Weinvestigatedimmunoneuroendocrineinteractionsinvivo and in vitro following infection by Trypanosoma cruzi, the causative agent of Chagas disease. In a first set of experiments, we studied the hypothalamus–pituitary–adrenalaxis.Nestsofparasiteswereseeninthe adrenal gland, whereas T. cruzi–specific PCR gene amplification product was found in both the adrenal and pituitary glands of infected mice. These endocrine glands also revealed alterations including vascular stasis, increase in the deposition of extracellular matrix (ECM), as well as T cell and macrophage infiltration. Functionally, we found a decrease in corticotrophin-releasinghormoneandanincreaseincorticosteronecontents, in hypothalamus and serum, respectively, whereas no significant changes were seen in serum adrenocortricotropic hormone of infected animals. Nevertheless, the serum levels of interleukin-6 (known to directly stimulate glucocorticoid secretion) were increased, as compared to controls. Considering the presence of T cells within the nervous tissue of chagasic animals, we performed a number of in vitro experiments co-culturing spleen-derived T cells from control or infected mice, with neuronal cells (being or not being directly infected in vitro). In particular, we looked for ECM-mediated interactions, known to affect T cell migration.WefoundanincreaseinECMdepositionininfectedcultures, as compared to controls. Moreover, adhesion of T cells was enhanced when neuronal cells were infected in vitro, or when T cells were derived from T. cruzi–infected mice, events that could be abrogated with antiECM antibodies. Together, the data summarized above clearly reveal that neuroendocrine axes are altered in experimental Chagas disease.