Date of Award

2023-12-01

Degree Name

Doctor of Philosophy

Department

Biological Sciences

Advisor(s)

Igor C. Almeida

Second Advisor

Rosa A. Maldonado

Abstract

Chagas disease (CD) and cutaneous leishmaniasis (CL) are neglected tropical diseases caused by the protozoan trypanosomatids, Trypanosoma cruzi and Leishmania spp., respectively. There are approximately 6-8 million people infected with T. cruzi worldwide and ~300,000 people in the US. Between 700,000 and 1.2 million new cases of CL occur worldwide yearly. The approved chemotherapies for both diseases are partially effective and may cause serious adverse events, resulting in premature treatment interruption. Moreover, no effective vaccine for either disease is available. Therefore, developing a vaccine that would provide effective cross-protection against both diseases would provide a cost-effective alternative to the existing toxic chemotherapies. Due to the evolutionary loss of the a1,3-galactosyltransferase (a1,3-GalT) gene in humans and Old- World nonhuman primates, a-galactopyranosyl (a-Gal) epitopes highly expressed on both Trypanosoma cruzi and Leishmania spp. cell surfaces are highly immunogenic. We have previously shown that synthetic a-Gal-based vaccines can effectively protect against either murine acute T. cruzi or L. major infection. We also explore a b-galactofuranosyl (b-Galf) epitope as potential vaccine candidate against T. cruzi and L. major co-infection since this sugar is highly abundant in these kinetoplastids, but absent in humans and all other mammals. We, therefore, hypothesize that a synthetic a-Gal- and/or b-Galf-based vaccine could provide effective cross- protection against a co-infection with T. cruzi and L. major (and other a-Gal- an/or bGalf- expressing Leishmania species). Here we use an a1,3-GalT- knockout (a1,3-GalT-KO) murine model to evaluate the efficacy of two new synthetic neoglycoproteins (NGPs), NGP28b and NGP29b, containing nonreducing, terminal a-Galp and b-Galf glycotopes, respectively, found in both parasites and absent in the a1,3-GalT-KO mouse, as potential vaccine candidates against CD and CL. Our data suggests that both vaccine candidates induce a robust cross-protective immune response. This leads to a significant reduction in the parasite burden, enhances animal survival, and triggers a potent Th1 response. Additionally, these vaccines elicit a cytokine profile that promotes class-switching events in this co-infection experimental model.

Language

en

Provenance

Recieved from ProQuest

File Size

129 p.

File Format

application/pdf

Rights Holder

Colin D Knight

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