Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Locking Parasites in Host Cell Could Be New Way to Fight Malaria

07.04.2009
Researchers at the University of Pennsylvania have discovered that parasites hijack host-cell proteins to ensure their survival and proliferation, suggesting new ways to control the diseases they cause. The study, appearing this week online in Science, was led by Doron Greenbaum, PhD, Assistant Professor of Pharmacology in the Penn School of Medicine.

“Researchers can now develop ways to kill parasites by placing roadblocks in the path they use to destroy their victims,” says Greenbaum. The team discovered that malaria parasites depend upon an enzyme stolen from the host cell for successful infection.

Historically, many researchers have focused on developing ways to keep parasites from entering host cells, but Greenbaum’s group was curious about an alternative route of attack: locking the parasites inside the host cell.

These studies began with Plasmodium falciparum, which causes the most deadly form of human malaria. Each year, the Centers for Disease Control and Prevention report 350–500 million cases of malaria occur worldwide, killing more than a million people. In collaboration with the laboratory of Penn biologist David Roos, PhD, the work was broadened to include Toxoplasma gondii, which causes a parasitic disease called toxoplasmosis, the leading cause of birth defects worldwide and harmful to people with compromised immune systems. The CDC estimates more than 60 million people living in the U.S. carry T. gondii.

“We always suspected that enzymes called proteases might be required to help parasites escape from the infected cell, but had assumed that these enzymes were produced by the parasites themselves. We had never considered that parasites might instead hijack host cell proteases. It's an ingenious system,” says Greenbaum. “Our findings open up whole new window for drug discovery.”

“This work is a triumph of integrative science, combining modern techniques in chemistry, biology, genetics, pharmacology, and genomics," says Roos, the E. Otis Kendal Professor of Biology and Ellison Medical Foundation Senior Scholar of Global Infectious Diseases. Collaborations between the Greenbaum and Roos laboratories have been facilitated by proximity, as these researchers are housed in adjacent space, under the auspices of the Penn Genome Frontiers Institute.

Because Plasmodium and Toxoplasma kill infected cells, they must constantly hop from cell to cell to survive. When parasites burst out of an infected cell, they leave a mess behind, shredding the dense meshwork of proteins comprising the host cell cytoskeleton and breaking the cell apart, causing cell death. But researchers were unsure what proteins the parasites were using as tools to help them break through the walls of the cell.

To observe the behavior of P. falciparum parasites, the team infected human red blood cells, using pharmacological and biochemical evidence to discover that parasites activate the host protease calpain-1. Blocking or removing calpain-1, a calcium regulated protease, left parasites trapped inside the host cell. By adding calpain-1 back into the cell, parasites were able to once again blast free.

Curious to know if the distantly related parasite T. gondii might use the same process, Greenbaum worked with Roos, who has pioneered the use of T. gondii for a wide range of molecular genetic and cellular studies. Infecting mouse fibroblasts with T. gondii, the team used genetic techniques to remove, and restore, calpain activity. They found that in the absence of calpain, parasites could not escape the infected cell, just as they had observed for malaria parasites.

Over the past 40 years, malaria has become increasingly resistant to drugs that once controlled this devastating disease, leading to an alarming increase in deaths. Targeting host proteins rather than the parasite itself might give the parasite less scope to develop resistance, since the parasite doesn't have genetic control over host proteins. Greenbaum plans to continue to explore the viability of calpain as a drug target for antiparasitic drugs.

This work was funded by the Ellison Medical Foundation, National Institute for Allergy and Infectious Diseases, the Ritter Foundation, and the Penn Genome Frontiers institute, and the Penn Institute for Translational Medicine and Therapeutics.

PENN Medicine is a $3.6 billion enterprise dedicated to the related missions of medical education, biomedical research, and excellence in patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System.

Penn's School of Medicine is currently ranked #4 in the nation in U.S.News & World Report's survey of top research-oriented medical schools; and, according to most recent data from the National Institutes of Health, received over $379 million in NIH research funds in the 2006 fiscal year. Supporting 1,700 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System (UPHS) includes its flagship hospital, the Hospital of the University of Pennsylvania, rated one of the nation’s top ten “Honor Roll” hospitals by U.S.News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center. In addition UPHS includes a primary-care provider network; a faculty practice plan; home care, hospice, and nursing home; three multispecialty satellite facilities; as well as the Penn Medicine at Rittenhouse campus, which offers comprehensive inpatient rehabilitation facilities and outpatient services in multiple specialties.

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.edu

More articles from Health and Medicine:

nachricht 'Icebreaker' protein opens genome for t cell development, Penn researchers find
21.02.2018 | University of Pennsylvania School of Medicine

nachricht Similarities found in cancer initiation in kidney, liver, stomach, pancreas
21.02.2018 | Washington University School of Medicine

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

Im Focus: Hybrid optics bring color imaging using ultrathin metalenses into focus

For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.

But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...

Im Focus: Stem cell divisions in the adult brain seen for the first time

Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.

The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...

Im Focus: Interference as a new method for cooling quantum devices

Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters

Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Researchers invent tiny, light-powered wires to modulate brain's electrical signals

21.02.2018 | Life Sciences

The “Holy Grail” of peptide chemistry: Making peptide active agents available orally

21.02.2018 | Life Sciences

Atomic structure of ultrasound material not what anyone expected

21.02.2018 | Materials Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>