NOD2 receptor is crucial for protecting against the digestive form of Chagas disease.

Author summary Chagas disease is caused by the protozoanTrypanosoma cruzi, during the chronic phase of infection 2-27% of patients develop digestive form of the disease (megaesophagus and megacolon) that contributes to patient morbidity and mortality, generating costs for public health services, and especially affecting significantly the life quality of the patients. Although is known that many factors inherent of the parasite (tropism, genetics, virulence and antigenicity), host (age, gender, nutritional status, genetics and immune response) and geographical distribution may influence the development of the different clinical forms of Chagas disease, the exact mechanism that leads to megacolon and megaesophagus development are unknown. Here we showed that patients with digestive form of Chagas`Disease do not express the innate immune receptor NOD2. By isolating a parasite from a digestive patient and infecting NOD2-deficient mice we observed a reduced intestinal motility, chronic development of colon and jejunum wall thickness associated with increased inflammatory mediators in the organ, when compared to wild type animals. Our results indicate that the NOD2 receptor protects against the development of the digestive form of Chagas disease and could be used as a biomarker for the development of gastrointestinal changes duringT.cruziinfection in patients. Digestive and cardiodigestive forms of Chagas' disease are observed in 2% to 27% of the patients, depending on their geographic location,Trypanosoma cruzistrain and immunopathological responses. The aim of this work was to evaluate the role of NOD2 innate immune receptor in the pathogenesis of the digestive system in Chagas' disease. Patients with digestive form of the disease showed lower mRNA expression of NOD2, higher expression of RIP2 and alpha-defensin 6, compared to indeterminate form, detected by Real-time PCR in peripheral blood mononuclear cells. In addition, there was a negative correlation between the expression of NOD2 and the degree of dilation of the esophagus, sigmoid and rectum in those patients. The infection of NOD2(-/-)mice withT.cruzistrain isolated from the digestive patient induced a decrease in intestinal motility. Histopathological analysis of the colon and jejunum of NOD2(-/-)and wild type C57BL/6 animals revealed discrete inflammatory foci during the acute phase of infection. Interestingly, during the chronic phase of the infection there was inflammation and hypertrophy of the longitudinal and circular muscular layer more pronounced in the colon and jejunum from NOD2(-/-)animals, when compared to wild type C57BL/6 mice. Together, our results suggest that NOD2 plays a protective role against the development of digestive form of Chagas' disease.