Controlling Inflammation: The Neurotrophic Anti-inflammatory Pathway in Chagas Heart Disease.
cruzi is an obligate intracellular parasite that causes incurable Chagas disease that
affects millions of people worldwide. In acute infection, T cruzi grows abundantly
throughout the body, triggering severe inflammatory responses in most organs, including
the nervous system and heart. Infected hearts display focal inflammatory infiltrates and
fibrosis that lead to ... read morehistological and functional alterations, such as
cardiomyocytolysis, cardiac murmur, pleural effusion, and conduction abnormalities. Yet,
acute myocarditis subsides in most patients without sequelae. This raises the
possibility that T cruzi expresses agents that stimulate host repair mechanisms to help
heal infected tissues. These putative agents cannot help in chronic Chagasic
cardiomyopathy (CCC), characterized by relentless excessive inflammation and fibrosis
that result in cardiac insufficiency and death in approximately 30% of patients, because
tissue parasitism and, consequently, T cruzi–enabled tissue repair agents in CCC
is extremely scarce. Therefore, administration of beneficial T cruzi–derived
repair agents in CCC could prevent or revert tissue destruction. We have discovered one
such agent, T cruzi’s parasite derived neurotrophic factor (PDNF), which, by
binding neurotrophin receptors TrkA and TrkC, triggers parasite entry into cardiac host
cells while promoting host cell survival, induces secretion of chemokines that
facilitate migration of resident cardiac progenitor/stem cells (CPCs) in the myocardium,
and further expand, induce cell survival, and stimulate the production of the
anti–inflammatory protein TSG–6 (tumor necrosis factor–α
stimulated gene–6) by CPCs. Equally important, intravenous administration of
recombinant PDNF dramatically ameliorates inflammation and fibrosis, and reduces
pro–inflammatory cytokine expression in the hearts of mice with CCC. Therefore,
our results validate the novel concept of a microbial pathogen stimulating mutually
beneficial repair of infected tissues, and suggest a novel therapeutic opportunity for
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Immunology.
Advisor: Mercio PereiraPerrin.
Committee: Honorine Ward, Henry Wortis, and Erik Selsing.
Keyword: Immunology.read less