Stanford discovery may help predict when toxoplasma can be deadly

December 14, 2006

STANFORD, Calif. - Toxoplasma is arguably the most successful animal parasite on earth: It infects hundreds of species of warm-blooded animals, most notably half of humanity. Its unusual ability to overcome the numerous challenges of infecting and reproducing inside such a wide range of creatures has long intrigued scientists, and now researchers at the Stanford University School of Medicine have identified two of the proteins critical to its ability to thrive.

The findings will be published in the Dec. 15 issue of Science by a team led by John Boothroyd, PhD, professor of microbiology and immunology. Working with mice, the researchers identified two genes that produce two proteins that Toxoplasma introduces into the cells of the host it infects. What's more, the researchers showed for the first time that certain changes in either of the proteins - called kinases - ramped up 10,000-fold the damage that Toxoplasma inflicted on the lab mice.

"This was a totally unknown phenomenon," said Boothroyd.

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. The new findings have implications for determining how to treat these and other infected people: More aggressive therapy may be warranted if a strain that contains the proteins that increase virulence is the cause of the infection.

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 significance of these newly discovered proteins is also highlighted in the same issue of Science by another paper with similar findings from a different group of researchers. Additional evidence of the proteins' critical role will be offered by a paper slated to appear in an upcoming issue of Nature, in which Boothroyd and his colleagues describe the molecular underpinnings of the mechanism used by these parasites to hijack cellular processes in their hosts.

"We think that the different versions of Toxoplasma strains evolved for optimal interaction with different hosts," said Boothroyd, noting that the wrong pairing of parasite and host can have dire consequences. "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."

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 thousand-fold 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. By conducting a comprehensive scan of gene sequences of Toxoplasma strains, postdoctoral scholars Jeroen Saeij, PhD, and Jon Boyle, PhD, first authors of the paper in the Dec. 15 Science, searched for the gene or genes responsible for markedly increased virulence.

To do such a survey, however, the researchers needed to produce an array of strains. Because Toxoplasma strains only recombine in cats, the researchers provided mice infected with different Toxoplasma strains for the cats to eat. The researchers then took the resulting recombinant strains from the cats and infected other mice with them. Based on how these mice fared, the researchers could pinpoint stretches of DNA that contain the genes underlying severe virulence. Based on the DNA sequences, they could determine the proteins involved.

From 140 candidate proteins identified in the initial screen, they focused on those with qualities logically involved in differing levels of virulence, such as high variability of the sequence and the ability to be secreted from the organism to enter the host. This led them to two particularly compelling proteins - ROP16 and ROP18. Both are protein kinases, molecules that are used in the transmission of cellular messages. "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.

The findings may play a role in helping pregnant women who become infected for the first time with the parasite. If doctors can test whether the women have one of the more virulent strains, they can then better assess the risks to the fetuses. The group's further exploration of the Toxoplasma virulence process may also have implications for immune-system modulating drugs that could specifically dampen the effects of toxoplasmosis.
-end-
EMBARGOED FOR RELEASE UNTIL: Thursday, Dec. 14, 2006, at 11 a.m.

Pacific time to coincide with publication in the journal Science

BROADCAST MEDIA CONTACT: M.A. Malone at (650) 723-6912 (mamalone@stanford.edu)

This work was supported by grants from the National Institutes of Health, the Ellison Medical Foundation and the University of California Universitywide AIDS Research Program. Postdoctoral scholar Susan Coller, PhD, is the other Stanford researcher included as an author of this publication.

Stanford University Medical Center integrates research, medical education and patient care at its three institutions - Stanford University School of Medicine, Stanford Hospital & Clinics and Lucile Packard Children's Hospital at Stanford. For more information, please visit the Web site of the medical center's Office of Communication & Public Affairs at http://mednews.stanford.edu.

Stanford University Medical Center

Related Proteins Articles from Brightsurf:

New understanding of how proteins operate
A ground-breaking discovery by Centenary Institute scientists has provided new understanding as to the nature of proteins and how they exist and operate in the human body.

Finding a handle to bag the right proteins
A method that lights up tags attached to selected proteins can help to purify the proteins from a mixed protein pool.

Designing vaccines from artificial proteins
EPFL scientists have developed a new computational approach to create artificial proteins, which showed promising results in vivo as functional vaccines.

New method to monitor Alzheimer's proteins
IBS-CINAP research team has reported a new method to identify the aggregation state of amyloid beta (Aβ) proteins in solution.

Composing new proteins with artificial intelligence
Scientists have long studied how to improve proteins or design new ones.

Hero proteins are here to save other proteins
Researchers at the University of Tokyo have discovered a new group of proteins, remarkable for their unusual shape and abilities to protect against protein clumps associated with neurodegenerative diseases in lab experiments.

Designer proteins
David Baker, Professor of Biochemistry at the University of Washington to speak at the AAAS 2020 session, 'Synthetic Biology: Digital Design of Living Systems.' Prof.

Gone fishin' -- for proteins
Casting lines into human cells to snag proteins, a team of Montreal researchers has solved a 20-year-old mystery of cell biology.

Coupled proteins
Researchers from Heidelberg University and Sendai University in Japan used new biotechnological methods to study how human cells react to and further process external signals.

Understanding the power of honey through its proteins
Honey is a culinary staple that can be found in kitchens around the world.

Read More: Proteins News and Proteins Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.