Cellular and genetic mechanisms involved in the generation of protective and pathogenic immune responses in human Chagas disease

Abstract

Perhaps one of the most intriguing aspects of human Chagas disease is the complex network of events that underlie the generation of protective versus pathogenic immune responses during the chronic phase of the disease. While most individuals do not develop patent disease, a large percentage may develop severe forms that eventually lead to death. Although many efforts have been devoted to deciphering these mechanisms, there is still much to be learned before we can fully understand the pathogenesis of Chagas disease. It is clear that the host’s immune response is decisive in this process. While characteristics of the parasite influence the immune response, it is becoming evident that the host genetic background plays a fundamental role in the establishment of pathogenic versus protective responses. The involvement of three complex organisms, host, parasite and vector, is certainly one of the key aspects that calls for multidisciplinary approaches towards the understanding of Chagas disease. We believe that now, one hundred years after the discovery of Chagas disease, it is imperative to continue with highly interactive research in order to elucidate the immune response associated with disease evolution, which will be essential in designing prophylactic or therapeutic interventions.

Trypanosoma cruzi -Induced Activation of Functionally Distinct αβ and γδ CD4 − CD8 − T Cells in Individuals with Polar Forms of Chagas' Disease

“…Further studies are being carried out in our laboratory to clarify these questions. However, the observed functional differences presented here are clearly associated with important clinical features of the patients and continue to support earlier findings by our group and others defining key differences in the immunoregulatory environments between indeterminate and cardiac chagasic patients (20).…”

“…on the analysis of expression of factors that control the establishment of inflammatory responses in Chagas' disease, such as inflammatory cytokines and chemokines (20,21). Studies performed by us and other groups have shown that major T-cell populations, defined by the expression of CD4 and CD8, display phenotypic and functional differences in individuals with different clinical forms of Chagas' disease.…”

“…As a result of thousands of years of coevolution between human host and the parasite (6), most infected individuals develop an asymptomatic, or "indeterminate" (I), form of Chagas' disease. This form is characterized by a lack of clinical signs and symptoms and has been associated predominantly with a modulatory cellular immune response based on cytokine profiles and downregulatory molecule expression (5,20,48,49,51). Chronic patients may also develop symptomatic clinical forms, mainly with digestive or cardiac alterations.…”

“…Cardiac patients display a T-cell-mediated inflammatory response in situ (13,24,41), which is responsible for the pathology; this inflammatory profile is also observed in circulating activated T cells found at high frequencies in these patients (2,16,19,32). Although it is clear that a plethora of parasite and host factors influences the clinical outcome of Chagas' disease, recent studies have suggested that activation of functionally distinct Tcell populations in T. cruzi-infected individuals may be responsible for the establishment of different clinical forms (17,20). Thus, identifying these populations and the factors responsible for their activation will be critical for driving immune-based interventions to prevent pathology.…”

Infection With Trypanosoma cruzi and Progression to Cardiomyopathy

“…Two main hypotheses have been proposed: parasite persistence and human host immune response to infection. 15,16 In the acute phase, the host controls infection by multiple pathways. 16 In the chronic phase, antigens that are elicited by the immune response are mediated by T cells, which play an important role in the pathological development.…”