Development of Glycoconjugate Vaccines for Schistosomiasis Público
Luyai, Anthony Esheminye (2010)
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
About this Dissertation
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