The mechanism by which the parasite Plasmodium intensively replicates itself in human blood to spread malaria has eluded scientists despite decades of rigorous research. But now biologists writing in the journal Genome Research say they have discovered how the deadly parasite regulates its infectious cycle.

In the cells of eukaryotes, such as the unicellular Plasmodium and humans, DNA, which can be as long as two meters, is closely packed to fit into the cell's tiny nucleus. Huge complex proteins called nucleosomes facilitate this DNA compaction so that eventually the DNA is coiled in an ordered manner to form chromosomes.

Made up of histone, a kind of protein, the nucleosomes are repeating units around which the double helix of DNA gets wrapped and vast amounts of genetic information get organized.

In trying to understand how the malaria parasite multiplies in red blood cells, researches found that in Plasmodium a kind of "histone crash" takes place – a massive breakdown of histone that explains how the parasite can replicate extensively its DNA and coding gene in human red blood cells.

Infected human red blood cells (top; and right of center) by the human malaria parasite, Plasmodium falciparum (the parasite is shown in purple). The newly-formed parasites (left of center) are ready to invade new red blood cells.

(Photo Credit: Le Roch lab, UC Riverside.)

For cell multiplication to occur, the genes in a DNA strand need to first be transcribed and translated (converted) into protein. For this transcription to take place, however, the nucleosomes must first get evicted (removed), a process that opens up the DNA strand to give special "transcription factors" full access to the genes. The transcription factors then convert these genes into protein.

While in humans such eviction of nucleosomes is specific to only some sections of the DNA strand and performed only when needed, in Plasmodium the situation is vastly different.

Experiments in the lab show that 18 hours after Plasmodium enters a red blood cell, a huge eviction of nucleosomes occurs in the Plasmodium DNA. Gene transcription throughout the genome follows; after multiplication into up to 32 daughter cells, the newly-formed parasites are ready to exit the red blood cell and invade new ones about 18 hours later.

"We found in our experiments that histones are massively evicted everywhere in the Plasmodium genome, resulting in most of the Plasmodium genes to be transcribed at once," Le Roch said. If this mechanism can be stopped," said co- author Karine Le Roch, "Plasmodium replication would cease or be severely inhibited, thus controlling the spread of malaria."

Citation: Ponts et al., 'Nucleosome landscape and control of transcription in the human malaria parasite', Genome Research, February 2010, 20, 228-238; doi:10.1101/gr.101063.109