Date of Award

2024-12-01

Degree Name

Doctor of Philosophy

Department

Biological Sciences

Advisor(s)

Rosa A. Maldonado

Abstract

Chagas disease (CD) is caused by the hemoflagellate protozoan Trypanosoma cruzi. This disease is considered one of the 20 neglected tropical diseases (NTD), and it is estimated that 6 to 8 million people worldwide are diagnosed with CD. In the United States, Chagas infection is not reported in all states; however, most reported CD cases are chronic infections. Chagas infection is characterized by two phases: an acute and a chronic phase. Until this present moment, no prophylactic or therapeutic human vaccine is available. However, in a recent study in a murine model, our group showed that the synthetic 20-merpeptide (DAENPGGEVFNDNKKGLSRV) MASPpep derived from the mucin-associated surface proteins (MASPs) conjugated with keyhole limpet hemocyanin (KLH) has 86% prophylactic protection. MASPs are proteins highly expressed on both T. cruzi plasma membrane and extracellular vesicles. To potentiate the therapeutic activity, we used a mixture of these peptides (m-MASPpep) conjugated with the non-virulent diphtheria toxoid (CRM197). We aimed to enhance both the humoral and cellular immune responses by administering Poly (I:C) alongside the m-MASPpep-CRM197 vaccine. The efficacy of this combination was evaluated in a chronic model using male and female C3H/HeNsd mice, organized into six groups (10 mice each): Naïve, Placebo, Poly(I:C) at 20µg, m-MASPpep-CRM197 at 50µg, and a combination group with m-MASPpe-CRM197/Poly (I:C) at 50 µg /20 µg. Vaccination involved an initial priming dose followed by two booster doses spaced 20 days apart. Notably, the m-MASPpep-CRM197 in conjunction with Poly(I:C) elicited elevated levels of total IgG and IgG2a antibodies. These antibodies were found to exert lytic activity against T. cruzi trypomastigotes, and the treated groups exhibited a significant reduction in parasitic load within colon tissue. Additionally, the combination of the m-MASPpep-CRM197/Poly(I:C) vaccine with a full course of benznidazole treatment resulted in areas of sterile colon and heart tissues.

Language

en

Provenance

Recieved from ProQuest

File Size

110 p.

File Format

application/pdf

Rights Holder

Juan Carlos Silva

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