Leishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition

Autor(es):Mostrar menos -

de Carvalho, Renan V. H. ^[1] ; Lima-Junior, Djalma S. ^[1] ; da Silva, Marcus Vinicius G. ^[1] ; Dilucca, Marisa ^[1] ; Rodrigues, Tamara S. ^[1] ; Horta, Catarina V. ^[1] ; Silva, Alexandre L. N. ^[1] ; da Silva, Patrick F. ^[2] ; Frantz, Fabiani G. ^[2] ; Lorenzon, Lucas B. ^[1] ; Souza, Marcos Michel ^[1] ; Almeida, Fausto ^[3] ; Cantanhede, Lilian M. ^[4] ; Ferreira, Ricardo de Godoi M. ^[4] ; Cruz, Angela K. ^[1] ; Zamboni, Dario S. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Biol Celular & Mol Bioagentes Patogen, Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Anal Clin, Lab Imunol & Epigenet, Ribeirao Preto - Brazil

^[3] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Bioquim & Imunol, Sao Paulo, SP - Brazil

^[4] Fundacao Oswaldo Cruz, Unidade Rondonia, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: NATURE COMMUNICATIONS; v. 10, NOV 21 2019.
• Citações Web of Science: 0

Resumo

Leishmania RNA virus (LRV) is an important virulence factor associated with the development of mucocutaneous Leishmaniasis, a severe form of the disease. LRV-mediated disease exacerbation relies on TLR3 activation, but downstream mechanisms remain largely unexplored. Here, we combine human and mouse data to demonstrate that LRV triggers TLR3 and TRIF to induce type I IFN production, which induces autophagy. This process results in ATG5-mediated degradation of NLRP3 and ASC, thereby limiting NLRP3 inflammasome activation in macrophages. Consistent with the known restricting role of NLRP3 for Leishmania replication, the signaling pathway triggered by LRV results in increased parasite survival and disease progression. In support of this data, we find that lesions in patients infected with LRV+ Leishmania are associated with reduced inflammasome activation and the development of mucocutaneous disease. Our findings reveal the mechanisms triggered by LRV that contribute to the development of the debilitating mucocutaneous form of Leishmaniasis. (AU)

• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 14/04684-4 - O inflamassoma na resposta contra patógenos intracelulares e os mecanismos microbianos relacionados à evasão
• Beneficiário: Dario Simões Zamboni
• Modalidade de apoio: Auxílio à Pesquisa - Temático