TLR4 abrogates the Th1 immune response through IRF1 and IFN-beta to prevent immunopathology during L. infantum infection

Autor(es):Mostrar menos -

Sacramento, Lais Amorim ^[1] ; Benevides, Luciana ^{[1, 2]} ; Maruyama, Sandra Regina ^[3] ; Tavares, Lucas ^[4] ; Fukutani, Kiyoshi Ferreira ^[1] ; Francozo, Marcela ^{[5, 6]} ; Sparwasser, Tim ^{[5, 6, 7]} ; Cunha, Fernando Queiroz ^[8] ; Almeida, Roque Pacheco ^[9] ; da Silva, Joao Santana ^{[1, 2]} ; Carregaro, Vanessa ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, Ribeirao Preto - Brazil

^[2] Fiocruz MS, Bi Inst Translat Med, Rio De Janeiro - Brazil

^[3] Univ Fed Sao Carlos, Ctr Biol & Hlth Sci, Sao Carlos - Brazil

^[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Cellular & Mol Biol, Ribeirao Preto - Brazil

^[5] Hannover Med Sch MHH, Ctr Expt & Clin Infect Res Twincore, Inst Infect Immunol, Hannover - Germany

^[6] Helmholtz Ctr Infect Res HZI, Hannover - Germany

^[7] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Dept Med Microbiol & Hyg, D-55131 Mainz - Germany

^[8] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ribeirao Preto - Brazil

^[9] Univ Fed Sergipe, Ctr Biol & Hlth Sci, Aracaju, SE - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLOS PATHOGENS; v. 16, n. 3 MAR 2020.
• Citações Web of Science: 0

Resumo

A striking feature of human visceral leishmaniasis (VL) is chronic inflammation in the spleen and liver, and VL patients present increased production levels of multiple inflammatory mediators, which contribute to tissue damage and disease severity. Here, we combined an experimental model with the transcriptional profile of human VL to demonstrate that the TLR4-IFN-beta pathway regulates the chronic inflammatory process and is associated with the asymptomatic form of the disease. Tlr4-deficient mice harbored fewer parasites in their spleen and liver than wild-type mice. TLR4 deficiency enhanced the Th1 immune response against the parasite, which was correlated with an increased activation of dendritic cells (DCs). Gene expression analyses demonstrated that IRF1 and IFN-beta were expressed downstream of TLR4 after infection. Accordingly, IRF1- and IFNAR-deficient mice harbored fewer parasites in the target organs than wild-type mice due to having an increased Th1 immune response. However, the absence of TLR4 or IFNAR increased the serum transaminase levels in infected mice, indicating the presence of liver damage in these animals. In addition, IFN-beta limits IFN-gamma production by acting directly on Th1 cells. Using RNA sequencing analysis of human samples, we demonstrated that the transcriptional signature for the TLR4 and type I IFN (IFN-I) pathways was positively modulated in asymptomatic subjects compared with VL patients and thus provide direct evidence demonstrating that the TLR4-IFN-I pathway is related to the nondevelopment of the disease. In conclusion, our results demonstrate that the TLR4-IRF1 pathway culminates in IFN-beta production as a mechanism for dampening the chronic inflammatory process and preventing immunopathology development. Author summary Visceral leishmaniasis (VL) is one of the most lethal neglected tropical diseases and is caused by Leishmania parasites. Most subjects infected with Leishmania present subclinical VL symptoms, and their immune response is mediated by Th1 cells and immunoregulatory mechanisms. However, when infection progresses to disease, VL patients present increased levels of inflammatory mediators in the serum which are related to the severity of disease. During infection, Toll-like receptors (TLRs) interact with Leishmania parasites and contribute to the outcome of the disease. Herein, we report that TLR4 signaling hampers the chronic immune response during VL to prevent immunopathology. TLR4 triggers the activation of IRF1 and thus induces the transcription of IFN-beta, which in turn acts directly on Th1 cells to limit the production of IFN-gamma. In addition, a transcription analysis of human VL samples provides direct evidence demonstrating that the TLR4-IFN-I pathway is related to the asymptomatic form of the disease. Collectively, our findings reveal that TLR4 hampers the Th1 immune response through IRF1 and IFN-beta to prevent immunopathology during VL. (AU)

• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 15/12526-2 - Mecanismos reguladores da resposta inflamatória na gravidade da Leishmaniose visceral
• Beneficiário: Vanessa Carregaro Pereira
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 17/04347-6 - Cooperação entre as vias de sinalização mediadas por TLR4 e IL-1R na regulação da resposta imune durante a infecção humana e experimental por l. infantum
• Beneficiário: Laís Amorim Sacramento
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 12/14524-9 - Modulação da diferenciação de linfócitos T em infecções por protozoários, fungos e bactérias
• Beneficiário: João Santana da Silva
• Linha de fomento: Auxílio à Pesquisa - Temático