Understanding cell-to-cell heterogeneity in African trypanosomes field isolates

• Applicant: Professor Dr. Tim Nicolai Siegel
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens ; Veterinary Medical Science
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 444811942

Cell-to-cell heterogeneity is key to the ability of pathogens to establish successful infections. It can enable drug resistance, allow immune evasion, or trigger differentiation to life cycle stages capable of surviving in different hosts. One of the best studied examples of cell-to-cell heterogeneity is antigenic variation – the ability of an organism to periodically change the identity of the proteins displayed to the host immune system. Despite the importance of cell-to-cell heterogeneity within pathogen populations during infections, research has long focused on pathogen isolates adapted to cell-culture conditions that typically exhibit much less heterogeneity than its relatives in the field. As a consequence, it has been difficult to elucidate the mechanism contributing to cellular variation.The protozoan parasite Trypanosoma brucei, the causative agent of sleeping sickness in humans and animal African trypanosomiasis in livestock, contains the largest family of variant surface antigens described to date and possesses many attributes that have made it one of the most important models to study antigenic variation. The major T. brucei surface antigen is the variant surface glycoprotein (VSG), and whilst the parasite’s genome encodes for more than 2,000 VSGs, only one is expressed in a mutually exclusive manner at any one time. Periodic switching in VSG isoform expression allows the parasite to evade the host immune response and to establish chronic infections. Yet, most T. brucei research uses isolates adapted to cell culture that switch at much lower frequency and are more homogenous in morphology than recent field isolates.To address this problem, the central goal of the research proposed here is to uncover the genetic or molecular events that lead to a decrease in cell-to-cell heterogeneity during cell-culture adaption of T. brucei field isolates. More specifically, we intend to merge single-cell omics approaches with field research to study the events occurring during cell-culture adaptation of trypanosomes. A specific focus will be placed on the heterogeneity in expression of the parasite’s surface antigens.A better understanding of the mechanisms affecting the level of heterogeneity within a pathogen population will enable us to better predict how pathogens adapt to environmental challenges, including the immune response of their mammalian hosts.

• DFG Programme: Research Grants
• International Connection: Kenya, Uganda
• International Co-Applicants: Privatdozent Dr. Kevin Marucha, Ph.D.; Professor Dr. Julius Mulindwa