Targeting the Biology of Parasite Behind African Sleeping Sickness

Listed among the global great neglected diseases, African sleeping sickness and the livestock disease Nagana are caused by the parasite African trypanosomes.

The researchers aim to illuminate the basic natural biology of the parasite, which is transmitted by the bite of an infected tsetse fly and lives in the bloodstream and tissues of the infected humans or cattle.

“Our goal is to understand how they avoid elimination by the host immune response and how they acquire iron as an essential nutrient from the bloodstream,” Bangs says.

These processes are mediated by two unique and related parasite virulence factors: variant surface glycoprotein (VSG) (for immune evasion) and transferrin receptor (for iron acquisition).  

The researchers will study how these proteins are synthesized and transported to their site of action, the parasite cell surface.

VSG is the linchpin for survival of trypanosomes in the face of the host immune response, Bangs says, noting the parasites have genes for more than 1,000 immunologically distinct VSGs but make only one at time to make a protective coat covering its entire surface.

As they grow up in the bloodstream, an immune response is mounted to clear the wave of parasites. However, trypanosomes spontaneously switch from expressing one VSG to another at a low rate, so there is always a background pool of antigenically distinct parasites from which new waves arise.  

“We have studied how VSG is synthesized, anchored in membranes and, more recently, how it is transported to the parasite cell surface,” Bangs says. “This work will continue, focusing on the role of its sugar-lipid membrane anchor in normal trafficking, turnover and replacement with new VSG molecules.”

Similar studies will be performed with the transferrin receptor to understand its role in iron acquisition.  

“Our newest area of investigation will ask how the parasite copes when the inevitable situation arises that it expresses a ‘defective’ VSG that is unable to assemble and move to the cell surface,” Bangs says.

Bangs credited a resource on campus, the South Campus Instrument Center at the School of Dental Medicine, for providing a key contribution to the project.

Peter Bush, the center’s director, is a world-class expert on scanning electron microscopy.

“Peter is highly collaborative and creative in developing new techniques for visualizing anything from bacteria to larger inert materials at the ultramicroscopic scale,” Bangs says.

“Specifically, for our work, he has allowed us to visualize trypanosomes at a level that is unprecedented,” he says.  

Sleeping sickness is endemic throughout sub-Saharan Africa, where it infects tens of thousands of people yearly.  

This is low relative to other parasitic tropical diseases, such as malaria, but it is highly significant in that infection is always fatal, and treatments are expensive, difficult to administer and often ineffective.  

Animal trypanosomiasis is similarly lethal and difficult to control, and consequently it levels an enormous economic burden throughout areas of Africa where trypanosomes are found.

The $2 million, five-year fundamental science grant through the National Institute of Allergy and Infectious Diseases marks years 21 to 25 of continuous funding for Bangs as an independent investigator and extends back even further to work he performed as a graduate student at Johns Hopkins University.

“Our work is not directly targeted at developing new therapeutic strategies for treatment of trypanosomiasis. Rather, we investigate basic cell biological processes that might provide critical insights into how these parasites subvert the natural defenses that are so effective against other infectious organisms,” Bangs says.