Publicação
Uncovering the role of host peroxisomal functions in Plasmodium liver stage infection
| Resumo: | Malaria, the world’s leading tropical parasitic disease, is caused by protozoan parasites of the genus Plasmodium. During its life cycle, Plasmodium inhabits an insect vector and a vertebrate host. Liver infection in the vertebrate host is the asymptomatic obligatory step before the onset of malaria disease. Cellular and molecular interactions between host and parasite play a key role in the establishment of susceptibility to malaria infection, and so the identification of relevant host factors is crucial for the rational development of new antimalarial strategies. We hypothesized that peroxisomes-less Plasmodium may have acquired host-dependency at the level of liver peroxisomes, and that it can take advantage of host cell peroxisomal functions and metabolites during liver stage. The myriad pathways in which peroxisomes are involved and their abundance in mammalian livers seems to place these organelles in a privileged position to be exploited in the context of intracellular parasitism. Live fluorescence microscopy and flow cytometry of DsRedlabeled peroxisomes revealed that the intracellular presence of Plasmodium can alter the dynamic properties of the host peroxisomal population. We then focused on the two major mammalian peroxisomal functions, fatty acid β-oxidation and detoxification of reactive oxygen species. Impairment of fatty acid β-oxidation by a drug inhibitor, knockdown of β- oxidation enzymes and overexpression of a key peroxisomal thiolase showed that a hostfactor dependency does exist and that it is important for both cell invasion and subsequent parasite development. This is probably tied to the parasite’s metabolic requirements for membrane biosynthesis during these processes. Catalase inhibition and knockdown of other peroxisomal peroxidases showed that this antioxidant network does not play a strong role in Plasmodium infection, but fluorescence microscopy revealed that the peroxisomal marker enzyme catalase may be recruited by the parasite to complement the functions of its own antioxidant systems in the maintenance of redox homeostasis during liver stage. |
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| Autores principais: | Carrelha, Joana Isabel de Teixeira, 1988- |
| Assunto: | Malária Plasmodium Parasitas Biologia molecular Teses de mestrado - 2011 |
| Ano: | 2011 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Malaria, the world’s leading tropical parasitic disease, is caused by protozoan parasites of the genus Plasmodium. During its life cycle, Plasmodium inhabits an insect vector and a vertebrate host. Liver infection in the vertebrate host is the asymptomatic obligatory step before the onset of malaria disease. Cellular and molecular interactions between host and parasite play a key role in the establishment of susceptibility to malaria infection, and so the identification of relevant host factors is crucial for the rational development of new antimalarial strategies. We hypothesized that peroxisomes-less Plasmodium may have acquired host-dependency at the level of liver peroxisomes, and that it can take advantage of host cell peroxisomal functions and metabolites during liver stage. The myriad pathways in which peroxisomes are involved and their abundance in mammalian livers seems to place these organelles in a privileged position to be exploited in the context of intracellular parasitism. Live fluorescence microscopy and flow cytometry of DsRedlabeled peroxisomes revealed that the intracellular presence of Plasmodium can alter the dynamic properties of the host peroxisomal population. We then focused on the two major mammalian peroxisomal functions, fatty acid β-oxidation and detoxification of reactive oxygen species. Impairment of fatty acid β-oxidation by a drug inhibitor, knockdown of β- oxidation enzymes and overexpression of a key peroxisomal thiolase showed that a hostfactor dependency does exist and that it is important for both cell invasion and subsequent parasite development. This is probably tied to the parasite’s metabolic requirements for membrane biosynthesis during these processes. Catalase inhibition and knockdown of other peroxisomal peroxidases showed that this antioxidant network does not play a strong role in Plasmodium infection, but fluorescence microscopy revealed that the peroxisomal marker enzyme catalase may be recruited by the parasite to complement the functions of its own antioxidant systems in the maintenance of redox homeostasis during liver stage. |
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