In
Chagas disease, understanding how the immune response controls parasite growth but also leads to heart damage may provide insight into the design of new therapeutic strategies.
Tumor necrosis factor-alpha (
TNF-alpha) is important for resistance to acute
Trypanosoma cruzi infection; however, in patients suffering from chronic T. cruzi
infection, plasma
TNF-alpha levels correlate with
cardiomyopathy. Recent data suggest that CD8-enriched chagasic
myocarditis formation involves CCR1/CCR5-mediated cell migration. Herein, the contribution of
TNF-alpha, especially signaling through the receptor
TNFR1/p55, to the pathophysiology of T. cruzi
infection was evaluated with a focus on the development of
myocarditis and heart dysfunction. Colombian strain-infected C57BL/6 mice had increased frequencies of
TNFR1/p55+ and TNF-alpha+ splenocytes. Although
TNFR1-/- mice exhibited reduced
myocarditis in the absence of parasite burden, they succumbed to acute
infection. Similar to C57BL/6 mice,
Benznidazole-treated
TNFR1-/- mice survived acute
infection. In
TNFR1-/- mice, reduced CD8-enriched
myocarditis was associated with defective activation of CD44+CD62Llow/- and CCR5+ CD8+ lymphocytes. Also, anti-
TNF-alpha treatment reduced the frequency of CD8+CCR5+ circulating cells and
myocarditis, though parasite load was unaltered in infected C3H/HeJ mice.
TNFR1-/- and anti-
TNF-alpha-treated infected mice showed regular expression of connexin-43 and reduced
fibronectin deposition, respectively. Furthermore, anti-
TNF-alpha treatment resulted in lower levels of CK-MB, a cardiomyocyte lesion marker. Our results suggest that TNF/
TNFR1 signaling promotes CD8-enriched
myocarditis formation and heart tissue damage, implicating the TNF/
TNFR1 signaling pathway as a potential therapeutic target for control of T. cruzi-elicited
cardiomyopathy.