BioWorld International Correspondent

LONDON - A new understanding of how a genetic variation determines whether the parasite Toxoplasma gondii causes severe disease or just a mild infection could lead to new therapies for the condition.

The findings also could make it possible to develop tests that would determine whether someone is infected with a virulent or a mild strain of the parasite. Such tests would be particularly useful to help physicians advise women who become infected with T. gondii during pregnancy, as the effect of infection on the developing fetus is highly variable.

Antonio Barragan, assistant professor at the Karolinska Institute and a section head at the Swedish Institute for Infectious Disease Control, both in Stockholm, Sweden, told BioWorld International: "We have identified a gene that encodes a kinase, which in mice is present in two forms, virulent and non-virulent. This molecule is certain to play an important function in the control of cell signalling. Our discovery opens up the possibility of new therapeutic strategies to treat this disease."

Barragan and his colleagues reported their findings in the Dec. 15, 2006, issue of Science in a paper titled "A Secreted Serine-Threonine Kinase Determines Virulence in the Eukaryotic Pathogen Toxoplasma gondii."

Researchers led by John Boothroyd of Stanford University School of Medicine in California reported identical findings in the same issue of Science. Their paper is titled "Polymorphic Secreted Kinases are Key Virulence Factors in Toxoplasmosis."

T. gondii is a common parasitic infection. The organism is present in the natural environment, and people catch it through food, dirty water or contact with cats. An estimated 25 percent to 50 percent of the global population are infected with it; in the UK, up to 30 percent of people have antibodies to it.

When a healthy person becomes infected with T. gondii, an influenza-like illness may result, but after that, the parasite persists in a state of dormancy. For humans with weakened immune systems, such as those with HIV, cancer or taking immunosuppressant drugs, the infection can flare up, with potentially lethal results. Untreated, T. gondii encephalitis in people with HIV is fatal in one in three cases.

If a pregnant woman becomes infected, the effects on the fetus can range from negligible to severe: Some are unaffected, while others develop hydrocephalus or mental retardation, or are born blind or deaf. A miscarriage also might result.

Barragan, with collaborators at Washington University, set out to establish why different strains of T. gondii had different effects. One strain can cause death in laboratory mice at low doses, while other strains rarely caused any symptoms.

Their strategy was to cross-breed the different strains, and analyze which genes associated with virulent characteristics. That led the team to a "locus of virulence" on chromosome 7 of the organism.

Barragan said: "There were several candidate genes there, but it boiled down to one that encoded a kinase that was expressed in several different forms."

Further experiments confirmed that one form of the gene was found in T. gondii organisms that caused mild disease, while another was present in organisms causing severe disease.

To clinch the finding, Barragan's collaborators, led by David Sibley at Washington University School of Medicine in St. Louis, took the virulent form of the gene and transfected it into non-virulent strains of T. gondii. "The recipient strain normally caused no deaths in mice, but when the virulent form of the gene was inserted into the parasite's genome, we found that the mortality rate rose to 100 percent," Barragan said.

The polymorphic gene encodes a kinase called Rop18. The protein is one of a family that the parasite secretes from organelles called rhoptries. Those organelles discharge their contents during the process of invading the host cell, and continue to do so once they are inside the host cell.

Barragan said: "One of our next goals is to study the interactions of Rop18 and other Rop molecules, with host proteins. This will help increase our understanding of how the parasite is communicating with the host cell for its own benefit."

In the long term, he added, a diagnostic test that would determine whether someone was infected with a virulent or a non-virulent strain would be very useful. First, however, researchers need to confirm that, in humans, as in mice, parasites that contain the virulent form of the gene encoding Rop18 cause severe disease, while those carrying the non-virulent form suffer few symptoms.