Enteric nervous system regeneration and functional cure of experimental digestive Chagas disease with trypanocidal chemotherapy

Archie A. Khan, Harry C. Langston, Louis Walsh, Rebecca Roscoe, Shiromani Jayawardhana, Amanda Fortes Francisco, Martin C. Taylor, Conor J. McCann, John M. Kelly and Michael D. Lewis ()
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Archie A. Khan: London School of Hygiene and Tropical Medicine
Harry C. Langston: London School of Hygiene and Tropical Medicine
Louis Walsh: London School of Hygiene and Tropical Medicine
Rebecca Roscoe: London School of Hygiene and Tropical Medicine
Shiromani Jayawardhana: London School of Hygiene and Tropical Medicine
Amanda Fortes Francisco: London School of Hygiene and Tropical Medicine
Martin C. Taylor: London School of Hygiene and Tropical Medicine
Conor J. McCann: Great Ormond Street Institute of Child Health
John M. Kelly: London School of Hygiene and Tropical Medicine
Michael D. Lewis: London School of Hygiene and Tropical Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Digestive Chagas disease (DCD) is an enteric neuropathy caused by Trypanosoma cruzi infection. There is a lack of evidence on the mechanism of pathogenesis and rationales for treatment. We used a female C3H/HeN mouse model that recapitulates key clinical manifestations to study how infection dynamics shape DCD pathology and the impact of treatment with the front-line, anti-parasitic drug benznidazole. Curative treatment 6 weeks post-infection resulted in sustained recovery of gastrointestinal transit function, whereas treatment failure led to infection relapse and gradual return of DCD symptoms. Neuro/immune gene expression patterns shifted from chronic inflammation to a tissue repair profile after cure, accompanied by increased cellular proliferation, glial cell marker expression and recovery of neuronal density in the myenteric plexus. Delaying treatment until 24 weeks post-infection led to partial reversal of DCD, suggesting the accumulation of permanent tissue damage over the course of chronic infection. Our study shows that murine DCD pathogenesis is sustained by chronic T. cruzi infection and is not an inevitable consequence of acute stage denervation. The risk of irreversible enteric neuromuscular tissue damage and dysfunction developing highlights the importance of prompt diagnosis and treatment. These findings support the concept of treating asymptomatic, T. cruzi-infected individuals with benznidazole to prevent DCD development.

Date: 2024
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DOI: 10.1038/s41467-024-48749-5

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