Neurodegeneration and neuroregeneration in Chagas disease

Autonomic dysfunction plays a significant role in the development of chronic Chagas disease (CD). Destruction of cardiac parasympathetic ganglia can underlie arrhythmia and heart failure, while lesions of enteric neurons in the intestinal plexuses are a direct cause of aperistalsis and megasyndromes. Neuropathology is generated by acute infection when the parasite, though not directly damaging to neuronal cells, elicits immune reactions that can become cytotoxic, inducing oxidative stress and neurodegeneration. Anti-neuronal autoimmunity may further contribute to neuropathology. Much less clear is the mechanism of subsequent neuronal regeneration in patients that survive acute infection. Morphological and functional recovery of the peripheral neurons in these patients correlates with the absence of CD clinical symptoms, while persistent neuronal deficiency is observed for the symptomatic group. The discovery that Trypanosoma cruzi trans-sialidase can moonlight as a parasite-derived neurotrophic factor (PDNF) suggests that the parasite might influence the balance between neuronal degeneration and regeneration. PDNF functionally mimics mammalian neurotrophic factors in that it binds and activates neurotrophin Trk tyrosine kinase receptors, a mechanism which prevents neurodegeneration. PDNF binding to Trk receptors triggers PI3K/Akt/GSK-3β and MAPK/Erk/CREB signalling cascades which in neurons translates into resistance to oxidative and nutritional stress, and inhibition of apoptosis, whereas in the cytoplasm of infected cells, PDNF represents a substrate-activator of the host Akt kinase, enhancing host-cell survival until completion of the intracellular cycle of the parasite. Such dual activity of PDNF provides sustained activation of survival mechanisms which, while prolonging parasite persistence in host tissues, can underlie distinct outcomes of CD.