Final Report Summary - PARASITENUTRISENSING (Nutrient sensing by parasites)
Despite renewed eradication efforts from the international community, malaria still exerts an enormous disease burden, with nearly half the planet’s population at risk of infection. Within the human host, the disease-causing Plasmodium parasites pass through two distinct lifecycle stages, each in a different cellular environment. During the liver stage, a single Plasmodium sporozoite will invade a hepatocyte, and while sheltered there, supposedly undetected by the host, gives rise to thousands of new parasites, which will go on to initiate the subsequent blood stage of infection. While only 10-20 new parasites will be generated inside an erythrocyte, consecutive cycles of cell lysis and reinfection causing a potent host response, as well as the symptoms of malaria.
While the relevance of genetic factors in conferring protection to severe malaria has been demonstrated, e.g. sickle cell trait and G6PD deficiency, the contribution of environmental components, such as dietary or metabolic variations, remained utterly unexplored. We have now shown that dietary alterations strongly impact on the establishment and progression of malaria infection by interfering with both host and parasite pathways during different stages of infection.
First, administration of a high-fat diet to mice for a period as short as 4 days impairs Plasmodium liver infection by over 90% because reactive oxygen species, probably spawned from fatty acid β-oxidation, directly impact Plasmodium survival inside hepatocytes (Zuzarte-Luis et al., Nat Micro, 2017).
On the other hand, we have also recently shown that Plasmodium blood-stage parasites actively respond to host dietary calorie alterations through rearrangement of their transcriptome accompanied by substantial adjustment of their multiplication rate. A kinome analysis combined with chemical and genetic approaches revealed a key novel parasite nutrient-sensing mechanism that is critical for modulating parasite replication and virulence (Mâncio-Silva et al., Nature, 2017).
Overall, the ERC-funded project allowed our research team to established a novel paradigm for host-Plasmodium interactions – the outcome of an infection, including the virulence of the parasite, depends on the environment surrounding it paving the way to several distinct but complementary future lines of research.
While the relevance of genetic factors in conferring protection to severe malaria has been demonstrated, e.g. sickle cell trait and G6PD deficiency, the contribution of environmental components, such as dietary or metabolic variations, remained utterly unexplored. We have now shown that dietary alterations strongly impact on the establishment and progression of malaria infection by interfering with both host and parasite pathways during different stages of infection.
First, administration of a high-fat diet to mice for a period as short as 4 days impairs Plasmodium liver infection by over 90% because reactive oxygen species, probably spawned from fatty acid β-oxidation, directly impact Plasmodium survival inside hepatocytes (Zuzarte-Luis et al., Nat Micro, 2017).
On the other hand, we have also recently shown that Plasmodium blood-stage parasites actively respond to host dietary calorie alterations through rearrangement of their transcriptome accompanied by substantial adjustment of their multiplication rate. A kinome analysis combined with chemical and genetic approaches revealed a key novel parasite nutrient-sensing mechanism that is critical for modulating parasite replication and virulence (Mâncio-Silva et al., Nature, 2017).
Overall, the ERC-funded project allowed our research team to established a novel paradigm for host-Plasmodium interactions – the outcome of an infection, including the virulence of the parasite, depends on the environment surrounding it paving the way to several distinct but complementary future lines of research.