The relevance of genetic factors in conferring protection to severe malaria has been demonstrated, as in the case of sickle cell trait and G6PD deficiency1. However, it remains unknown whether environmental components, such as dietary or metabolic variations, can contribute to the outcome of infection2. Here, we show that administration of a high-fat diet to mice for a period as short as 4 days impairs Plasmodium liver infection by over 90%. Plasmodium sporozoites can successfully invade and initiate replication but die inside hepatocytes, thereby are unable to cause severe disease. Transcriptional analyses combined with genetic and chemical approaches reveal that this impairment of infection is mediated by oxidative stress. We show that reactive oxygen species, probably spawned from fatty acid β-oxidation, directly impact Plasmodium survival inside hepatocytes, and parasite load can be rescued by exogenous administration of the antioxidant N-acetylcysteine or the β-oxidation inhibitor etomoxir. Together, these data reveal that acute and transient dietary alterations markedly impact the establishment of a Plasmodium infection and disease outcome.
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The authors would like to thank A. Parreira for mosquito and sporozoite production; iMM’s rodent facility and histology unit; A.M. Vigário, A. Pamplona and S. Portugal for discussion; A.M. Vigário, I. Bento and I. Vera for critical reading of the manuscript. This work was supported by Fundação para a Ciência e Tecnologia (Portugal) through grant EXCL/IMI-MIC/0056/2012 and the ERC (agreement No. 311502) to M.M.M. V.Z.-L. was sponsored by EMBO (ALTF 357-2009) and FCT (BPD-81953-2011).
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