Publicação
The role of host lipid metabolism in the regulation of antifungal immunity
| Resumo: | The prevalence of fungal diseases increased significantly in the second half of the twentieth century, and this increase was due, at least in part, to the expansion of the immunocompromised population. These patients display extreme susceptibility to opportunistic life-threatening forms of fungal infections, such as invasive pulmonary aspergillosis (IPA), being IPA a leading cause of mortality among immunocompromised patients. It is known that many microbes exploit host cellular lipid contents during the interaction with the host, however no link between lipid metabolism and A. fumigatus infection has been uncovered so far. In this thesis, we aimed to elucidate the mechanisms through which lipid metabolism shapes the host defence against the opportunistic fungal pathogen A. fumigatus. We observed that the cholesterol homeostasis pathway is induced during in vitro infection, and that infected macrophages showed decrease levels of palmitate and neutral lipids when compared to uninfected macrophages. Furthermore, by resorting to pharmacological tools, we were able to reveal that both pathways, although having antagonistic effects, play an important role in the ability of macrophages to eliminate the fungus. Also, we found that infected macrophages treated with cholesterol synthesis inhibitors upstream of farnesyl-pyrophosphate led to higher cytokine production. In contrast, infected macrophages treated with fatty acid synthesis inhibitors displayed instead a decreased cytokine production, thus pinpointing a crucial role for lipid metabolism in the establishment of protective anti-fungal responses. In summary, this work allowed improving our understanding of host lipid metabolism and its impact on immune cell function, laying the foundations towards innovative therapeutic approaches against IPA, based on the manipulation of lipid metabolism of immune cells. |
|---|---|
| Autores principais: | Barnutiu, Adrian |
| Assunto: | A. fumigatus Immunometabolism |
| Ano: | 2023 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Trás-os-Montes e Alto Douro |
| Idioma: | inglês |
| Origem: | Repositório da UTAD |
| Resumo: | The prevalence of fungal diseases increased significantly in the second half of the twentieth century, and this increase was due, at least in part, to the expansion of the immunocompromised population. These patients display extreme susceptibility to opportunistic life-threatening forms of fungal infections, such as invasive pulmonary aspergillosis (IPA), being IPA a leading cause of mortality among immunocompromised patients. It is known that many microbes exploit host cellular lipid contents during the interaction with the host, however no link between lipid metabolism and A. fumigatus infection has been uncovered so far. In this thesis, we aimed to elucidate the mechanisms through which lipid metabolism shapes the host defence against the opportunistic fungal pathogen A. fumigatus. We observed that the cholesterol homeostasis pathway is induced during in vitro infection, and that infected macrophages showed decrease levels of palmitate and neutral lipids when compared to uninfected macrophages. Furthermore, by resorting to pharmacological tools, we were able to reveal that both pathways, although having antagonistic effects, play an important role in the ability of macrophages to eliminate the fungus. Also, we found that infected macrophages treated with cholesterol synthesis inhibitors upstream of farnesyl-pyrophosphate led to higher cytokine production. In contrast, infected macrophages treated with fatty acid synthesis inhibitors displayed instead a decreased cytokine production, thus pinpointing a crucial role for lipid metabolism in the establishment of protective anti-fungal responses. In summary, this work allowed improving our understanding of host lipid metabolism and its impact on immune cell function, laying the foundations towards innovative therapeutic approaches against IPA, based on the manipulation of lipid metabolism of immune cells. |
|---|