| Texto completo | |
| Autor(es): |
Fernandes, J. C. R.
;
Muxel, S. M.
;
Lopez-Gonzalvez, M. A.
;
Barbas, C.
;
Floeter-Winter, L. M.
Número total de Autores: 5
|
| Tipo de documento: | Artigo Científico |
| Fonte: | SCIENTIFIC REPORTS; v. 14, n. 1, p. 16-pg., 2024-01-10. |
| Resumo | |
Leishmania amazonensis is a protozoan that primarily causes cutaneous leishmaniasis in humans. The parasite relies on the amino acid arginine to survive within macrophages and establish infection, since it is a precursor for producing polyamines. On the other hand, arginine can be metabolized via nitric oxide synthase 2 (NOS2) to produce the microbicidal molecule nitric oxide (NO), although this mechanism does not apply to human macrophages since they lack NOS2 activity. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at posttranscriptional levels. Our previous work showed that mmu-miR-294 targets Nos2 favoring Leishmania survival in murine macrophages. Here, we demonstrate that human macrophages upregulate the hsa-miR-372, hsa-miR-373, and hsa-miR-520d, which present the same seed sequence as the murine mmu-miR-294. Inhibition of the miR-372 impaired Leishmania survival in THP-1 macrophages and the effect was further enhanced with combinatorial inhibition of the miR-372/373/520d family, pointing to a cooperative mechanism. However, this reduction in survival is not caused by miRNA-targeting of NOS2, since the seed-binding motif found in mice is not conserved in the human 3 ' UTR. Instead, we showed the miR-372/373/520d family targeting the macrophage's main arginine transporter SLC7A2/CAT2 during infection. Arginine-related metabolism was markedly altered in response to infection and miRNA inhibition, as measured by Mass Spectrometry-based metabolomics. We found that Leishmania infection upregulates polyamines production in macrophages, as opposed to simultaneous inhibition of miR-372/373/520d, which decreased putrescine and spermine levels compared to the negative control. Overall, our study demonstrates miRNA-dependent modulation of polyamines production, establishing permissive conditions for intracellular parasite survival. Although the effector mechanisms causing host cell immunometabolic adaptations involve various parasite and host-derived signals, our findings suggest that the miR-372/373/520d family may represent a potential target for the development of new therapeutic strategies against cutaneous leishmaniasis. (AU) | |
| Processo FAPESP: | 17/21906-9 - Papel de miRNAs na regulação da via de produção de poliaminas/NO em macrófagos derivados de THP-1 infectados com Leishmania amazonensis |
| Beneficiário: | Juliane Cristina Ribeiro Fernandes |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado Direto |
| Processo FAPESP: | 18/23512-0 - A relação Leishmania-hospedeiro sob a ótica das ‘ômicas’ |
| Beneficiário: | Lucile Maria Floeter-Winter |
| Modalidade de apoio: | Auxílio à Pesquisa - Temático |
| Processo FAPESP: | 21/09111-6 - Reprogramação metabólica de macrófagos humanos THP-1 infectados com Leishmania mediada por microRNA |
| Beneficiário: | Juliane Cristina Ribeiro Fernandes |
| Modalidade de apoio: | Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto |
| Processo FAPESP: | 22/00291-4 - Função de long-noncoding RNAs e microRNAs na resposta imune e metabolismo na infecção por Leishmania e uso de interferência metabólica como estratégia terapêutica |
| Beneficiário: | Sandra Marcia Muxel |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |