Neuronal Parasitism, Early Myenteric Neurons Depopulation and Continuous Axonal Networking Damage as Underlying Mechanisms of the Experimental Intestinal Chagas' Disease

Abstract

There is a growing consensus that the balance between the persistence of infection and the host immune response is crucial for chronification of Chagas heart disease. Extrapolation for chagasic megacolon is hampered because research in humans and animal models that reproduce intestinal pathology is lacking. The parasite-host relationship and its consequence to the disease are not well-known. Our model describes the temporal changes in the mice intestine wall throughout the infection, parasitism, and the development of megacolon. It also presents the consequence of the infection of primary myenteric neurons in culture with Trypanosoma cruzi (T. cruzi). Oxidative neuronal damage, involving reactive nitrogen species induced by parasite infection and cytokine production, results in the denervation of the myenteric ganglia in the acute phase. The long-term inflammation induced by the parasite's DNA causes intramuscular axonal damage, smooth muscle hypertrophy, and inconsistent innervation, affecting contractility. Acute phase neuronal loss may be irreversible. However, the dynamics of the damages revealed herein indicate that neuroprotection interventions in acute and chronic phases may help to eradicate the parasite and control the inflammatory-induced increase of the intestinal wall thickness and axonal loss. Our model is a powerful approach to integrate the acute and chronic events triggered by T. cruzi, leading to megacolon.

Aspirin and Infection: A Narrative Review

“…The chronic digestive disease consists of megaesophagus or megacolon or both [ 109 ]. The main pathogenetic mechanism involved in the chronic digestive disease is the denervation of the enteric nervous system [ 109 , 117 ]. Administration of ASA was found to be neuro-protective in mice models [ 118 , 119 ], leading to an increase in the number of nitrergic neurons and preventing hypertrophy of the esophagus [ 118 , 119 ] and the colon [ 113 ].…”

Local association ofTrypanosoma cruzichronic infection foci and enteric neuropathic lesions at the tissue micro-domain scale

“…Nevertheless, denervation and other features of nascent enteropathy have been described in mouse models at the histological level 14,[29][30][31][32] . Delayed transit has also been reported 33,34 but neither the GI region involved nor associations with infection dynamics were determined.…”

Local association of Trypanosoma cruzi chronic infection foci and enteric neuropathic lesions at the tissue micro-domain scale

“…T. cruzi infected mice do not develop advanced digestive megasyndromes resembling those in humans, but these are late stage manifestations that usually take many years to develop. Nevertheless, denervation and other features of nascent enteropathy have been described in several mouse models at the histological level [27,[41][42][43][44][45]. Delayed transit has also been reported [44,46,47], but neither the GI region involved, nor associations with infection dynamics have been determined.…”