The findings reveal an essential step in the biology of the most common and severe malaria parasite, Plasmodium falciparum, and offer a new drug target for fighting one of the world’s most common and dangerous infections.
Malaria sickens up to one half billion people every year and kills up to one million, mostly children in sub-Saharan Africa. The high fevers, shaking chills, flu-like symptoms, and anemia can be fatal unless treated quickly. Malaria has grown resistant to a long list of drugs, and vaccines are still in experimental stages.
Working with the malaria parasite and human blood in test tubes and lab dishes, the research team identified a single fast-acting protein in the parasite that enables it and several dozen of its offspring to escape from a human red blood cell in preparation for quick invasion of many more healthy blood cells. Eliminating that protein traps the parasites in the cell.
After an infected mosquito bites a person, malaria parasites move into the liver, where they silently mature and multiply within weeks. Malaria parasites make people sick weeks or months later when they enter red blood cells and begin an exponential expansion. In a single cell, a parasite produces up to 32 offspring in about two days, which burst out to infect more red blood cells.
“This is the stage where things have to happen very fast for the parasite,” said senior author Manoj Duraisingh, HSPH assistant professor of immunology and infectious diseases and senior author of the paper in the May 14 Science. “The parasite doesn’t like to spend much time outside the cell. It grows and matures, and immediately following rupture, enters a new cell. It was a surprise that this protein kinase, which we thought would be involved in red blood cell invasion, turns out to be essential for the parasite getting out of the cell.”
The study helps define the exit of the parasite from a blood cell as a highly choreographed process and distinguishes the egress and invasion steps, the researchers said.
“When the parasite gets out of the red blood cell, it has a matter of seconds or minutes to get into new red blood cells, or it will be cleared or killed by the human immune system,” said first author Jeffrey Dvorin, a postdoctoral research fellow in the Duraisingh Lab at HSPH and a clinical fellow in pediatric infectious diseases at Children's Hospital Boston. “We found an important trigger for the parasite to exit cells that may be independent from the invasion trigger.”
Even better, the protein is found in the parasite and in plants, but not in humans, which means a drug targeted to that protein may be less toxic for people. The protein belongs to a family of Plasmodium falciparum calcium-dependent protein kinases, or PfCDPK5 for short in this case. Other members of the family have been implicated in parasite egress of red blood cells, but this is the first study using a genetic technique to validate a protein critical for parasite egress of red blood cells, according to the researchers.
Many companies and labs are looking for inhibitors of parasite egress and invasion of red blood cells, but no anti-malarial drugs yet target these stages of the parasite lifecycle, Dvorin said.
The paper also demonstrates the usefulness of a new tool that can be used to evaluate additional members of the kinase family, as well as other signaling pathways that regulate key events in the blood stage of malaria infection. As of 2002, “we have a malaria genome of about 6,000 genes,” said Duraisingh. “We need a means of prioritizing specific gene candidates for further drug development.”
The method, first developed in a mammalian cell culture system by co-author Thomas Wandless of Stanford University, allows scientists to analyze the function of certain proteins and to identify other potential therapeutic targets in the malaria parasite, the researchers said.
As adapted for this study, Dvorin and his colleagues reverse-engineered candidate genes to make faulty proteins that would only survive in the presence of a stabilizing chemical. Without that constant protection, the protein is eliminated from the parasite.
“For 24 hours a day, 7 days a week, we grew the parasites in the presence of the stabilizing chemical,” Dvorin said. “After the parasites invaded new red blood cells, we washed away the stabilizing drug. Even though the parasites seemed to develop just fine, they were unable to leave the red blood cell.”
Interestingly, the team’s work also produced an elusive scientific tool for their colleagues in the vaccine field: Mature invasive parasites. “One of the experiments in the paper mechanically releases the parasites, which have matured into virulent and invasive forms,” Duraisingh said. “People have been trying to get viable parasites in this form for study. This is a great resource for vaccine studies.”
"A Plant-Like Kinase in Plasmodium falciparum Regulates Parasite Egress From Erythrocytes," Science, May 14, 2010, J.D. Dvorin et. al.
This work was supported by Pediatric Scientist Development Program Fellowship awards, National Institutes of Health, Burroughs Wellcome Fund New Investigator in the Pathogenesis of Infectious Diseases Fellowship, the Medical Research Council UK, a Wellcome Trust Project grant, and an EU FP7 grant MALSIG.
Visit the HSPH website for the latest news, press releases and multimedia offerings.Contact: Christina Roache
Christina Roache | EurekAlert!
New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg
Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz
In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport
Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...
The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.
The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...
Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...
Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".
Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...
13.02.2017 | Event News
10.02.2017 | Event News
09.02.2017 | Event News
24.02.2017 | Life Sciences
24.02.2017 | Life Sciences
24.02.2017 | Trade Fair News