| Trypanosoma 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 histological 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-alpha 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 CCC. |
