Leishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition
Authors: Marcus Vinícius G da Silva
Ricardo de Godoi M Ferreira
Angela K Cruz
Marcos Michel Souza
Catarina V Horta
Lilian M Cantanhêde
Fabiani G Frantz
Lucas B Lorenzon
Patrick F da Silva
Dario S Zamboni
Marisa Dilucca
Djalma S Lima-Junior
Tamara S Rodrigues
Fausto Almeida
Alexandre L N Silva
Renan V H de Carvalho
Journal: Nature Communications (2019)
Discipline: Multidisciplinary
Keywords: Leishmania RNA virus; mucocutaneous Leishmaniasis; TLR3 activation; TRIF; type I IFN production
Affiliations: Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil., Laboratório de Imunologia e Epigenética, Departamento de Análises Clínicas, Toxicológicas e Bromatologia, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil., Departamento de Bioquímica e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil., Fundação Oswaldo Cruz, Unidade Rondônia, Porto Velho, Rondônia, Brazil., Departamento de Biologia Celular e Molecular e Bioagentes Patogênicos, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil. .

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. 

Retracted: No

PubPeer comments:
 At the authors request, the Editor-in-Chief and Publisher of Cancer Management and Research wish to retract the published article. Following a review of their article the authors found some errors had been made in Figure 4E, specifically images in panels Migration miR-935 inhibitor + si-IREB2 + and Invasion miR-935 inhibitor + si-IREB2 +. After carefully going through the raw data for their study the authors were unable to locate the original images for Figure 4E. The authors were also unable to locate the original images for the western blots shown in the article. Both the editor and authors determined the findings of this study could no longer be supported and agreed for the article to be retracted. The authors wish to apologise for this error. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as u201cRetractedu201d. ,