eprintid: 30932
rev_number: 9
eprint_status: archive
userid: 5996
dir: disk0/00/03/09/32
datestamp: 2021-12-20 08:31:55
lastmod: 2022-01-13 06:50:41
status_changed: 2021-12-20 08:31:55
type: doctoralThesis
succeeds: 30930
metadata_visibility: show
creators_name: Gkeka, Anastasia
title: Host Antibody Responses against the Variant Surface Glycoproteins of Trypanosoma brucei
subjects: ddc-570
divisions: i-140001
divisions: i-850300
adv_faculty: af-14
abstract: Trypanosoma brucei is an extracellular pathogen, that causes human and animal African trypanosomiasis. It actively evades the host ́s immune response, in a process termed antigenic variation, by continuously changing its dense coat of Variant Surface Glycoproteins (VSGs). Structurally, VSGs are surface proteins, connected to the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor, and consisting of a smaller C-terminal domain (CTD) attached to a larger N-terminal domain (NTD) by an unstructured region (linker). The CTD is considered to be inaccessible to antibodies, because of the coat ́s dense packaging. On the NTD, post-translation modifications (PTMs) have been shown to alter the immune response, as observed by the O-glycosylation on VSG3. Here, I focused initially on the plasma cell antibody repertoires elicited during infection with the double-, single-or non-glycosylated VSG3. I showed that these infections induce a similar response in mice infected with the same strain and elicit repertoires that are directed towards immunodominant epitopes on the surface of the VSGs. I also found that minor alterations within these epitopes, elicit distinct repertoires, reducing cross-reactivity amongst VSGs and facilitating prolonged immune evasion. On a second step, I also explored the structural differences and elicited repertoires of mosaic VSGs, created by swapping the CTDs of different variants. I found that mosaic and parental VSGs can be antigenically distinct, leading to differential binding by monoclonal antibodies. Their repertoires can be diverse and have heavy and light chain genes that are also present in the repertoires of the parental VSGs, but they form new and distinct pairs in the mosaics. As VSG mosaic formation is most commonly seen in the swapping of CTDs, where the same NTD can be found with different CTDs, these observations could imply that the antigenicity of the VSG protein is indirectly impacted by the CTD, despite the CTD itself being protected from antibody exposure. Overall, my findings suggest that VSGs elicit a stereotyped immune response, focused on a restricted set of immunodominant epitopes and that swapping of the CTD can change this response, further increasing VSG diversity, limiting cross-reactivity and facilitating long-term infection in the host.
date: 2021
id_scheme: DOI
id_number: 10.11588/heidok.00030932
ppn_swb: 1785181688
own_urn: urn:nbn:de:bsz:16-heidok-309321
date_accepted: 2021-12-08
advisor: HASH(0x55602a6725c0)
language: eng
bibsort: GKEKAANASTHOSTANTIBO2021
full_text_status: public
place_of_pub: Heidelberg
citation:   Gkeka, Anastasia  (2021) Host Antibody Responses against the Variant Surface Glycoproteins of Trypanosoma brucei.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/30932/1/Gkeka_Thesis_2021.pdf