After many years of exhaustive research, Professor Alan Cowman and colleagues from the Walter And Eliza Hall Institute of Medical Research in Melbourne, Australia and the Howard Hughes Medical Institute identified previously unknown steps of how malaria parasites invade and remodel host erythrocytes. Their “systematic examination of remodeling proteins from the most deadly species of the malaria parasite, Plasmodium falciparum” may lead to new therapeutic strategies against the disease.
Howard Hughes Medical Institute released the following statement:
Malaria parasites go through a series of steps on their way to causing human disease. They travel from a mosquito bite on the skin to the liver, where they hunker down and multiply. They then fan out into the bloodstream, where they invade red blood cells both in an attempt to evade the immune system and to remodel them for their own use. “This is key to the parasite’s survival in the host and the key to its pathogenesis,” Cowman said.
To identify the role of each protein involved in red blood cell remodeling, the research team had to create a parasite without the gene that creates it. This modified parasite is called a knockout. While red blood cell rehabilitation requires a work crew of as many as 400 proteins, Cowman’s team started their analysis with 200 of these, focusing on those that seemed unique or that had been linked to important roles before. This Cell paper describes the first 83 genes, many found only in P. falciparum.
The research has taken five years because identifying the function of genes in P. falciparum isn’t easy, Cowman explained. They have to knock out the genes one by one, then run a number of tests to find out what has changed about the parasite and the red blood cell it attacked. “It’s very difficult, and no one has every attempted anything on this scale before,” he said.
What they found was worth the effort. The team has identified two proteins responsible for building porcupine-like protrusions on the walls of red blood cells; without these knobs, infected cells don’t stick to vessel walls. Several other proteins were responsible for turning a flexible red blood cell into a rigid sphere that clogs up small blood vessels. The most interesting of the newly-identified proteins may be those responsible for placing a glue-like adhesive called PfEMP1 on the outer walls of the red blood cell. This adhesive, called a virulence protein, is the primary factor that sticks these rehabbed red blood cells to blood vessel walls. Cowman expects they will find more proteins involved in creating PfEMP1.
Full story at Howard Hughes Medical Institute: Research Identifies Malaria Proteins that Remodel Red Blood Cells…
Abstract: Exported Proteins Required for Virulence and Rigidity of Plasmodium falciparum-Infected Human Erythrocytes Cell, Vol 134, 48-61, 11 July 2008
Much more at Professor Alan Cowman’s lab…
Image: Merozoite form of P. falciparum and its interaction with the human erythrocyte
