The role of cytokines in the control of tissue parasitism and pathogenesis of experimental Chagas' disease was investigated. Wild-type and different cytokine as well as inducible nitric oxide synthase (iNOS) knockout mice were infected with the Colombian strain of Trypanosoma cruzi, and the kinetics of tissue parasitism, inflammatory reaction, parasitemia, and mortality were determined. We demonstrate the pivotal role of the interleukin (IL)-12/interferon (IFN)-gamma/iNOS axis and the antagonistic effect of IL-4 in controlling heart tissue parasitism, inflammation, and host resistance to acute infection with T. cruzi. Further, the heart and central nervous system were shown the main sites of reactivation of T. cruzi infection in mice lacking functional genes for IFN-gamma and IL-12, respectively. Our results also show that in contrast to IFN-gamma knockout (KO) mice, splenocytes from IL-12 KO mice infected with T. cruzi produced low levels of IFN-gamma upon stimulation with antigen. Consistently, high levels of anti-T. cruzi IgG2a antibodies were detected in the sera from IL-12 KO, but not from IFN-gamma KO mice, infected with the Colombian strain of T. cruzi. Thus, our results suggest that the level of IFN-gamma deficiency is a major determinant of the site of reactivation of T. cruzi infection in immunocompromised host.

Toxoplasma gondii is an obligate intracellular protozoan parasite, which infects a wide range of intermediate hosts that include different species of birds and mammals, including humans. The tachyzoites, the rapid multiplying form of the parasite, can invade and replicate within all nucleated cells and, if left unchecked by the immune system, causes extensive tissue damage and death of the intermediate host (11). Resistance to acute infection with T. gondii in the murine model is highly dependent on endogenous gamma interferon (IFN-␥) (11,12,37,43). Soon after initial infection in the intermediate host, T. gondii tachyzoites trigger the synthesis of interleukin-12 (2, 12, 13, 23, 34) and other costimulatory cytokines (13,17,22,23), which initiate the synthesis of IFN-␥ by NK cells (13, 23) and CD4 ϩ CD8 Ϫ ␣␤ ϩ T lymphocytes (12). IFN-␥ combined with tumor necrosis factor alpha will activate macrophages to produce high levels of reactive nitrogen intermediates (RNI) that are involved in the control of parasite replication (1, 26). However, RNI is only one of the IFN-␥-inducible mechanisms involved in the control of tachyzoite replication, and mice treated with inducible nitric oxide synthase (iNOS) inhibitor (20) or deficient in iNOS (38) are relatively more resistant than mice treated with neutralizing antibodies to IFN-␥ (12) or deficient in IFN-␥ or IFN-␥ receptor (10, 37). Thus, additional effector mechanisms induced by IFN-␥ and active during early experimental infection with T. gondii in the mouse model still have to be defined (11,21).Indoleamine 2,3-dioxygenase (INDO) is an enzyme that catalyzes the initial rate-limiting step of tryptophan (Trp) catabolism to N-formylkynurenine and kynurenine (Kyn) (21, 44). Many human cell lines express INDO upon stimulation with IFN-␥. Restriction of available Trp due to degradation by INDO leads to the control of various intracellular pathogens, including T. gondii, in both nonprofessional phagocytic cells (NPPC) and professional phagocytic cells (PPC) (4,5,7,8,28,29,32,39,45). In the absence of Trp, an essential amino acid for T. gondii, parasite growth also becomes restricted (32,36,41). In fact, in human NPPC the induction of INDO appears to be the main mechanism by which IFN-␥ controls the intracellular replication of T. gondii tachyzoites (4,5,7,8,29,32).The INDO activity and the Trp-Kyn metabolic pathway can be induced in murine tissues under various conditions (21,27,35,36). However, it has been difficult to demonstrate the role of INDO and Trp degradation in the control of tachyzoite replication in cell lines of mouse origin (18,19,40). In addition, no information is available about the induction of the Trp-Kyn metabolic pathway and its possible role in the restriction of parasite replication during in vivo experimental infection with T. gondii. In the present study, we evaluated the induction of INDO mRNA, Trp degradation, and Kyn formation during infection with T. gondii. Our results show that during the early stage of infection with T. gondii in the mouse ...

In attempts to investigate the role of galectin-3 in innate immunity, we studied galectin-3-deficient (gal3 ؊/؊ ) mice with regard to their response to Toxoplasma gondii infection, which is characterized by inflammation in affected organs, Th-1-polarized immune response, and accumulation of cysts in the central nervous system. In wild-type (gal3 ؉/؉ ) mice, infected orally, galectin-3 was highly expressed in the leukocytes infiltrating the intestines, liver, lungs, and brain. Compared with gal3 ؉/؉ , infected gal3 ؊/؊ mice developed reduced inflammatory response in all of these organs but the lungs. Brain of gal3 ؊/؊ mice displayed a significantly reduced number of infiltrating monocytes/macrophages and CD8 ؉ cells and a higher parasite burden. Furthermore, gal3 ؊/؊ mice mounted a higher Th1-polarized response and had comparable survival rates on peroral T. gondii infection, even though they were more susceptible to intraperitoneal infection. Interestingly, splenic cells and purified CD11c ؉ dendritic cells from gal3 ؊/؊ mice produced higher amounts of interleukin-12 than cells from gal3 ؉/؉ mice, possibly explaining the higher Th1 response verified in the gal3 ؊/؊ mice. We conclude that galectin-3 exerts an important role in innate immunity, including not only a proinflammatory effect but also a regulatory role on dendritic cells, capable of interfering in the adaptive immune response.