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Researchers Find Potential Human Influence on Malarial Parasite Gene Expression

BOSTON (GenomeWeb News) – Malarial parasites show different patterns of gene expression in the human body, a finding which could potentially result in new treatments for the disease, according to research presented at the American Association for the Advancement of Science annual meeting this weekend.

A group of Massachusetts and California researchers used a custom-made Affymetrix GeneChip to evaluate gene expression in the malaria-causing parasite Plasmodium falciparum and highlighted differences between P. falciparum biology in humans and in lab cultures. The research, published in Nature in mid-December, describes three P. falciparum transcriptional states, including two that haven’t been previously described in the lab.

Co-author Dyann Wirth, a Harvard University tropical disease researcher and molecular biologist, presented the work on Saturday at the AAAS meeting.

Malaria is characterized by anemia, blood acidity, and fluid build-up in the lungs and brain that can cause symptoms ranging from flu-like symptoms to a coma or death. Four Plasmodium species cause the disease — and the deadliest of these is P. falciparum. But even though the offending pathogens are known, malaria eradication remains elusive. The disease still kills more than a million people each year, Wirth noted.

Part of the problem is Plasmodium’s extensive drug resistance. As Wirth explained, genomics tools are increasingly being applied in an effort to understand how Plasmodium species become resistant to drugs and evade the human immune system.

The P. falciparum genome, which consists of about 6,000 genes, is about one percent the size of the human genome and about as complex as that of yeast. But it is incredibly diverse and varied.

“The Plasmodium parasite has significant diversity beyond that seen in humans,” Wirth said. “Drug resistance is not a single mutation on a singe gene.”

Using the Affymetrix chip based on the malaria 3D7 genome, the team analyzed the gene expression profiles of parasites taken from the blood of 43 malaria patients in Senegal. They then used non-negative matrix factorization or NMF algorithm clustering with GenePattern software to arrange the 43 expression profiles into three metagene groups.

In an effort to understand each of these transcription states, they compared the P. falciparum gene expression in each with nearly 1,500 published gene expression profiles in yeast, mapping yeast genes to P. falciparum orthologues. They also used Gene Set Enrichment Analysis to look for known functional pathways that are induced or repressed.

One gene expression profile was similar to that seen in typical lab-grown strains. But the other two gene expression states were not. Instead, these resembled gene expression profiles associated with environmental stress response and starvation response. Interestingly, the patients carrying P. falciparum with the latter gene expression profile also tended to have the most serious symptoms, including high fevers, inflammation, and elevated cytokine immune cell levels.

“These novel states may result in enhanced virulence and the generation of metabolites such as reactive oxygen species, or in the consumption of substrates that could affect the host and contribute to disease severity,” the authors wrote. “[I]f the distinct profiles represent persistent physiological differences, they may identify novel drug targets for malaria or may indicate possible alternative therapies.”

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