Leishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition
| Autor: | Marisa Dilucca, Tamara S Rodrigues, Renan V. H. de Carvalho, Djalma S. Lima-Junior, Angela K. Cruz, Dario S. Zamboni, Ricardo de Godoi Mattos Ferreira, Fausto Almeida, Alexandre L. N. Silva, Fabiani Gai Frantz, Catarina V. Horta, Marcos Michel de Souza, Patrick F. da Silva, Lucas B. Lorenzon, Lilian Motta Cantanhêde, Marcus Vinicius Gomes da Silva |
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| Rok vydání: | 2019 |
| Předmět: |
Leishmaniasis
Mucocutaneous 0301 basic medicine MACRÓFAGOS Inflammasomes Interleukin-1beta General Physics and Astronomy Inflammasome Mice 0302 clinical medicine lcsh:Science Leishmania Multidisciplinary integumentary system biology Publisher Correction Pathogens Signal Transduction medicine.drug Parasitic infection Science Mucocutaneous zone Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Immunity NLR Family Pyrin Domain-Containing 3 Protein parasitic diseases Autophagy medicine Animals Humans RNA Viruses Monocytes and macrophages Innate immune system Macrophages Leishmaniasis General Chemistry medicine.disease biology.organism_classification Immunity Innate Toll-Like Receptor 3 030104 developmental biology TRIF TLR3 Immunology Parasitology lcsh:Q 030215 immunology |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-17 (2019) Nature Communications Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 2041-1723 |
| Popis: | 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. NLRP3 activation by Leishmania parasites is critical to the outcome of the disease. Here the authors show that LRV, a virus infecting Leishmania strains associated with more severe human disease, enables the parasite to suppress the inflammasome by activating type 1 interferon through TLR3, which leads to autophagy-mediated NLRP3 degradation. |
| Databáze: | OpenAIRE |
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