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-α) is important for resistance to acute
Trypanosoma cruzi
infection; however, in patients suffering from chronic
T. cruzi infection, plasma TNF-α levels correlate with cardiomyopathy. Recent data suggest that CD8-enriched chagasic myocarditis formation involves CCR1/CCR5-mediated cell migration. Herein, the contribution of TNF-α, 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-α
+ 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
+CD62L
low/- and CCR5
+ CD8
+ lymphocytes. Also, anti-TNF-α 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-α-treated infected mice showed regular expression of connexin-43 and reduced fibronectin deposition, respectively. Furthermore, anti-TNF-α 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.
