Plasmodium Exploitation of Liver-specific Methionine Metabolism

Malaria remains the most serious parasitic infectious disease, killing one child every two minutes.

Plasmodium infection starts when the female Anopheles mosquito injects sporozoites into the skin of the vertebrate host.

All Plasmodium species go through a phase of replication inside nucleated cells prior to infecting red blood cells and causing malaria, however, only mammalian-infectious parasites target the liver and replicate inside hepatocytes at an extraordinary rate to generate tens of thousands of erythrocyte-infectious merozoites.

Avian and reptile malaria parasites, in contrast, infect macrophages near the bite site and differentiate into only dozens of erythrocyte-infectious merozoites.

The reason behind the high replication rate achieved by mammalian-infectious parasites inside hepatocytes, key to guarantee the establishment of infection by overcoming the bottleneck of malaria transmission caused by a low sporozoite inoculum, remains utterly unexplored.

The hypothesizes of this proposal is that the explanation for this lies in the uniqueness of the mammalian hepatic methionine metabolism bestowed by the mammalian liver-specific methionine adenosyltransferase (MAT1) enzyme and its capacity for generating unlimited amounts of S-adenosylmethionine.

In agreement with this hypothesis, preliminary data show that Plasmodiums high replication rate inside hepatocytes relies on the host liver-specific MAT1.

By using a combination of genetic, cellular and molecular approaches I will decipher how the liver-specific methionine metabolism present in hepatocytes is hijacked and used by the parasite to achieve such high replication rates and assess the competence of the liver-specific MAT1 in sustaining Plasmodium replication.

This proposal has the potential to establish a novel paradigm on how the environment and the resources provided by the host have evolutionarily influenced Plasmodiums life cycle and will pave the way for new therapeutic targets against malaria.