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Structural Biology of Infection and Immunity

Division of Structural Biology of Infection and Immunity

Dr. Erec Stebbins

Left: Images of the African trypanosome replicating in the blood, its surface coat shown at the bottom as it switches from one VSG to the other. Right top: protein crystal and diffraction pattern. Right bottom: Structure of VSGsur bound to the anti-trypanosome drug suramin.
© dkfz.de

Immune evasion typifies long-term pathogenesis in both infectious disease and malignancy. The immune system recognizes foreign and dangerous "self" antigens, clearing cells harbouring them such as microbes and tumours. Some microbial pathogens and persistent cancers counter immunity by varying surface antigens. We use a controlled, bio-safe, genetically tractable model system (the African Trypanosome, T. brucei) to study such a long-term, immune-evasive process in a collaborative, strong immunology program at the DKFZ.

T. brucei causes sleeping sickness in humans and nagana in animals. Central to its immune-evasion strategy is the Variant Surface Glycoprotein (VSG), a dense coat of ~10 million molecules carpeting the surface of the organism. The VSG coat elicits a robust antibody response that the parasite evades by accessing a large genetic repertoire of divergent VSGs and “switching” to a new (antigenically distinct) variant, resulting in long-term infection with observable peaks and valleys of parasitemia that are the repeated outcome of cycles of antibody generation, parasite killing, and VSG switching.

We are undertaking a program to structurally characterize VSG proteins derived from infection models and their complexes with antibodies. This initial effort has already altered our view of T. brucei immune evasion with discoveries of underappreciated structural divergence in the coat (Zeelen et al., in press) as well as identifying unexpected surface post-translational modifications that we show potently inhibit the immune response (Pinger et al., 2018).

Current studies in collaboration with two divisions in immunology at the DKFZ will extend these results to antibody-VSG interactions. While these studies focus on a model binary surface whose co-evolution is central to T. brucei pathogenicity, paradigms in immune evasion we uncover are potentially applicable to any situation where pathogenic entities vary antigens to evade antibody binding [in HIV, influenza, malaria, and cancer].

Contact

Dr. Erec Stebbins
Structural Biology of Infection and Immunity (D160)
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280
69120 Heidelberg
Tel: +49 6221 42-1380

Selected Publications

  • M.R. Mugnier, C.E. Stebbins, and F.N. Papavasiliou. (2016) "Masters of Disguise: Antigenic Variation and the VSG Coat in Trypanosoma brucei." PLoS Pathog. Sep 1;12(9):e1005784. doi: 10.1371/journal.ppat.1005784.
  • J. Pinger, D. Nešic, L. Ali, F. Aresta-Branco, M. Lilic, S. Chowdhury, H-S. Kim, J. Verdi, J. Raper, M.A.J. Ferguson, F. N. Papavasiliou, C.E. Stebbins. Nature Microbiol. (2018). “African trypanosomes evade immune clearance by O-glycosylation of the VSG surface coat." Nat Microbiol. Aug;3(8):932-938. doi: 10.1038/s41564-018-0187-6. Epub 2018 Jul 9. PMID: 29988048
  • F. Aresta-Branco, E. Erben, F.N. Papavasiliou, C.E. Stebbins. (2019) "Mechanistic Similarities between Antigenic Variation and Antibody Diversification during Trypanosoma brucei Infection." Trends Parasitol. 2019 Apr;35(4):302-315. doi: 10.1016/j.pt.2019.01.011. Epub 2019 Feb 28. PMID: 30826207
  • J. Zeelen, M.v. Straaten, J. Verdi, A. Hempelmann, H. Hashemi, K. Perez3, P.D. Jeffrey, S. Hälg, N. Wiedemar, P. Mäser, F.N. Papavasiliou, C.E. Stebbins. (2020) Nature Microbiol. in press. “Structure of Trypanosome Coat Protein VSGsur and Function in Suramin Resistance.”
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