Hepatic metabolism driving Plasmodium replication

Malaria remains the most serious parasitic infectious disease, killing one child every minute. Plasmodium infection starts when the female Anopheles mosquito injects sporozoites into the skin of the vertebrate host. While all Plasmodium species go through a phase of replication inside nucleated cells prior to infecting red blood cells and causing malaria, 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 the low sporozoite inoculum, remains utterly unexplored, underlying the following unanswered fundamental questions: Why was the liver selected by mammalian-infectious Plasmodium species? What specific features of the mammalian liver allow Plasmodium to achieve such high replication rates? Based on strong preliminary data, the study hypothesize that the answer to these questions lies in the uniqueness of the mammalian hepatic methionine metabolism, an essential amino acid used in protein synthesis and in the generation of S-adenosylmethionine SAM, the major biological methyl donor, precursor of polyamines and glutathione. The mammalian liver is a key organ in the metabolism of methionine, generating 85% of the total SAM pool. The present proposal has the potential to establish a novel paradigm on how the environment and the resources provided by the host led to an evolutionary adaptation in the parasite life cycle and will pave the way for new prophylactic/therapeutic targets against malaria.

Basic Science
Genetics and Genomics

Jun 2018 — Dec 2021

$276,471

Portugal