Study Describes Key Mechanism the Parasite Uses to Stay Viable in Blood Cells
NEW YORK (Feb. 11, 2008) — A scourge to millions worldwide, malaria is proving resistant to older drugs. But a new, collaborative study may have uncovered a new point of weakness that might be exploited to keep P. falciparum at bay.
Using resources and expertise developed at Weill Cornell Medical College, a team of French and American scientists have discovered the genetic and biochemical mechanism the malaria parasite uses to set up house inside an infected red blood cell.
"To survive, P. falciparum creates a tiny pore called an anion channel, through which it takes in nutrients from outside the host cell's membrane and excretes its waste. In our paper, we describe for the first time how this channel functions and how we might impair that function — thereby sickening and killing the parasite," explains co-researcher Dr. Kirk Deitsch, associate professor of microbiology and immunology at Weill Cornell.
The study was led by Dr. Stéphane Egée of Université Pierre et Marie Curie, in Roscoff, France, who conducted much of the research in Dr. Deitsch's lab at Weill Cornell. The researchers published their findings in the February issue of the journal PLoS Pathogens.
Malaria is transmitted via the bite of mosquitoes carrying a microscopic parasite Plasmodium falciparum. This parasite infects red blood cells, eventually destroying them. Malaria typically causes fever, chills and flu-like symptoms. Left untreated, severe complications can ensue and the disease can prove fatal. According to the U.S. Centers for Disease Control and Prevention, each year over one million people die of malaria, most of them young children in sub-Saharan Africa.
"Medications to treat malaria exist but the parasite gradually develops a resistance, so the search for new and better treatment is imperative and ongoing," notes Dr. Deitsch. "Most anti-infective agents rely on finding points of weakness in the pathogen's life cycle and exploiting it. That's what we are trying to do here."
Specifically, the Franco-American team looked at the anion channel, P. falciparum's self-made lifeline to the world outside the host cell's outer membrane.
In prior work, a biochemical mechanism called the cAMP-dependent signaling pathway was identified that activated simple anion channels in the red cell membrane. Blocking that pathway blocked anion channel production and function.
"In this new work we wanted to go deeper, to find the genetic and regulatory agents that the parasite uses to direct this process," Dr. Deitsch says. "We discovered an important regulatory subunit enzyme, called PfPKA-R, that is encoded in the parasite's genome. PfPKA-R appears to be key to the proper function of the cAMP-dependent pathway and, by extension, of the anion channel itself."
To test their theory, the researchers used the unique resources and expertise at Dr. Deitsch's lab to genetically engineer so-called transgenic strains of P. falciparu that would over-express PfPKA-R.
"The transgenic strain of the parasite that over-expressed PfPKA-R displayed a real impairment and dysfunction in its anion channel, confirming that this subunit and the cAMP-dependent pathway are crucial to keeping this pore working as it should," Dr. Deitsch says.
The finding could point to a whole new target for pharmaceutical agents against the malaria parasite.
"What's key here is that PfPKA-R and other enzymes and proteins in the pathway are made by the parasite, not the host cell, and have properties that may distinguish them from similar mechanisms in the host cell," Dr. Deitsch said. "That's important, because the ultimate goal is to find agents that would block anion channel function in the parasite, but leave anion channels in healthy cells alone."
He stressed that it will still take some "fancy pharmacology" to turn these discoveries into effective antimalarial medicines, and more detailed research is needed before that can take place. "We have to determine, for example, the biochemical targets of the enzymes we have studied here," Dr. Deitsch says.
Still, he and the French co-researchers remain optimistic. "What's needed are innovative, effective and affordable medicines that can make new inroads against a global killer," Dr. Deitsch says. "We believe we're headed on the right path."
This work was supported by the French Ministère de la Recherche et de la Technologie, the Délégation Générale pour l'Armement, the United Nations Development Program/World Bank/World Health Organization Special Program for Research and Training in Tropical Diseases, the European Commission FP6, INSERM, the Wellcome Trust, and the U.S. National Institutes of Health. In addition, the Department of Microbiology and Immunology at Weill Cornell Medical College is supported by the William Randolph Hearst Foundation.
Co-researchers include lead researcher Dr. Anais Merckx of Glasgow Biomedical Research Center, Scotland, and Université Paris Descartes, Paris; Dr. Marie-Paul Nivez and Christian Doerig, of Glasgow Biomedical Research Center, Scotland; Dr. Guillaume Boyer and Dr. Serge Thomas, of Université Pierre et Marie Curie, Roscoff, France; Dr. Gordon Langsley of Université Paris Descartes, Paris; and Dr. Pietro Alano of the Instituto Superiore di Sanità, Rome, Italy.
Weill Cornell Medical College
Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in areas such as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, infectious disease, obesity, cancer, psychiatry and public health — and continue to delve ever deeper into the molecular basis of disease in an effort to unlock the mysteries of the human body in health and sickness. In its commitment to global health and education, the Medical College has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, Cornell University is the first in the U.S. to offer a M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, the first indication of bone marrow's critical role in tumor growth, and most recently, the world's first successful use of deep brain stimulation to treat a minimally-conscious brain-injured patient. For more information, visit www.med.cornell.edu.
Andrew Klein
ank2017@med.cornell.edu