title: A Host-Pathogen Interaction Reduced to First Principles: Antigenic Variation in T. brucei.
abstract: Antigenic variation is a common microbial survival strategy, powered by diversity in expressed surface antigens across the pathogen population over the course of infection. Even so, among pathogens, African trypanosomes have the most comprehensive system of antigenic variation described. African trypanosomes (Trypanosoma brucei spp.) are unicellular parasites native to sub-Saharan Africa, and the causative agents of sleeping sickness in humans and of n'agana in livestock. They cycle between two habitats: a specific species of fly (Glossina spp. or, colloquially, the tsetse) and the bloodstream of their mammalian hosts, by assuming a succession of proliferative and quiescent developmental forms, which vary widely in cell architecture and function. Key to each of the developmental forms that arise during these transitions is the composition of the surface coat that covers the plasma membrane. The trypanosome surface coat is extremely dense, covered by millions of repeats of developmentally specified proteins: procyclin gene products cover the organism while it resides in the tsetse and metacyclic gene products cover it while in the fly salivary glands, ready to make the transition to the mammalian bloodstream. But by far the most interesting coat is the Variant Surface Glycoprotein (VSG) coat that covers the organism in its infectious form (during which it must survive free living in the mammalian bloodstream). This coat is highly antigenic and elicits robust VSG-specific antibodies that mediate efficient opsonization and complement mediated lysis of the parasites carrying the coat against which the response was made. Meanwhile, a small proportion of the parasite population switches coats, which stimulates a new antibody response to the prevalent (new) VSG species and this process repeats until immune system failure. The disease is fatal unless treated, and treatment at the later stages is extremely toxic. Because the organism is free living in the blood, the VSG:antibody surface represents the interface between pathogen and host, and defines the interaction of the parasite with the immune response. This interaction (cycles of VSG switching, antibody generation, and parasite deletion) results in stereotypical peaks and troughs of parasitemia that were first recognized more than 100 years ago. Essentially, the mechanism of antigenic variation in T. brucei results from a need, at the population level, to maintain an extensive repertoire, to evade the antibody response. In this chapter, we will examine what is currently known about the VSG repertoire, its depth, and the mechanisms that diversify it both at the molecular (DNA) and at the phenotypic (surface displayed) level, as well as how it could interact with antibodies raised specifically against it in the host.
authors.affiliation: Laboratory of Lymphocyte Biology, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.
authors.forename: Galadriel
authors.initials: G
authors.lastname: Hovel-Miner
authors.affiliation: Laboratory of Lymphocyte Biology, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Mugnier
authors.affiliation: Laboratory of Lymphocyte Biology, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA. papavasiliou@rockefeller.edu.
authors.forename: F Nina
authors.initials: FN
authors.lastname: Papavasiliou
authors.affiliation: Laboratory of Lymphocyte Biology, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Pinger
authors.affiliation: Laboratory of Lymphocyte Biology, The Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.
authors.forename: Danae
authors.initials: D
authors.lastname: Schulz
mesh_terms: D000818:Animals; D014644:Genetic Variation / Q000235:genetics / Q000276:immunology; D006790:Host-Parasite Interactions / Q000276:immunology; D006801:Humans; D007303:Insect Vectors / Q000276:immunology* / Q000469:parasitology; D014346:Trypanosoma brucei brucei / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D014353:Trypanosomiasis, African / Q000276:immunology* / Q000469:parasitology; D014643:Variant Surface Glycoproteins, Trypanosoma / Q000235:genetics / Q000276:immunology*
chemical_list: D014643:Variant Surface Glycoproteins, Trypanosoma
keywords: Antigenic variation; Chromatin biology; Chromosomal translocations; DNA repair; Trypanosoma brucei