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

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.

SUBMITTER: de Carvalho RVH

PROVIDER: S-EPMC6872735 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

de Carvalho Renan V H RVH Lima-Junior Djalma S DS da Silva Marcus Vinícius G MVG Dilucca Marisa M Rodrigues Tamara S TS Horta Catarina V CV Silva Alexandre L N ALN da Silva Patrick F PF Frantz Fabiani G FG Lorenzon Lucas B LB Souza Marcos Michel MM Almeida Fausto F Cantanhêde Lilian M LM Ferreira Ricardo de Godoi M RGM Cruz Angela K AK Zamboni Dario S DS

Nature communications 20191121 1

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 NLRP ...[more]

PMID: 31754185

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Project description:Microtubules play critical roles in regulating the activation of NLRP3 inflammasome and microtubule-destabilizing agents such as colchicine have been shown to suppress the activation of this inflammasome. However, it remains largely unknown whether paclitaxel, a microtubule-stabilizing agent being used in cancer therapy, has any influences on NLRP3 inflammasome activation. Here we showed that paclitaxel pre-treatment greatly enhanced ATP- or nigericin-induced NLRP3 inflammasome activation as indicated by increased release of cleaved caspase-1 and mature IL-1?, enhanced formation of ASC speck, and increased gasdermin D cleavage and pyroptosis. Paclitaxel time- and dose-dependently induced ?-tubulin acetylation in LPS-primed murine and human macrophages and further increased ATP- or nigericin-induced ?-tubulin acetylation. Such increased ?-tubulin acetylation was significantly suppressed either by resveratrol or NAD+ (coenzyme required for deacetylase activity of SIRT2), or by genetic knockdown of MEC-17 (gene encoding ?-tubulin acetyltransferase 1). Concurrently, the paclitaxel-mediated enhancement of NLRP3 inflammasome activation was significantly suppressed by resveratrol, NAD+, or MEC-17 knockdown, indicating the involvement of paclitaxel-induced ?-tubulin acetylation in the augmentation of NLRP3 inflammasome activation. Similar to paclitaxel, epothilone B that is another microtubule-stabilizing agent also induced ?-tubulin acetylation and increased NLRP3 inflammasome activation in macrophages in response to ATP treatment. Consistent with the in vitro results, intraperitoneal administration of paclitaxel significantly increased serum IL-1? levels, reduced bacterial burden, dampened infiltration of inflammatory cells in the liver, and improved animal survival in a mouse model of bacterial infection. Collectively, our data indicate that paclitaxel potentiated NLRP3 inflammasome activation by inducing ?-tubulin acetylation and thereby conferred enhanced antibacterial innate responses, suggesting its potential application against pathogenic infections beyond its use as a chemotherapeutic agent.

Dataset Information

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

Publications

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

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