Congenital Chagas Murine Model Development and Nanovaccine Efficacy Against Maternal-fetal Trypanosoma cruzi Pathogenesis
Maternal infection with Trypanosoma cruzi (Tc) parasite can lead to the vertical transmission from mother to fetus known as congenital Chagas’ disease (cCD). The objective was to develop a murine model of cCD to test the efficacy of a DNA nanovaccine developed by our laboratory. In this dissertation, we demonstrate that Tc infection in female mice delayed the initiation of pregnancy, reduced fertility rate, and resulted in vertical transmission of the parasite to the offspring. Pups born to infected dams showed lower survival rates, decreased birth weights, and impaired growth rates. Moreover, these pups exhibited significantly elevated levels of inflammation, necrosis, and fibrosis in their cardiac and brain tissues. A higher initial dose of the parasite had more detrimental effects on both fertility rates and the health of the pups, regardless of whether the dams were acutely or chronically infected. We have also established that Tc infection triggered delayed and insufficient activation of T cells, resulting in low levels of effector molecules that are needed for controlling the spread and replication of the parasite in both pregnant and non-pregnant dams. The nanovaccine showed enhanced immunity in pregnant mice compared to non-pregnant mice. Following challenge infection, the vaccine effectively enhanced the splenic differentiation, maturation and polyfunctional activation of CD4+ and CD8+ effector/effector memory and central memory subsets, with increased production of interferon gamma, perforin and granzyme B that exhibit cytolytic activities against the infected cells. Further, nanovaccine immunized pregnant mice exhibited effective control of the parasite burden in maternal tissues and inflammatory infiltrate, necrosis, and fibrosis in maternal (heart, skeletal muscle) and fetal placentas. Consequently, maternal fertility rate and pregnancy outcomes were improved in vaccinated infected mice. Together, we demonstrate that nanovaccine offers a valid strategy to elicit protective immunity against Tc infection during pregnancy, leading to improved control of maternal Tc infection and favorable fetal outcomes.
Networked Digital Library of Theses and Dissertations
The University of Texas Medical Branch at Galveston