Characterization of Trypanosoma cruzi-induced cytokine expression in a Cebus monkey model and in chagasic individuals from high and low endemic areas of Paraguay
Description
Although the immunopathology of chronic chagasic cardiomyopathy (CCC) caused by Trypanosoma cruzi is poorly understood, cytokines are likely to play a role in its mediation. The Cebus apella monkey is a good model system for Chagas' disease, since it is possible to experimentally induce cardiac lesions after one year of T. cruzi infection. A T. cruzi strain (Y) that has been previously shown to induce cardiomyopathy in C. apella monkeys was used to experimentally infect 10 monkeys. Clinical, parasitological, serological parameters plus systemic cytokine gene expression were then sequentially assessed for a 19-month period. In addition, ten other monkeys, which had been infected with the same strain 5, 10 and 12 yr earlier were also analyzed cross-sectionally for the same parameters. Three monkeys/time point and one uninfected control were sacrificed for gross pathology, histology, presence of parasites, and local cytokine gene expression. Elevated expression of IL-4 was observed throughout the study period in monkeys that had persistently high parasitemias for over five months, whereas a high level of IFN-gamma was demonstrated in monkeys that controlled parasitemia soon after infection. Chronically-infected monkeys expressed a Th0 type response. Cardiac tissue from a monkey that died from acute infection expressed elevated expression of IL-$1\beta ,$ IL-6, TNF-alpha, ICAM-1, PDGF-a, TGF-$\beta$ and IL-10. Local cytokine production in chronic monkeys was also characterized by elevated expression of ICAM-1, PDGF-a, and TGF-beta, which was correlated with the detection of T. cruzi DNA by PCR. A Th1 type (IFN-gamma) response and early parasite clearance and the Th2 type (IL-4) with persistent and high parasitemia resulted in similar cardiac damage Chagas' disease is a serious public health problem in Paraguay. A cross-sectional study in low endemic (Oriental) and high endemic (Chaco) regions was conducted from June to December 1994. A seroprevalence of 72% was found in a population of 314 native Indians from the Chaco. For the Oriental Region, a seroprevalence of 13% in 1542 individuals was determined. Electrocardiograms (EKG) were conducted on a group of 209 individuals. Thirty-two seropositive individuals were selected for an analysis of T. cruzi-induced cytokine gene expression of IL-2, IFN-gamma, IL-4 and IL-10. The individuals under study were grouped according to the presence or absence of abnormal EKGs. In 63% of individuals with abnormal EKGs from a high endemic area, a dominant Th2 type response was observed, whereas 63% of individuals from low endemic area expressed a strong Th1 type response, with 40% presented a Th0 type response. All subjects from the high endemic region showed a Th0 type response, whereas 100% of the individuals from the low endemic area presented a Th1 type response. In most chagasic patients IL-2 expression was depressed while IL-10 predominated in response to infection In addition, T. cruzi-induced IL-2, IFN-gamma, IL-4, and IL-10 gene expression were analyzed in 28 school children (25 seropositive, 3 seronegative). The seropositive children were categorized as acute (n = 2) or early indeterminate (n = 23). The acutely-infected children showed a distinct Th1 type and the early indeterminate group a Th0 type responses to infection. In the seronegative control group, T. cruzi-induced expression of Th1 and Th2 cytokines was minimal. The results of this study suggest that selective induction of a Th0 type cyrokine pattern may be important for development of effective immune responses