New research from the US suggests that targeting and destroying a particular amino acid in the human body could be an important survival tactic for the deadly malaria parasite Plasmodium falciparum.
The study is the work of scientists at Princeton University in New Jersey and Drexel University College of Medicine in Philadelphia and is published in the 19 February issue of Cell Host & Microbe. The lead investigator was Manuel Llinás, assistant professor in the department of molecular biology and the Lewis-Sigler Institute for Integrative Genomics, both at Princeton.
Pathogens that invade the cells of their hosts have evolved biochemical mechanisms to help them make best use of their environment in order to survive and multiply. One such pathogen, the malaria parasite Plasmodium falciparum uses the host’s metabolites, the chemicals derived from digested nutrients that are found inside cells that help the host make and use energy and do other things like repair and make new cells.
There are hundreds of metabolites in the human body, these include amino acids, sugars, nucleotides and vitamins. A new scientific field called metabolomics specializes in the study of the “metabolic network” of organisms: there can be as many as 500 core metabolites in such a network. Metabolomic scientists measure levels of core metabolites and produce a “metabolomic profile” of an organism, in essence a chemical signature of the genetic expression of an organism at the cellular level.
First author Kellen Olszewski, a graduate student at Princeton University, said:
“The more we know about the parasite’s metabolic network, the more intelligent we can be about targeting therapies that will cure malaria.”
For this study, the researchers used mass spectrometry to trace the changes in chemical signature in human red blood cells infected with the parasite over the parasite’s 48-hour intraerythrocytic development cycle (a single “generation” of parasite replication).
Mass spectrometry detects the presence of chemicals in a mix because each one has its own unique wavelength at which it absorbs or emits electromagnetic radiation.
This metabolomic analysis showed that levels of several metabolites went up and down in phase with the parasite’s development cycle. It showed that one in particular, the amino acid arginine, had dipped dramatically by the end of one 48-hour cycle.
The parasite was targetting it in preference to other available amino acids and converting it to ornithine.
To find how it was doing this, the researchers used a rodent model of malaria based on Plasmodium berghei and switched off the parasite’s arginase gene. The parasites survived but did not convert the arginine to ornithine, suggesting it wasn’t using it in order to grow but for some other purpose that helps it survive.
The researchers concluded that:
“Our results suggest that systemic arginine depletion by the parasite may be a factor in human malarial hypoargininemia associated with cerebral malaria pathogenesis.”
They suggested that by depleting arginine, the parasite was triggering a more critical and deadly phase of the infection. Perhaps the parasite was getting rid of arginine to weaken the host immune system: arginine is an important fuel for the human immune system which also coverts it to nitric oxide, a chemical that is toxic to pathogens.
Perhaps the next generation of anti-malarial drugs will use detailed knowledge of the parasite’s weaknesses, such as that revealed by its metabolic network, said Llinás.
The World Health Organization estimates that 350 to 500 million people are infected with malaria every year by mosquitos that carry one of the four human malaria parasites, P. falciparum, P. vivax, P. malariae or P. ovale. P. falciparum is by far the deadliest and kills more than than 1 million people a year, mainly young children and pregnant women.
“Host-Parasite Interactions Revealed by Plasmodium falciparum Metabolomics.”
Kellen L. Olszewski, Joanne M. Morrisey, Daniel Wilinski, James M. Burns, Akhil B. Vaidya, Joshua D. Rabinowitz, andManuel Llinás.
Cell Host & Microbe, Volume 5, Issue 2, 191-199, 19 February 2009
doi:10.1016/j.chom.2009.01.004
Sources: Journal abstract, Princeton University press release.
Written by: Catharine Paddock, PhD