Dream home: Malaria parasite renovates to suit its tastes

December 09, 2004

The malaria parasite survives in its host by remodelling the red blood cells in which it dwells. Once ensconced in its newly refurbished home, the parasite evades detection by the host's immune system. Alan F. Cowman, a Howard Hughes Medical Institute (HHMI) international research scholar at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, and colleagues report on studies that reveal this clever survival strategy, in the December 10, 2004 issue of the journal Science. Their findings provide a novel target for new anti-malaria drugs.

Cowman and his research team have identified the mechanism that enables the malaria parasite Plasmodium falciparum to export proteins across a cell membrane to establish infection in the erythrocytes, or red blood cells, of the host. The researchers also have identified a subset of proteins - from about 400 surveyed - that appear vital to the parasite's survival in the host.

Cowman is one of 132 HHMI international research scholars in 29 countries. Through its international research program, HHMI is building a global network of outstanding scientists whose work outside the United States is contributing to our understanding of basic biological processes or disease mechanisms. There are 11 international research scholars in Australia.

P. falciparum, which infects several hundred million people each year and kills one to two million, causes the most severe form of malaria in humans. Once in the blood, the parasite's continuous asexual multiplication inside the red blood cells is responsible for the clinical symptoms of malaria and the associated incidence of disease and death.

To infect the host, the parasite exports proteins through three membranes: the parasite membrane, the parasitophorous vacuole and the erythrocyte membrane.

"It has been an enigma in biology how the parasite transfers proteins across the second membrane, the parasitophorous vacuole, and establishes infection in the erythrocyte," said Cowman. "Once past the parasitophorous vacuole it can renovate the erythrocyte, obtain nutrients and avoid destruction by the body's immune system."

According to Cowman, the sequence in the proteins is the key that enables the parasite to traverse all three membranes. For example, the researchers found that during the asexual stage, the parasite, which is present in the parasitophorous vacuole, remodels the erythrocyte by forming an elaborate membranous network in the cytoplasm of the red blood cell. The invading parasite forms structures important for protein trafficking and for locating the nutrients it needs for survival.

The parasite also remodels the surface of the infected red blood cell membrane with dense elevations called knobs. A protein called PfEMP1 enables the parasite to adhere to the erythrocyte, which is essential if the parasite is to survive in the host. The parasite disguises these alterations, which are made to the surface of the cells, enabling it to complete its 48-hour life cycle, multiply, and cause severe infection without detection by the immune system.

"Adhesion of parasite-infected erythrocytes to host cells is a major factor in the pathology of malaria," Cowman explained. "If the parasite didn't stick to the host erythrocyte, it would be dislodged in the blood stream and eliminated rapidly by organs such as the spleen."

Previous studies have identified five or six P. falciparum proteins involved in the infection of host's red blood cells But Cowman's team--thanks to the completion of the malaria genome sequence--have identified approximately 400 P. falciparum proteins that the parasite exports into the erythrocyte. By analysing the fully sequenced parasite genome, they have identified all the genes and proteins involved in malarial infection and deciphered the signalling code, which is critical for the protein export mechanism.

"We have tried removing certain proteins from the parasite - gene knockouts, for example - and the parasite survived well in most cases. So those proteins were not useful drug targets. But some of the exported proteins are unique to Plasmodium species, and identifying them has been a major step forward in establishing which are the important ones," Cowman said.

The exported proteins present in all Plasmodium species are critical for the malaria parasite's survival. This subset of proteins can cross the parasitophorous vacuole and remodel the erythrocyte, enabling the parasite to grow and infection to succeed. Now, instead of testing all 400 proteins for the development of antimalarial drugs, the researchers can concentrate on the key 10 to 15 proteins implicated in host infection.

Cowman is excited about the implications of the research. The identification of an export mechanism unique to Plasmodium species, he said, "raises the possibility of developing completely novel strategies to interfere with multiple aspects of parasite development through a single target."
-end-


Howard Hughes Medical Institute

Related Malaria Articles from Brightsurf:

Clocking in with malaria parasites
Discovery of a malaria parasite's internal clock could lead to new treatment strategies.

Breakthrough in malaria research
An international scientific consortium led by the cell biologists Volker Heussler from the University of Bern and Oliver Billker from the UmeƄ University in Sweden has for the first time systematically investigated the genome of the malaria parasite Plasmodium throughout its life cycle in a large-scale experiment.

Scientists close in on malaria vaccine
Scientists have taken another big step forward towards developing a vaccine that's effective against the most severe forms of malaria.

New tool in fight against malaria
Modifying a class of molecules originally developed to treat the skin disease psoriasis could lead to a new malaria drug that is effective against malaria parasites resistant to currently available drugs.

Malaria expert warns of need for malaria drug to treat severe cases in US
The US each year sees more than 1,500 cases of malaria, and currently there is limited access to an intravenously administered (IV) drug needed for the more serious cases.

Monkey malaria breakthrough offers cure for relapsing malaria
A breakthrough in monkey malaria research by two University of Otago scientists could help scientists diagnose and treat a relapsing form of human malaria.

Getting to zero malaria cases in zanzibar
New research led by the Johns Hopkins Center for Communication Programs, Ifakara Health Institute and the Zanzibar Malaria Elimination Program suggests that a better understanding of human behavior at night -- when malaria mosquitoes are biting -- could be key to preventing lingering cases.

Widely used malaria treatment to prevent malaria in pregnant women
A global team of researchers, led by a research team at the Liverpool School of Tropical Medicine (LSTM), are calling for a review of drug-based strategies used to prevent malaria infections in pregnant women, in areas where there is widespread resistance to existing antimalarial medicines.

Protection against Malaria: A matter of balance
A balanced production of pro and anti-inflammatory cytokines at two years of age protects against clinical malaria in early childhood, according to a study led by ISGlobal, an institution supported by ''la Caixa'' Foundation.

The math of malaria
A new mathematical model for malaria shows how competition between parasite strains within a human host reduces the odds of drug resistance developing in a high-transmission setting.

Read More: Malaria News and Malaria Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.