University of North Carolina
at Chapel Hill scientists have discovered a protein in the cell wall of parasites that’s crucial to the molecular mechanism allowing them to move between cells, survive and cause disease.
The discovery was made in Toxoplasma gondii, an organism that can cause blindness and brain damage in people with an impaired immune system and can cause severe disease in first-trimester fetuses. In addition, the organism is used as a model experimental system for studying the closely related mosquito-borne malaria parasite Plasmodium.
"The way these organisms move and the way their movement is controlled is absolutely critical to their ability to cause disease," said Dr. Con Beckers, associate professor of cell and developmental biology at UNC’s School of Medicine.
"Movement is necessary for these parasites to spread within the host animal, it is necessary for their ability to enter host cells, and movement is also necessary for parasites to escape from the host cell, to swim off and find a new cell."
A report of the research appeared in the May 10 issue of the Journal of Cell Biology. Co-authors are Beckers, Elizabeth Gaskins, Nicollete DeVore and Tara Mann, all of UNC; and Stacey Gilk and Gary Ward, of the University of Vermont.
The research will have relevance to malaria and a variety of related pathogens including Cryptosporidium, which causes disease in the elderly and in people with AIDS.
Protozoan parasites in the phylum that includes Toxoplasma and Plasmodium normally lack external structures such as hairlike cilia, pseudopodia and whiplike flagella for movement, the report said. Instead, their movement is through a unique process called gliding motility – a circular and forward twisting movement – that remains poorly defined, the scientists said.
In an attempt to understand the parasite’s movement machinery, the study team began by characterizing the protein composition of the organism’s cell wall. Among the many proteins they found was one that was novel, Beckers said.
"This particular protein, TgGAP50, was probably the major discovery here, an integral membrane protein, a protein embedded in the membrane of the parasite."
The researchers found that TgGAP50 associates with another major protein expressed by the parasite TgMyoA. Myosins are known to be involved in motility. For example, they are present in muscle, where, in combination with the protein actin, they form the thick filaments of muscle.
"This new protein is embedded in the inner membrane complex of the parasite, where it’s directly involved in anchoring myosin to the membrane," Beckers said. "This is, in fact, only the second example of a protein that directly does this."
Thus, the new protein is a specific membrane receptor for what the researchers say is a "myosin motor."
Toxoplasma motility may be a result of the myosin moving along the length of actin filaments in the parasite, Beckers said.
Alternatively, it may be caused by the myosin holding onto the end of a growing actin filament. Either way, the myosin molecule needs to be anchored in the parasite for movement to occur.
"If the myosin is not anchored anywhere, its movement with respect to an actin filament will not result in parasite motility," Beckers said. "As an analogy, if you’re sitting in a small boat and throw a rope out to the dock and someone’s there to hold it, you can pull yourself toward that person. But if no one is there, all you’ll do is pull the rope and no net movement will occur."
Thus, apart from having identified a complex of proteins containing a major myosin in Toxoplasma, the new study has "gone one step further because we identified a protein that actually anchors this myosin-containing complex in the membrane. And this protein is absolutely critical to parasite motility," Beckers said.
"Since motility is so central to survival of this class of parasites, it’s incredibly important that we understand the basic elements of their motile apparatus and how the different components are controlled by the parasite," Beckers said.
"Toxoplasma is motile outside the host cell, not inside it. If we understood parasite motility, we may find a way through some interference with its control mechanisms to convince the organism that it’s actually inside the cell. And if we did that you’d have a non-motile parasite that would not survive to cause disease."
Funding for the research came from the National Institute of Allergy and Infectious Diseases and the Burroughs-Wellcome Fund.