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

Renan V. H. de Carvalho, Djalma S. Lima-Junior, Marcus Vinícius G. Silva, Marisa Dilucca, Tamara S. Rodrigues, Catarina V. Horta, Alexandre L. N. Silva, Patrick F. Silva, Fabiani G. Frantz, Lucas B. Lorenzon, Marcos Michel Souza, Fausto Almeida, Lilian M. Cantanhêde, Ricardo de Godoi M. Ferreira, Angela K. Cruz and Dario S. Zamboni ()
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Renan V. H. de Carvalho: Universidade de São Paulo
Djalma S. Lima-Junior: Universidade de São Paulo
Marcus Vinícius G. Silva: Universidade de São Paulo
Marisa Dilucca: Universidade de São Paulo
Tamara S. Rodrigues: Universidade de São Paulo
Catarina V. Horta: Universidade de São Paulo
Alexandre L. N. Silva: Universidade de São Paulo
Patrick F. Silva: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo
Fabiani G. Frantz: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo
Lucas B. Lorenzon: Universidade de São Paulo
Marcos Michel Souza: Universidade de São Paulo
Fausto Almeida: Universidade de São Paulo
Lilian M. Cantanhêde: Fundação Oswaldo Cruz, Unidade Rondônia
Ricardo de Godoi M. Ferreira: Fundação Oswaldo Cruz, Unidade Rondônia
Angela K. Cruz: Universidade de São Paulo
Dario S. Zamboni: Universidade de São Paulo

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-13356-2

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