Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New Twist on Potential Malaria Drug Target Acts by Trapping Parasites in Cells

17.05.2010
Harvard School of Public Health (HSPH) researchers and colleagues seeking to block invasion of healthy red blood cells by malaria parasites have instead succeeded in locking the parasites within infected blood cells, potentially containing the disease.

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
croache@hsph.harvard.edu
617-384-8979
Harvard School of Public Health ( http://www.hsph.harvard.edu ) is dedicated to advancing the public's health through learning, discovery, and communication. More than 400 faculty members are engaged in teaching and training the 1,000-plus student body in a broad spectrum of disciplines crucial to the health and well being of individuals and populations around the world. Programs and projects range from the molecular biology of AIDS vaccines to the epidemiology of cancer; from risk analysis to violence prevention; from maternal and children's health to quality of care measurement; from health care management to international health and human rights. For more information on the school visit: http://www.hsph.harvard.edu

Christina Roache | EurekAlert!
Further information:
http://www.hsph.harvard.edu

More articles from Life Sciences:

nachricht Single-stranded DNA and RNA origami go live
15.12.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard

nachricht New antbird species discovered in Peru by LSU ornithologists
15.12.2017 | Louisiana State University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: First-of-its-kind chemical oscillator offers new level of molecular control

DNA molecules that follow specific instructions could offer more precise molecular control of synthetic chemical systems, a discovery that opens the door for engineers to create molecular machines with new and complex behaviors.

Researchers have created chemical amplifiers and a chemical oscillator using a systematic method that has the potential to embed sophisticated circuit...

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Diamond Lenses and Space Lasers at Photonics West

15.12.2017 | Trade Fair News

A better way to weigh millions of solitary stars

15.12.2017 | Physics and Astronomy

New epidemic management system combats monkeypox outbreak in Nigeria

15.12.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>