Correlation between intestinal BMP2, IFNγ, and neural death in experimental infection with Trypanosoma cruzi

Abstract

Megacolon is one of the main late complications of Chagas disease, affecting approximately 10% of symptomatic patients. However, studies are needed to understand the mechanisms involved in the progression of this condition. During infection by Trypanosoma cruzi (T. cruzi), an inflammatory profile sets in that is involved in neural death, and this destruction is known to be essential for megacolon progression. One of the proteins related to the maintenance of intestinal neurons is the type 2 bone morphogenetic protein (BMP2). Intestinal BMP2 homeostasis is directly involved in the maintenance of organ function. Thus, the aim of this study was to correlate the production of intestinal BMP2 with immunopathological changes in C57Bl/6 mice infected with the T. cruzi Y strain in the acute and chronic phases. The mice were infected with 1000 blood trypomastigote forms. After euthanasia, the colon was collected, divided into two fragments, and a half was used for histological analysis and the other half for BMP2, IFNγ, TNF-α, and IL-10 quantification. The infection induced increased intestinal IFNγ and BMP2 production during the acute phase as well as an increase in the inflammatory infiltrate. In contrast, a decreased number of neurons in the myenteric plexus were observed during this phase. Collagen deposition increased gradually throughout the infection, as demonstrated in the chronic phase. Additionally, a BMP2 increase during the acute phase was positively correlated with intestinal IFNγ. In the same analyzed period, BMP2 and IFNγ showed negative correlations with the number of neurons in the myenteric plexus. As the first report of BMP2 alteration after infection by T. cruzi, we suggest that this imbalance is not only related to neuronal damage but may also represent a new route for maintaining the intestinal proinflammatory profile during the acute phase.

Local association of Trypanosoma cruzi chronic 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.…”

“…T. cruzi infected mice do not develop digestive megasyndromes, but these are late stage manifestations of human disease, and usually take many years to develop. Nevertheless, denervation and other features of nascent enteropathy have been described in mouse models at the histological level 14,29–32 . Delayed transit has also been reported 33,34 but neither the GI region involved nor associations with infection dynamics were determined.…”

“…Adult enteric neurogenesis has been described in response to chemically-mediated tissue injury 10 and in the steady state 11 . A series of advances has also highlighted previously unappreciated levels of interconnectedness between the gut’s immune and nervous systems 12–14 . We therefore hypothesized that host-parasite interactions in the chronically infected gut might impact continuously on the enteric nervous system (ENS) and musculature to drive DCD pathogenesis.…”

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.…”

“…Adult enteric neurogenesis has been described in response to chemically-mediated tissue injury [23] and in the steady state [24]. A series of advances has also highlighted previously unappreciated levels of interconnectedness between the gut's immune and nervous systems [25][26][27]. We therefore sought to develop murine DCD models suitable to address the hypothesis that host-parasite interactions in the chronically infected gut might impact continuously on the enteric nervous system (ENS) and musculature to drive disease pathogenesis.…”