Invasion and escape of a stealthy brain parasite
Think of a parasitic disease, and something like malaria probably comes to mind—a serious health threat to be sure, but one that mainly affects unknown people in far-away places.
What most Americans don’t realize is that one in four of us is infected with the parasite Toxoplasma gondii.
“We think of ourselves as being pretty hygienic and parasite-free, but many people have this parasite and live with it without even knowing it,” says Vernon Carruthers. Eating undercooked, contaminated pork, lamb or venison, or coming into contact with contaminated cat feces are the main routes of infection. In people with healthy immune systems Toxoplasma remains in an inactive stage, but in people with HIV/AIDS, organ transplant recipients or cancer patients undergoing chemotherapy, the infection—called toxoplasmosis—can erupt explosively and damage the brain, eyes and other organs.
Toxoplasmosis also is a concern in women who contract it while pregnant. If a woman passes on the infection to her baby, the child may develop mental retardation and blindness. And there’s disturbing recent evidence that the parasite in its supposedly dormant stage is not as harmless as once thought. Chronic infection with Toxoplasma is known to affect behavior in animals, and in humans may contribute to mental illness, schizophrenia in particular.
For Vernon Carruthers, who was drawn to medical research because “it was like being a detective,” toxoplasmosis is worthy of investigation not only because it’s one of the most common human infections throughout the world, but also because it serves as a model for malaria, which is more difficult to study in the lab.
Carruthers is examining how the parasite invades the cells it infects. Unlike viruses and bacteria that passively depend on host cell mechanisms to gain entry, Toxoplasma actively bores its way in. The process involves a number of steps, the first of which is attaching itself to a target cell. A protein called MIC2 (pronounced “mike two”), which oozes out the parasite’s front end, plays a key role.
“We think this protein binds to receptors on the host cell—you can think of it like reaching out and grabbing handles,” says Carruthers. Conveniently, MIC2 is connected to a motor system inside the parasite. “So you can imagine that if MIC2 is bound to a handle and connected to this motor system, then if the motor is running and driving MIC2 from the front end to the back end of the parasite, the parasite will be propelled forward into the cell.”
Another protein, PLP1, not only helps Toxoplasma invade cells, it also provides a means of escape when the parasite breaks out and obliterates the host cell in which it’s been holed up, as happens in severe, acute toxoplasmosis.
“PLP1 appears to punch holes in the host cell membrane to weaken it,” says Carruthers. When his research group engineered Toxoplasma strains lacking the protein and then filmed what happened as the parasites tried to escape from lab-grown cells, they saw the parasites dart around inside the host cell, persistently poking at its membranous sides. Only after about 10 minutes of effort did some finally break out. Additional experiments in mice showed that these PLP1-deficient parasites also were incapable of causing disease, even at high levels of infection.
Because PLP1 and MIC2 are found in both Toxoplasma and the organism that causes malaria, Carruthers hopes that studying their roles, as well as those of other proteins involved in cell penetration and escape, will lead to drugs or vaccines with widespread applications.
In another project, Carruthers is collaborating with researchers at Johns Hopkins University to test drugs on mice with toxoplasmosis, with a goal of finding treatments for early stages of schizophrenia.
“My collaborators think that infectious agents contribute to schizophrenia, and they’ve been trying to identify which agents are involved,” says Carruthers. “The one they’ve found the closest association with so far is Toxoplasma, and preliminary studies indicate that it may be involved in some 10 percent of cases of schizophrenia. It’s probably not just the parasitic infection that’s responsible, but that in conjunction with genetic susceptibility and other environmental influences.”
One particularly interesting drug candidate is a natural product, artimisinin, derived from the plant Artemisia annua (wormwood), which was used by Chinese herbalists in ancient times to treat fever. Artimisinin already is used as an antimalarial drug, so if it shows promise against Toxoplasma in mice, clinical trials with schizophrenia patients may not be far away.
