Discoveries shed light on powerful parasite's success

Toxoplasma is arguably the most successful animal parasite on Earth: It infects hundreds of species of warm-blooded animals, most notably half of humanity. The unusual ability of the organism to infect and reproduce inside almost all warm-blooded animals has led scientists to wonder about the tricks it uses so successfully to subvert the behavior of cells. Now, a team of medical school researchers has shown for the first time how it manages to be so effective.

The team, led by professor of microbiology and immunology John Boothroyd, PhD, identified two proteins critical to the parasite's ability to thrive. They have further documented how it injects one of the proteins into the cell it infects and how that protein then travels to the cell's nucleus, where it blocks the cell's normal response to invasion.

Never before have researchers offered such insight into the way this type of parasite can hijack a host cell's genetic machinery for its own benefit. And the discovery has wide-ranging implications for a number of diseases caused by other parasites in this class, which reproduce only inside of cells, including the parasite that causes malaria.

The results are published in two papers. One, appearing in the Dec. 15 issue of Science, identifies two proteins that can determine how much damage Toxoplasma can inflict on an animal. A change in either of the proteins can trigger a 10,000-fold escalation in the damage on lab mice.

A second paper in the Dec. 20 edition of Nature reveals a new mechanism for how an intracellular pathogen can interact with its host by injecting a protein that goes to the cell's nucleus. "This was a totally unknown phenomenon," said Boothroyd.

Together, the findings may help to explain important differences in how various Toxoplasma strains have evolved to exploit this interaction, said Susan Coller, PhD, one of the Nature study's lead authors and who was a postdoctoral scholar in Boothroyd's lab when the work was done. Postdoctoral scholars Jeroen Saeij, PhD, and Jon Boyle, PhD, are the other lead authors of the studies.

"We think that the different versions of Toxoplasma strains evolved for optimal interaction with different hosts," said Boothroyd. "If a given strain gets into the 'wrong' host, the result is a system out of kilter and extreme disease. It's the bull in the china shop."

Although the majority of people infected by Toxoplasma have no symptoms, it can cause severe infections in individuals with compromised immune systems. In addition, women infected for the first time while pregnant can pass the organism to their fetuses, potentially resulting in sight and hearing problems as well as learning disabilities.

Humans can become infected by the parasite by accidentally consuming or inhaling the cysts from infected cat feces, by eating meat from an infected animal—especially pork, lamb or venison—or by drinking contaminated water. Cats are the primary carriers of Toxoplasma, though they rarely exhibit symptoms.

The origins of the more virulent strains of Toxoplasma were first documented in a 2001 Science paper from Boothroyd's group; the researchers found that the recombination of two relatively benign strains of Toxoplasma can result in a thousandfold increase in their ability to cause serious disease. Over the last few years, the researchers have worked to track down exactly what happens to make some strains of Toxoplasma pack such an extra punch.

They identified two proteins—called ROP16 and ROP18—that controlled much of the devastating effects of toxoplasmosis. The researchers were shocked that two proteins were responsible for the dramatic differences between the strains; they had expected the answer to be much more complex.

Both proteins are kinases, which are enzymes used by all cells to regulate a variety of key physiological processes, including responding to the presence of an invader. "If a parasite needs to co-opt a host cell for its own purposes, there is no better way than to introduce a kinase that can completely alter the entire physiology of that host cell," said Boothroyd.

Saeij added, "Obviously the organism needs some powerful tools to manipulate the host's immune system to ensure its survival. So it is very well possible that each time Toxo encountered new hosts, it expanded its arsenal of tools (duplicating or evolving existing kinases) to deal with the new challenges."

Knowing what determines the extent of the immune response may allow for therapeutic manipulations: More aggressive therapy may be warranted if a strain that contains the proteins that increase virulence is the cause of the infection. Also, if doctors can test whether a pregnant woman infected with the parasite has a more virulent strains, they can then better assess the risks to the fetus.

The group's further exploration of the Toxoplasma virulence process may also have implications for immune-system modulating drugs that could specifically tune down a response that's out of control in some cases of toxoplasmosis.

The research involved a collaboration with Montana State University and was supported by grants from the National Institutes of Health, the Ellison Medical Foundation and the University of California University-wide AIDS Research Program.