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The newspaper of The Johns Hopkins University May 8, 2006 | Vol. 35 No. 33
Parasite research may lead to better understanding of atherosclerosis

By Kenna Lowe
School of Public Health

Researchers from the Johns Hopkins Bloomberg School of Public Health and other institutions have discovered how Toxoplasma gondii — an opportunistic parasite that causes toxoplasmosis and is responsible for damage to the brain, eyes and other organs — interacts with its host cell.

Rather than examine Toxoplasma as a parasite in and of itself, Isabelle Coppens, lead author of the study, and her colleagues set out to understand how it successfully obtains essential host nutrients, including cholesterol, which it needs to rapidly multiply. This is the first known study of its kind to examine Toxoplasma in this way. The study is published in the April 21 issue of the journal Cell.

Behind Salmonella and Listeria, Toxoplasma is the third most common cause of food-related deaths in the United States, affecting 60 million people in this country alone. Infections occur from accidentally swallowing cat feces from a Toxoplasma-infected cat, drinking from contaminated water or eating tainted raw or undercooked meat. More than 50 percent of the world's population is infected with the Toxoplasma parasite, although very few people show the flulike symptoms because a healthy person's immune system usually keeps the parasite from causing illness. However, pregnant women and individuals with compromised immune systems can be more susceptible to infection, according to the Centers for Disease Control and Prevention. Toxoplasma may also contribute to some cases of schizophrenia.

In order to survive in the human body, Toxoplasma needs to invade a host cell and multiply inside a vacuole, which is a self-made capsule, said Coppens, who is an assistant professor in the Bloomberg School's Department of Molecular Microbiology and Immunology. To satisfy its rapid growth, the parasite consumes the host cell's resources, which it gets from its digestive compartments (lysosomes). Toxoplasma is not able to synthesize many essential molecules, making its survival dependent on the host cell.

The study authors spent the last eight years examining Toxoplasma genes involved in nutrient acquisition. They discovered that the parasite essentially hijacks the microtubule organizing center of the cell, which controls cell architecture, movement and division. The parasite uses the microtubule organizing center to create pathways into the cell in order to attract lysosomes closer to its vacuole. The parasite then secretes a protein that cuts off the lysosome's pathway into the cell, in essence trapping the lysosome inside the vacuole. Lipids, amino acids, sugars and metals, which are food for the parasite, then escape from the lysosome through small pores and nourish the parasite, which allows it to multiply, sometimes doubling in quantity every eight hours.

"Now that we know how the parasite obtains a large variety of nutrient molecules from the host lysosomes, our goal is to disrupt the series of events that allow it to take in nutrients, which will essentially starve the parasite to death," Coppens said.

The host cell's response to cholesterol sequestration by the parasite has important implications in understanding cholesterol equilibrium in our cells. The work being done on Toxoplasma by Coppens and her co-authors may offer new perspectives for understanding cholesterol trafficking inside cells, and therefore atherosclerosis, which is caused by plaque that builds up in arteries. Symptoms from atherosclerosis include reduced blood flow in arms, legs and arteries, which can lead to poor circulation, stroke or heart attack. By 2020, it is expected to be the No. 1 cause of death worldwide.

Atherosclerosis is linked to high blood cholesterol, which results from a mismatch between cholesterol synthesis, dietary intake and storage within cells. The work of Coppens with Toxoplasma provides new insights into the mechanisms by which human cells process and store cholesterol, in this case in response to a parasite infection.

Additionally, deciphering the ways by which the parasite takes over the host cell's microtubule organizing center, which results in arrest in host cell division, is a promising area of research. It may contribute to a better understanding of the regulation of the microtubule organizing center function, which is required for better development of anti-cancer treatment strategies.

Additional authors of the study are Joe Dan Dunn, Julia D. Romano, Marc Pypaert, Hui Zhang, John C. Boothroyd and Keith A. Joiner.

The study was supported by grants from the American Heart Association, National Institutes of Health, Howard Hughes Medical Institute and Burroughs Wellcome Fund.


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