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

• Published in: Nature communications Vol. 10; no. 1; pp. 5273 - 17
• Main Authors: de Carvalho, Renan V. H., Lima-Junior, Djalma S., da Silva, Marcus Vinícius G., Dilucca, Marisa, Rodrigues, Tamara S., Horta, Catarina V., Silva, Alexandre L. N., da Silva, Patrick F., Frantz, Fabiani G., Lorenzon, Lucas B., Souza, Marcos Michel, Almeida, Fausto, Cantanhêde, Lilian M., Ferreira, Ricardo de Godoi M., Cruz, Angela K., Zamboni, Dario S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.11.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 631/250/2504/342; 631/250/255/1715; 631/250/256/2177; 631/326/417; 631/326/421; Animals; Autophagy; Autophagy - immunology; Cell activation; Humanities and Social Sciences; Humans; Immunity, Innate - immunology; Inflammasomes; Inflammasomes - immunology; Innate immunity; Interferon; Interleukin-1beta - immunology; Interleukin-1beta - metabolism; Leishmania; Leishmania - immunology; Leishmania - physiology; Leishmania - virology; Leishmaniasis, Mucocutaneous - immunology; Leishmaniasis, Mucocutaneous - parasitology; Leishmaniasis, Mucocutaneous - virology; Macrophages; Macrophages - immunology; Mice; Mucocutaneous leishmaniasis; multidisciplinary; NLR Family, Pyrin Domain-Containing 3 Protein - immunology; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Parasitic diseases; Phagocytosis; RNA viruses; RNA Viruses - immunology; RNA Viruses - physiology; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - immunology; TLR3 protein; Toll-Like Receptor 3 - immunology; Toll-Like Receptor 3 - metabolism; Toll-like receptors; Vector-borne diseases; Virulence; Virulence factors; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-13356-2

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.