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!
Are there sustainable solutions in dealing with dwindling phosphorus resources?
16.10.2017 | Leibniz-Institut für Nutzierbiologie (FBN)
Strange undertakings: ant queens bury dead to prevent disease
13.10.2017 | Institute of Science and Technology Austria
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.
It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...
It's possible to produce hydrogen to power fuel cells by extracting the gas from seawater, but the electricity required to do it makes the process costly. UCF...
Mercury, our smallest planetary neighbor, has very little to call an atmosphere, but it does have a strange weather pattern: morning micro-meteor showers.
Recent modeling along with previously published results from NASA's MESSENGER spacecraft -- short for Mercury Surface, Space Environment, Geochemistry and...
10.10.2017 | Event News
10.10.2017 | Event News
28.09.2017 | Event News
16.10.2017 | Physics and Astronomy
16.10.2017 | Earth Sciences
16.10.2017 | Physics and Astronomy