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.

Fig. 1

clinical evolution of human Chagas disease. Upon infection with Trypanosoma cruzi, individuals undergo an acute phase that lasts between 2–4 months and is characterized by high parasitemia. Detection of acute disease is one of the challenges of human Chagas disease, since individuals who live in endemic areas often do not display symptoms and, if symptoms appear, they are usually unspecific. As infection is detected, treatment is offered to the patients and about 75% of the treated acute patients are cured. In the case that disease is not cured (or detected early on), patients will enter the chronic phase of disease. The transition from acute to chronic phase is accompanied by a marked decrease in parasitemia, as a result of the host’s immune response. Most patients within the chronic phase are asymptomatic, classified as indeterminate. However, a significant percentage of the patients become symptomatic and develop pathology associated to cardiac or digestive tissues, which may lead to death. The reasons why some individuals remain asymptomatic while others develop severe pathology are not completely understood to date.

Fig. 2

immunoregulation in human Chagas disease: distinct functions of CD28𢀒 T-cells. Correlative analysis of the frequency of CD4⁺CD28-Vbeta5⁺ T-cells and TNF-alpha or IL-10-expressing cells was performed in indeterminate (A) and cardiac (B) chagasic patients. Peripheral blood mononuclear cells were obtained from indeterminate and severe cardiac chagasic patients and analyzed using flow cytometry to determine the values obtained in X and Y axis, as previously done by us (Menezes et al. 2004). The data showed a positive correlation between the frequency of CD4⁺CD28-Vbeta5⁺ cells and IL-10 as well as TNF-alpha in indeterminate, suggesting a balance in the expression of these cytokines by this cell sub-population, leading to a co-regulation of inflammatory/anti-inflammatory responses. On the other hand, a positive correlation was only observed between CD4⁺CD28-Vbeta5⁺ cells and TNF-alpha, but not IL-10, in cardiac patients. This suggests a predominance of inflammatory function of these cells in cardiac patients, which could be associated to the establishment of an unregulated immune response, favoring pathology development.

Fig. 3

cytokines and cell populations involved in the generation of protective and pathogenic responses in chronic Chagas disease. Shortly following infection by Trypanosoma cruzi, patent parasitemia will be controlled and patients enter the chronic phase of disease. During this phase, differential immune responses may be the defining factor which allow establishment of a well controlled immune response for maintaining the parasite in check (indeterminate clinical form) vs. a response which continues to control patent parasitemia, yet leads to pathology (cardiac and digestive clinical forms). The initial interaction between the parasite and the host is likely key in establishing effective control of patent parasitemia and at the same time is critical in the formation of cytokine microenvironments which could orchestrate subsequent differentiation of regulatory and effector T-cell populations. Depending on the balance between biologically active T-cell subpopulations and their relative life spans, activation thresholds and functional activity, the overall response will be successful in maintaining the indeterminate clinical form or progressing into the more severe cardiac or digestive forms. Several studies have demonstrated that activated CD4 and CD8 T-cells are present in all clinical forms with the production of inflammatory and regulatory cytokines, however, recent studies have also demonstrated differences among clinical forms in terms of relative production of inflammatory cytokines, expression of IL-10 and expression of regulatory molecules such as CTLA-4. To date, the roles of Th17 cells in pathology, or of Treg cells in controlling inflammation are unknown in human Chagas disease. In addition to differential immune responses, several other factors likely influence the differential progression of individuals into distinct clinical forms of Chagas disease including the parasite strain, the strength of inoculation, environmental factors, such as previous immunological experience and nutrition, and host genetics.