This study was carried out to determine the role of reactive nitrogen intermediates in Trypanosoma cruzi infection. In vitro, splenocytes obtained during the acute phase of infection produced elevated amounts of nitric oxide (NO) that were correlated with the resistance or susceptibility of the animals. In vivo, the levels of N02 plus N03 in plasma during the later phase of infection were higher in C57BV6 mice than in BALBLJc mice. The treatment of infected C57BL/6 mice with inhibitors of NO synthase increased parasitemia and mortality. Finally, we found that the NO donor drug S-nitroso-acetyl-penicillamine is able to kill trypomastigotes in vitro in the absence of any other cells, suggesting a direct NO-mediated killing of T. cruzi.

Cell invasion by Trypanosoma cruzi and its intracellular replication are essential for continuation of the parasite life cycle and for production of Chagas' disease. T. cruzi is able to replicate in nucleated cells and can be killed by activated macrophages. Gamma interferon (IFN-␥) is one of the major stimuli for the activation of macrophages and has been shown to be a key activation factor for the killing of intracellular parasites through a mechanism dependent upon nitric oxide (NO) biosynthesis. We show that although the addition of exogenous tumor necrosis factor alpha (TNF-␣) does not potentiate the trypanocidal activity of IFN-␥ in vitro, treatment of resistant C57BI/6 mice with an anti-TNF-␣ monoclonal antibody increased parasitemia and mortality. In addition, the anti-TNF-␣-treated animals had decreased NO production, both in vivo and in vitro, suggesting an important role for TNF-␣ in controlling infection. In order to better understand the role of TNF-␣ in the macrophage-mediating killing of parasites, cultures of T. cruzi-infected macrophages were treated with an anti-TNF-␣ monoclonal antibody. IFN-␥-activated macrophages failed to kill intracellular parasites following treatment with 100 g of anti-TNF-␣. In these cultures, the number of parasites released at various time points after infection was significantly increased while NO production was significantly reduced. We conclude that IFN-␥-activated macrophages produce TNF-␣ after infection by T. cruzi and suggest that this cytokine plays a role in amplifying NO production and parasite killing.

At the current vaccine price, conjugate vaccination could be a cost-effective investment compared to other options to control childhood diseases. Further analysis is required to determine whether vaccination at the current price is affordable to Brazil.

No abstract

Galectin-1 is an endogenous lectin expressed by thymic and lymph node stromal cells at sites of Ag presentation and T cell death during normal development. It is known to have immunomodulatory activity in vivo and can induce apoptosis in thymocytes and activated T cells (1–3). Here we demonstrate that galectin-1 stimulation cooperates with TCR engagement to induce apoptosis, but antagonizes TCR-induced IL-2 production and proliferation in a murine T cell hybridoma and freshly isolated mouse thymocytes, respectively. Although CD4+CD8+ double positive cells are the primary thymic subpopulation susceptible to galectin-1 treatment alone, concomitant CD3 engagement and galectin-1 stimulation broaden susceptible thymocyte subpopulations to include a subset of each CD4−CD8−, CD4+CD8+, CD4−CD8+, and CD4+CD8− subpopulations. Furthermore, CD3 engagement cooperates with suboptimal galectin-1 stimulation to enhance cell death in the CD4+CD8+ subpopulation. Galectin-1 stimulation is shown to synergize with TCR engagement to dramatically and specifically enhance extracellular signal-regulated kinase-2 (ERK-2) activation, though it does not uniformly enhance TCR-induced tyrosine phosphorylation. Unlike TCR-induced IL-2 production, TCR/galectin-1-induced apoptosis is not modulated by the expression of kinase inactive or constitutively activated Lck. These data support a role for galectin-1 as a potent modulator of TCR signals and functions and indicate that individual TCR-induced signals can be independently modulated to specifically affect distinct TCR functions.