Over a century ago, Dr. Ronald Ross won a Nobel Prize for his discovery that mosquitoes transmit the parasites that cause malaria. Since that time, a growing problem in South America, sub-Saharan Africa, and Southeast Asia is the number of malarial parasites which are resistant to existing anti-malaria drugs. Understanding exactly how malaria parasites invade and infect human blood cells will allow scientists and physicians to develop novel anti-malaria drugs and vaccines in order to thwart drug-resistant parasites.

Don’t be Rigid

The most virulent strain of malaria parasite, Plasmodium falciparum, has been the subject of intense scientific investigation. It is known that human red blood cells infected with this parasite are extremely rigid compared to uninfected red blood cells. This rigidity causes infected blood cells to attach to the blood vessels of the liver, brain, and kidneys, and can eventually lead to widespread organ damage by triggering liver and brain cell death. How does infection with this parasite change the structure of human red blood cells?

P. falciparum parasites have a gene that codes for a protein named PfEMP1 (P. falciparum erythrocyte membrane protein). Once the parasite makes PfEMP1, the protein is secreted into the human red blood cell. The presence of PfEMP1 inside the red blood cell causes the cell to adopt a rigid shape. In addition to the PfEMP1 gene, P. falciparum is known to have many other genes whose encoded proteins are also secreted by the parasite. In fact, P. falciparum has five to ten times more genes for these so-called export proteins than other less virulent strains of malaria parasites. Scientists began to wonder whether P. falciparum might secrete additional proteins (besides PfEMP1) that are required for the production of a rigid blood cell.

In a study reported in the July 11th issue of Cell, researchers at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, found novel parasite proteins that trigger red blood cells to adopt a rigid shape. The researchers took advantage of the sequenced genome of P. falciparum, and asked if they removed a given gene, would the deletion result in a non-rigid human red blood cell? If so, then the gene in question most likely has an important role in producing rigidity. The researchers scanned the P. falciparum genome, and used a computer algorithm to generate a list of candidate parasite genes that code for export proteins. They then used a clever genetic method to specifically delete each candidate and ask whether the resulting mutant parasite loses the ability to induce red blood cell rigidity in a test tube setting. By examining those mutants that did not produce rigid red blood cells, they were able to identify the genetic culprits. Through this functional genomics approach, the researchers identified previously unknown parasite proteins that are exported into the human red blood cell by the invading parasite and trigger cell rigidity. This important finding provides a foundation for developing novel therapies that selectively block the function of these proteins so that human red blood cells will not become rigid and contribute to the life-threatening symptoms of malaria.

Potential New Targets for Malaria Drugs

How does this finding inform the search for ways to combat drug resistant malaria? First, since these newly-identified parasite proteins have no mammalian counterpart, drugs that specifically inhibit these proteins will most likely not cause toxicity in patients. Of course, like all new drugs, these hypothetical anti-rigidity drugs would need to be tested to make sure they are indeed safe and effective before being used to treat patients suffering from malaria. Second, anti-malaria drugs that reverse infected red blood cell rigidity may be used in concert with existing anti-malaria treatments, thus making a potent “cocktail” therapy. Finally, developing malaria vaccines from these parasite rigidity-inducing proteins may serve as a cornerstone for allowing the patient’s immune system to fight off P. falciparum virulence.

This study raises fascinating questions about the interactions between malarial parasites and the red blood cells of their mammalian hosts. For instance, now that we know more about the secreted rigidity-inducing proteins from P. falciparum, how exactly do these proteins interact with red blood cell proteins to produce cell rigidity? If anti-rigidity drugs are developed and given to a patient infected with P. falciparum, will the parasites in the bloodstream still be capable of infecting other cells in the patient’s body? Or, will the infected cells lay dormant below the surveillance of the patient’s immune system? It seems that these unique rigidity-inducing parasite proteins constitute one more piece of the malaria puzzle and may inspire the next generation of anti-malaria drugs and vaccines

–Bob Kao, Molecular and Cellular Biology, Harvard University, with help from Kelly Dakin, Sindy Tang, and Amanda Sadacca

For More Information:

Howard Hughes Medical Institute website on Cowman Lab July 11, 2008 Cell Paper:
< http://www.hhmi.org/news/20080709cowman.html >

Ronald Ross, MD, awarded the 1902 Nobel Prize for his malaria research:
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Malaria Awareness website from the New York Times:
< http://health.nytimes.com/health/guides/disease/malaria/overview.html?scp=1-spot&sq=malaria&st=cse >

Science Daily Updates in Malaria Research:
< http://www.sciencedaily.com/search/?keyword=malaria >

Primary Literature:

Maier AG, Rug M, O’Neill MT, Brown M, Chakravorty S, Szestak T, Chesson J, Wu Y, Hughes K, Coppel RL, Newbold C, Beeson JG, Craig A, Crabb BS, Cowman AF. 2008. Exported proteins required for virulence and rigidity of Plasmodium falciparum-infected human erythrocytes. Cell. Jul 11;134(1):48-61.

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