Development of Glycoconjugate Vaccines for Schistosomiasis Open Access

Luyai, Anthony Esheminye (2010)

Permanent URL: https://etd.library.emory.edu/concern/etds/sb397874p?locale=en
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Abstract


Abstract
Development of Glycoconjugate Vaccines for Schistosomiasis

By Anthony Esheminye Luyai

Schistosomiasis is a debilitating parasitic disease of humans and endemic in the
tropics. Although the mortality attributed to schistosomiasis is second only to malaria,
surprisingly, it remains largely neglected and research efforts towards developing a
protective vaccine are minimal. In my studies, I have sought to dissect the humoral
immune responses to defined schistosome glycan epitopes in humans, rhesus
monkeys, and mice. Using glycopeptides terminating with schistosome specific glycan
epitopes, I have helped to develop a defined schistosome glycan microarray to show
that while rhesus monkeys generate predominantly high titer anti-core xylose/core
fucose IgG antibodies, humans generate low titer antibodies to the same epitope.
Interestingly, the peak of anti-core xylose/core fucose IgG generation in the rhesus
monkeys coincides with sera from these animals having the highest schistosomula
killing effect observed in vitro. Mice chronically infected with schistosomiasis generate
high titer anti-LDNF IgM antibodies that are cytolytic to schistosomula in vitro.
Additionally, mice immunized with BSA conjugates of LDN and Man3 generated
antibodies that are cytolytic to 3h-old schistosomula in vitro. To facilitate the
development of glycoconjugate candidate vaccines for schistosomiasis, I have used a
commercially available chemical, p-nitrophenyl anthranilate (PNPA), as a
heterobifunctional linker and helped to develop an efficient and quantitative way of
conjugating glycans with a free reducing end via reductive amination to carrier proteins.
Our studies support the concept of developing glycoconjugates as potential protective
candidate vaccines and for generating new serodiagnostic tools for schistosomiasis. In
my thesis work I show that core xylose and/or core fucose epitopes have a potential.

Table of Contents



Table of Contents


CHAPTER 1: INTRODUCTION Page

1.1 Introduction to Dissertation
1
1.2 The general biology of schistosomes 2
1.3 Killing of schistosomula by anti-glycan antibodies
1.4 Protective immunity to helminthes induced by partially defined glycan
antigens

21

1.5 Vaccination against schistosomiasis with irradiated cercariae 22
1.6 Synthesis of schistosome-specific glycopeptides 22
1.7 Conjugation of glycan epitopes to protein carriers

24
1.8 Significance of the study 26
1.9 References
27

CHAPTER 2: CONSTRUCTION OF A DEFINED SCHISTOSOMA MANSONI GLYCAN
ARRAY AND ELUCIDATION OF HUMORAL IMMUNE RESPONSES IN
SCHISTOSOME-INFECTED RHESUS MONKEYS, HUMANS, AND MICE TO
SCHISTOSOME-SPECIFIC GLYCAN EPITOPES

2.1 Abstract


32
2.2 Introduction
33
2.3 Materials and methods 35
2.4 Results
42
2.5 Discussion 73
2.6 References 81





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