Surface Coat Replacement Dynamics and Antigen Glycosylation in T. Brucei Influence Evasion of the Host Antibody Response
type: CreativeWork
description: The protozoan parasite Trypanosoma brucei, a causative agent of human and animal trypanosomiasis, evades host immunity through antigenic variation of its variant surface glycoprotein (VSG) coat. During infection, the VSG coat elicits a robust antibody response, but the parasite escapes antibody-mediated clearance by repeatedly accessing its large genomic VSG repertoire and switching expression to antigenically distinct VSGs. Much of our knowledge of the process of VSG switching and the extent of VSG diversity has come from genetic analyses, but deep understanding of the T. brucei host-pathogen interface also requires examination of these topics at the protein level. In this thesis, I describe two protein-based studies of the VSG coat that reveal factors influencing trypanosome evasion of the host antibody response. First, I discuss my examination of the dynamics of VSG coat replacement following a genetic VSG switch, and the impact of this process on the parasite's ability to escape the escalating host antibody response. Using a flow cytometry-based measurement strategy, I evaluated the rate of VSG replacement at the trypanosome surface, and showed that full coat replacement requires several days to complete. I then demonstrated through in vivo infection assays that parasites undergoing coat replacement are only vulnerable to clearance via early IgM antibodies for a limited time. Finally, IgM binding analyses and molecular modeling indicated that IgM loses its ability to mediate trypanosome clearance at unexpectedly early stages of coat replacement based on a critical density threshold of its cognate VSGs on the parasite surface. In the second part of this thesis, I describe a collaborative body of work examining the biochemical features of VSG3 (also termed MITat1.3 and VSG224) and their relevance to parasite interactions with host immunity. The crystal structure of VSG3 was solved, and analysis of the high-resolution structure revealed a glycan of a form previousl…
abstract: The protozoan parasite Trypanosoma brucei, a causative agent of human and animal trypanosomiasis, evades host immunity through antigenic variation of its variant surface glycoprotein (VSG) coat. During infection, the VSG coat elicits a robust antibody response, but the parasite escapes antibody-mediated clearance by repeatedly accessing its large genomic VSG repertoire and switching expression to antigenically distinct VSGs. Much of our knowledge of the process of VSG switching and the extent of VSG diversity has come from genetic analyses, but deep understanding of the T. brucei host-pathogen interface also requires examination of these topics at the protein level. In this thesis, I describe two protein-based studies of the VSG coat that reveal factors influencing trypanosome evasion of the host antibody response. First, I discuss my examination of the dynamics of VSG coat replacement following a genetic VSG switch, and the impact of this process on the parasite's ability to escape the escalating host antibody response. Using a flow cytometry-based measurement strategy, I evaluated the rate of VSG replacement at the trypanosome surface, and showed that full coat replacement requires several days to complete. I then demonstrated through in vivo infection assays that parasites undergoing coat replacement are only vulnerable to clearance via early IgM antibodies for a limited time. Finally, IgM binding analyses and molecular modeling indicated that IgM loses its ability to mediate trypanosome clearance at unexpectedly early stages of coat replacement based on a critical density threshold of its cognate VSGs on the parasite surface. In the second part of this thesis, I describe a collaborative body of work examining the biochemical features of VSG3 (also termed MITat1.3 and VSG224) and their relevance to parasite interactions with host immunity. The crystal structure of VSG3 was solved, and analysis of the high-resolution structure revealed a glycan of a form previousl…
author: Pinger, Jason M
keywords: Trypanosoma brucei, VSG, antigenic variation, immune evasion, IgM, host-pathogen interactions, Life Sciences
date published: 2018-01-01T08:00:00Z
date modified: 2026-07-24T04:10:47Z
provider: Rockefeller
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Rockefeller