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 Electrical 'switch' in brain's capillary network monitors activity and controls blood flow
27.03.2017 | Larner College of Medicine at the University of Vermont

nachricht Laser activated gold pyramids could deliver drugs, DNA into cells without harm
24.03.2017 | Harvard John A. Paulson School of Engineering and Applied Sciences

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: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Big data approach to predict protein structure

27.03.2017 | Life Sciences

Parallel computation provides deeper insight into brain function

27.03.2017 | Life Sciences

Weather extremes: Humans likely influence giant airstreams

27.03.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>