Discovery of a protein JBP2, an important tool for African sleeping sickness research

Feb 28 2005

Sixty million people in 36 countries of sub-Saharan Africa are threatened daily by a deadly parasitic disease known as African sleeping sickness.

African sleeping sickness is caused by trypanosomes which are protozoan parasites. It is transmitted to humans through the bite of the tsetse fly of the genus Glossina.

There are two forms, each caused by a different parasite :

• Trypanosoma brucei gambiense, which causes a chronic infection lasting years and affecting countries of western and central Africa;
• Trypanosoma brucei rhodesiense , which causes acute illness lasting several weeks in countries of eastern and southern Africa.

When a person becomes infected, the trypanosome multiples in the blood and lymph glands, crossing the blood-brain barrier to invade the central nervous system where it provokes major neurological disorders. Infection by trypanosomes causes neurological alterations which are often irreversible even after successful treatment. Psychomotor and neurological retardation even among cured children is frequent. Without treatment, the disease is invariably fatal.

Sleeping sickness is a daily threat to more than 60 million men, women and children in 36 countries of sub-Saharan Africa, 22 of which are among the least developed countries in the world. However, only 3 to 4 million of these people are under surveillance and the 45 000 cases reported in 1999 do not reflect the reality of the situation, but simply show the absence of case detection. The estimated number of people thought to have the disease is between 300 000 and 500 000.

Detection of people infected with sleeping sickness and subsequent patient care require well trained staff, resources, drugs and well-equipped health centres. Furthermore, without systematic screening of exposed populations and without treatment, the majority of sick people will die without ever having been diagnosed.

In the February issue (Volume 17, Issue 3) of the journal Molecular Cell, scientists in the Marine Biological Laboratory's (MBL's) Josephine Bay Paul Center for Comparative Molecular Biology and Evolution report their discovery of a protein called JBP2, which will help them test their hypothesis that a uniquely modified DNA base called base J is a key component of the trypanosome's mechanism for evading the immune system. If the hypothesis is correct, it will bring scientists closer to developing a more effective drug for treating African sleeping sickness.

The trypanosome evades the human immune system because it is coated with a surface antigen called variant surface glycoprotein (VSG). The human body makes antibodies for VSG, but trypanosomes randomly switch to another antigen when the organisms divide and reproduce. Trypanosomes whose VSG has switched evade the antibodies the human immune system made to fight the original antigen, thus assuring the long-term survival of these parasites within their hosts. The trypanosome has approximately 1,000 different VSG genes, but only expresses one at a time while the others are somehow silenced. This genetic trick, called antigenic variation, has severely limited sleeping sickness treatment options and essentially ruled out the possibility of a vaccine.

MBL trypanosome experts in Robert Sabatini's lab hypothesize that base J (beta-D-glucosylhydroxymethyluracil) may play an important role in the gene silencing process behind antigenic variation. With the goal of learning how the organism regulates the process of antigenic variation, the scientists have been trying to understand how the trypanosome makes base J.

The discovery of JBP2, a member of a protein family that helps control DNA-related functions, is a significant breakthrough in this quest because Sabatini and his colleagues were able to demonstrate that the protein is the key regulator of base J synthesis. This will provide the scientists a new tool to elucidate the biological function of this unique modified DNA base in the regulation of antigenic variation.

If base J does indeed play a role in the gene silencing that enables the trypanosome to change its antigen coating, the discovery of JBP2 may one day enable scientists to create a drug that prevents the manufacture of base J, affecting the trypanosome's ability to vary its antigenic coating, and therefore allowing the human immune system to kill it.

Understanding trypanosomes at the molecular level is key to fighting African sleeping sickness and diseases caused by similar parasites.