis infection. (AU)

Processo FAPESP: 13/14161-6 - Imunomodulação por Paracoccina: mecanismos da proteção conferida contra a paracoccidioidomicose experimental
Beneficiário:Mateus Silveira Freitas
Modalidade de apoio: Bolsas no Brasil - Mestrado
Processo FAPESP: 12/20809-6 - Caracterização da interação de proteínas de micronema de Toxoplasma gondii com glicanas de TLR2
Beneficiário:Flávia Costa Mendonça Natividade
Modalidade de apoio: Bolsas no Brasil - Mestrado
Processo FAPESP: 14/05359-0 - Distribuição de paracoccina na superfície de Paracoccidioides brasiliensis e interação com receptores de células da imunidade inata: papel na fase aguda da paracoccidioidomicose
Beneficiário:Aline Ferreira de Oliveira Pereira
Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 12/09611-0 - Efeito da lectina ArtinM sobre as células T CD4+ e T CD8+ murinas
Beneficiário:Thiago Aparecido da Silva
Modalidade de apoio: Bolsas no Brasil - Doutorado
Processo FAPESP: 10/01112-9 - Avaliação da interação de paracoccina com receptores de células da imunidade inata, com vistas a determinar seu papel na fase aguda da paracoccidioidomicose
Beneficiário:Ana Claudia Paiva Alegre
Modalidade de apoio: Bolsas no Brasil - Doutorado