Publicação
Immunometabolic crosstalk between host and pathogen: unveiling novel therapeutic approaches for visceral leishmaniasis
| Resumo: | Visceral leishmaniasis (VL) is a neglected tropical disease caused by parasites of the genus Leishmania, particularly L. donovani and L. infantum, and can be fatal if untreated. Although several available therapies are described for VL, the associated high costs, efficacy problems, and the high numbers of relapsing cases point this disease as one of the neglected tropical diseases for which the development of new treatments is a priority. Metabolic reprogramming of immune cells is well described in infectious diseases. Several reports have shown that Leishmania infection profoundly affects host cell metabolism, which is intimately correlated with intracellular parasite survival. While neutrophils are essential to early infection, the long-lasting Leishmania infection is established within macrophages. Thus, in this thesis, we proposed to characterize the metabolic networks regulating VL on macrophages and its relation to the anti-leishmanial immune response. Therefore, we combined the use of in vitro and in vivo models of L. donovani infection with different analysis methods (RNA sequencing, metabolomics, multiparametric flow cytometry analysis, gene expression profiling, and protein quantification). Leishmania-infected macrophages rely on glucose metabolism to control parasite growth during early infection. In parallel, we uncover a relevant role for L- glutamine metabolism in L. donovani-infected macrophages. We observed a metabolic signature of increased glutaminolysis on L. donovani-infected macrophages, whose pharmacological inhibition significantly increased the susceptibility to infection. Importantly, we have demonstrated that glutamine-miltefosine synergy is a novel combined host- and pathogen-directed treatment for combating VL. Transcriptomic and metabolomic analyses performed at later times of infection indicated that L. donovani parasites further impact the host metabolome by modulating lipid metabolism-associated pathways. Overall, our data contribute to elucidate the capacity of Leishmania parasites to manipulate host cell metabolome towards an appropriate immunometabolic environment for their survival inside the host, which can be continuously changing along with the course of the infection. Deciphering these queries is of great value to understand how Leishmania parasites can hijack host metabolism to persist inside the host and the mechanisms underlying its adaptation. |
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| Autores principais: | Ferreira, Carolina Alves |
| Assunto: | Immunometabolism L-glutamine metabolism Lipid metabolism Macrophages Visceral leishmaniasis Imunometabolismo Metabolismo da L-glutamina Metabolismo lipídico Macrófagos Leishmaniose visceral |
| Ano: | 2021 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Visceral leishmaniasis (VL) is a neglected tropical disease caused by parasites of the genus Leishmania, particularly L. donovani and L. infantum, and can be fatal if untreated. Although several available therapies are described for VL, the associated high costs, efficacy problems, and the high numbers of relapsing cases point this disease as one of the neglected tropical diseases for which the development of new treatments is a priority. Metabolic reprogramming of immune cells is well described in infectious diseases. Several reports have shown that Leishmania infection profoundly affects host cell metabolism, which is intimately correlated with intracellular parasite survival. While neutrophils are essential to early infection, the long-lasting Leishmania infection is established within macrophages. Thus, in this thesis, we proposed to characterize the metabolic networks regulating VL on macrophages and its relation to the anti-leishmanial immune response. Therefore, we combined the use of in vitro and in vivo models of L. donovani infection with different analysis methods (RNA sequencing, metabolomics, multiparametric flow cytometry analysis, gene expression profiling, and protein quantification). Leishmania-infected macrophages rely on glucose metabolism to control parasite growth during early infection. In parallel, we uncover a relevant role for L- glutamine metabolism in L. donovani-infected macrophages. We observed a metabolic signature of increased glutaminolysis on L. donovani-infected macrophages, whose pharmacological inhibition significantly increased the susceptibility to infection. Importantly, we have demonstrated that glutamine-miltefosine synergy is a novel combined host- and pathogen-directed treatment for combating VL. Transcriptomic and metabolomic analyses performed at later times of infection indicated that L. donovani parasites further impact the host metabolome by modulating lipid metabolism-associated pathways. Overall, our data contribute to elucidate the capacity of Leishmania parasites to manipulate host cell metabolome towards an appropriate immunometabolic environment for their survival inside the host, which can be continuously changing along with the course of the infection. Deciphering these queries is of great value to understand how Leishmania parasites can hijack host metabolism to persist inside the host and the mechanisms underlying its adaptation. |
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