Publicação
Development of effective antifungal strategies based on lactoferrin and autophagy inducers
| Resumo: | Lactoferrin (Lf) is an iron-binding globular protein that belongs to the transferrin family. This protein is usually encountered in various mammalian secretions with special higher concentration in milk and colostrum. In recent years, Lf has gained great interest due to its multifunctionality and cytotoxic activity against various cell types such as bacteria, fungi, cancer cells, and even viruses. One of the most promising Lf abilities is its powerful antifungal activity against different pathogenic fungi, whose molecular basis is not yet fully elucidated. Studies aiming to deeper understand the mechanisms underlying Lf antifungal capacity will therefore aid in potentiating this effect. Previous reports on Lf yeast killing activity were performed in buffer lacking nutrients. Since these conditions are likely to induce autophagy, we hypothesized that Lf cytotoxicity could be intrinsically associated with this process. Autophagy is a process that allows the transport and degradation of damaged cellular components in the lysosome/vacuole with the purpose of recycling them to be reused as building blocks for other metabolic processes. This thesis aims to elucidate the interplay between Lf and autophagy and to explore the combination of Lf with autophagy inducers as a novel strategy of antifungal treatment. The results showed that Lf cytotoxicity towards yeast cells is significantly enhanced under various autophagy inducing conditions, such as nutrient or nitrogen starvation media. Furthermore, we found that Lf antifungal activity is only impaired in strains lacking specific components of the autophagic machinery, suggesting that it depends on specific components/phases of autophagy. Our data also point to the conclusion that the combination of Lf with specific autophagy inducers, namely rapamycin and tunicamycin, increases Lf cytotoxicity indicating it may be a promising strategy for the treatment of fungal infections. Overall, these results further elucidate the mechanism of action behind Lf antifungal activity and its association with the autophagy process. In the future, it would be interesting to test the most promising combinations of Lf and autophagy inducers against human pathogenic yeast strains and clinical isolates to evaluate their efficiency as an antifungal strategy. |
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| Autores principais: | Pereira, João Filipe Bastos |
| Assunto: | Antifungal Autophagy Lactoferrin Saccharomyces cerevisiae Antifúngico Autofagia Lactoferrina Ciências Naturais::Outras Ciências Naturais |
| Ano: | 2024 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Lactoferrin (Lf) is an iron-binding globular protein that belongs to the transferrin family. This protein is usually encountered in various mammalian secretions with special higher concentration in milk and colostrum. In recent years, Lf has gained great interest due to its multifunctionality and cytotoxic activity against various cell types such as bacteria, fungi, cancer cells, and even viruses. One of the most promising Lf abilities is its powerful antifungal activity against different pathogenic fungi, whose molecular basis is not yet fully elucidated. Studies aiming to deeper understand the mechanisms underlying Lf antifungal capacity will therefore aid in potentiating this effect. Previous reports on Lf yeast killing activity were performed in buffer lacking nutrients. Since these conditions are likely to induce autophagy, we hypothesized that Lf cytotoxicity could be intrinsically associated with this process. Autophagy is a process that allows the transport and degradation of damaged cellular components in the lysosome/vacuole with the purpose of recycling them to be reused as building blocks for other metabolic processes. This thesis aims to elucidate the interplay between Lf and autophagy and to explore the combination of Lf with autophagy inducers as a novel strategy of antifungal treatment. The results showed that Lf cytotoxicity towards yeast cells is significantly enhanced under various autophagy inducing conditions, such as nutrient or nitrogen starvation media. Furthermore, we found that Lf antifungal activity is only impaired in strains lacking specific components of the autophagic machinery, suggesting that it depends on specific components/phases of autophagy. Our data also point to the conclusion that the combination of Lf with specific autophagy inducers, namely rapamycin and tunicamycin, increases Lf cytotoxicity indicating it may be a promising strategy for the treatment of fungal infections. Overall, these results further elucidate the mechanism of action behind Lf antifungal activity and its association with the autophagy process. In the future, it would be interesting to test the most promising combinations of Lf and autophagy inducers against human pathogenic yeast strains and clinical isolates to evaluate their efficiency as an antifungal strategy. |
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