Chronic Chagas Disease: A Paradoxical Host-Parasite Relationship
Ledoux, Tamar.
2019
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Chagas disease, one of
a handful of diseases on the World Health Organization's list of neglected tropical
diseases, is caused by the obligate intracellular parasite Trypanosoma cruzi. Endemic in
Central and South America, Chagas disease causes irreversible degenerative
cardiomyopathy in 30% of chronically infected patients, years or decades after they are
initially infected. This contrasts ... read morewith acute infection, which heals without sequelae in
95% of people. The reasons for this discrepancy are poorly understood by the scientific
and medical communities, and there is no cure for chronic Chagas cardiomyopathy (CCC).
Previous work completed in our lab has shown that T. cruzi is able to stimulate mutually
beneficial growth and survival pathways in a number of cell types by the same mechanisms
it employs to invade those cells. Much of T. cruzi's parasite-host binding interaction
is facilitated by its parasite-derived neurotrophic factor (PDNF). Of particular
interest, in the context of cardiac involvement in CCC, is the growth and survival
benefit, including protection from oxidative stress, that PDNF imparts upon cardiac
fibroblasts and cardiomyocytes, which comprise 90% of all cells in the myocardium.
Furthermore, PDNF can stimulate expansion of cardiac progenitor cells (CPCs) and protect
these, as well, from toxic insults. We hypothesize that PDNF, a cardioprotective CPC
growth factor, may be responsible for mediating cardiac repair after acute T. cruzi
infection, and that its absence in chronic infection, concurrent with low parasite
burden, promotes the progression of CCC. For this thesis, we explored the effects of
intravenous injection of recombinant PDNF in mice with experimentally induced CCC, and
demonstrated an expansion of the CPC population. Concurrently, when investigating the
pathology exhibited by CCC mice receiving sPDNF, we also noted a significant improvement
in cardiac structure and function. We quantified reduced T lymphocyte infiltration into
the heart, and measured a reversal of cardiac remodeling, including hypertrophy and
ventricular dilation, by echocardiography and gross anatomy. Furthermore, we showed that
the mice receiving injections of sPDNF were subject to significantly less fibrotic
scarring than their vehicle-injected counterparts, and demonstrated a marked reduction
in frequency and severity of atrioventricular block. In almost every measurable regard,
CCC mice treated with sPDNF were healthier than mice that received only vehicle; indeed,
with regard to hypertrophy and fibrosis, hearts of sPDNF-injected mice became nearly
indistinguishable from those of uninfected mice. Our findings support the novel concept
that T. cruzi facilitates repair of host tissues. However, this project was not without
its difficulties. In the course of this work, we will also discuss the challenges we
faced in working with a mouse model of human disease, particularly a disease whose
pathogenesis is not well understood. In conclusion, this work demonstrates support for
the seemingly paradoxical hypothesis that T. cruzi participates in cardiac repair in a
manner that is mutually beneficial to parasite and host, and introduces the therapeutic
potential of a parasite-derived neurotrophic
factor.
Thesis (Ph.D.)--Tufts University, 2019.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisor: Mercio Perrin.
Committee: Robert Blanton, John Castellot, Jonathan Davis, and Thereza Imanishi-Kari.
Keyword: Biology.read less - ID:
- 3484zw07w
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