**5.4 Pathogenesis and pathological changes**

### *5.4.1 Research achievements from relevant research institutions*

*T. cruzi* can colonize any nucleated cell. Most of the symptoms in the acute phase of the disease are thought to be caused by damage to host cells by *T. cruzi*. For the

chronic phase-related pathogenesis, there are currently two theories. One theory is that *T. cruzi* persists, leading to chronic inflammation [75], and the other theory is that it is caused by autoimmune damage [76]. Possible mechanisms include antigen cross-reactivity [77], direct cell-mediated cytotoxicity [78], antigenic Submitting changes [79], and cardiac mitochondrial dysfunction [80] etc.

Pathological changes in the acute phase showed mononuclear cell infiltration [81], interstitial edema [82], accumulation of amastigotes in muscle cells of subcutaneous tissue [83], and formation of pseudocysts at the invasion site of Trypanosoma [83]. Myocarditis with cardiac enlargement is usually seen in acute-phase deaths. In patients with sudden death in the chronic phase (mostly due to ventricular arrhythmia or conduction block), the heart size is usually normal or only slightly enlarged. In other patients with chronic Chagas heart disease, cardiac hypertrophy, dilation, and thickening can be seen, especially in the apex of the heart, resulting in apical aneurysm. Mural thrombosis and lung and peripheral organ embolism may be seen in some patients. Microscopic examination showed mononuclear cell infiltration, myocardial fiber hypertrophy, degeneration, necrosis and edema. Microscopic changes in megaesophagus or megacolon are similar to those of the heart.

#### *5.4.2 Research achievements from our institution*

We firstly have shown that cardiac mitochondria-response plays a very important roles in *T. cruzi–*induced cardiomyopathy [80, 84–92], and established the third theory that oxidative stress was involved in cardiac mitochondrial dysfunction [84, 86, 88] and heart dysfunction [80, 93–97]. In detail, we have contributed to the understanding of the mechanism behind the decline of MnSOD and enhancement of SIRT1/PGC1/PARP-1 in correlation with *T. cruzi–*induced consistently oxidative heart damage [90–92, 97]. From this research, we have observed that (1) MnSODtg mice/ MnSOD overexpression in cell lines are beneficial in preserving *T. cruzi–*induced mitochondrial/heart dysfunction [90]; (2) MnSOD−/+ mice were worse of *T. cruzi* infection*–*induced heart dysfunction [91]; and (3) inhibition of PARP-1 would prevent *T. cruzi–*induced heart function [92]. We also have observed *T. cruzi–*induced oxidative stress occurred in adipose tissues by utilizing oxidative markers, which is a novel finding [96, 98]. We have contributed to an understanding of *T. cruzi–*induced oxidative etiopathogenesis [85, 86, 88, 89]. Additionally, we have isolated high quality heart mitochondria to (1) recognize *T. cruzi–*induced oxidative mitochondrial proteins by using combination of BN-PAGE [84] and TOP MALDI MS/MS [88, 95]; (2) ascertain that mitochondrial complex III Qo site was prime source of *T. cruzi–*induced ROS generation [86]; and (3) find that administration of antioxidants improved *T. cruzi–*induced oxidative damage in heart mitochondria and heart tissues [85, 89]. We have conducted a thorough analysis of mitochondrial bioenergetic function as well as the biochemical and molecular factors that are deregulated and contribute to compromised adenosine triphosphate (ATP) production in the myocardium during *T. cruzi* infection. Our team is focused on the discovery and development of novel therapeutics against *T. cruzi*. We found that combination treatment (antioxidants and anti-parasites) is beneficial in arresting the *T. cruzi*–induced inflammatory and oxidative pathology and chronic heart failure in Chagasic rats. We have proven that the *T. cruzi*–induced oxidative alterations in circulation are correlated with heart tissue, suggesting that Chagasic human patients' circulation can replace heart tissue, as issue we are planning to investigate. We also confirmed that this was the case in human

patients with Chagasic cardiomyopathy development and assessed different ways to oxidatively modify mitochondrial respiratory complexes (**Figure 1**) [80, 94].
