Avaliação do papel da via de sinalização de TREM-1 na leishmaniose cutânea localizada (LCL) humana

• Ano de defesa: 2019
• Autor(a) principal: Ampuero, Mariana Rosa
• Orientador(a): Tavares, Natalia Machado
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Instituto Gonçalo Moniz
• Link de acesso: https://www.arca.fiocruz.br/handle/icict/37358

Leishmaniasis remains one of the most neglected tropical diseases in the world. The immune response of the host against Leishmania plays a critical role in promoting parasite death and also promotes the severity of the disease. The Myeloid Cell Expression Receptor (TREM) has recently been identified as an immune response amplifier, which acts synergistically with Toll-like receptors (TLRs) in the production of pro-inflammatory mediators. TREM-1 is expressed strictly in myeloide lineage cells, mainly neutrophils. Its signaling form depends on the adaptive protein DAP12, which results in the activation of NFêB and the expression of reference genes, as well as in the degranulation, production of ROS and cytokines. OBJECTIVE: Based on this, the present study investigated the role of TREM-1 during L. braziliensis infection. MATERIAL AND METHODS: First, public transcriptome data of lesions from patients infected by L. braziliensis compared to not infected skin obtained from GEODataSets. After, the results were validated by real-time PCR with new samples. Finally, the mechanisms of activation of TREM-1 during human neutrophil infection in vitro were investigated. RESULTS: The transcriptome data analysis demonstrated an increase in TREM-1 expression, including all signaling molecules. These results were confirmed by RT-qPCR and immunohistochemistry in new samples. On the other hand, a negative correlation of messenger RNA of TREM-1, DAP12, TLR2 and TLR4 was observed on the circulating neutrophils of these patients. In addition, exposure to L. braziliensis increased the expression of TREM-1 on the surface of human neutrophils, leading to the degranulation of matrix metalloproteinase 9. Finally, TREM-1 and TLR2 are synergists in neutrophil degeneration but not in internalization of L brasiliensis. CONCLUSION: TREM-1 may be a potential target for modulation of inflammatory response in LCL, remaining the ability of neutrophil to kill Leishmania.