TNF-α mediates resistance to Trypanosoma cruzy infection in mice by inducing nitric oxide production in infected IFN-γ-activated macrophages (original) (raw)
Related papers
1995
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.
Prostaglandin and nitric oxide regulate TNF-α production during Trypanosoma cruzi infection
Immunology Letters, 1998
The mechanisms that control TNF-h production by macrophages during Trypanosoma cruzi infection are still unknown. Destruction of intracellular forms by cytokine activated macrophages is considered to be a major mechanism of parasite elimination. Although in vitro TNF-h contributes to enhanced parasite destruction by macrophages, previous work in vivo has shown that as the parasite burden increases, serum TNF-h levels decline. In this report we show that TNF-h production by peritoneal adherent cells is elevated at the initial phase of T. cruzi infection. As infection progresses TNF-h production decreases. The observed reduction is partly due to inhibition, largely exerted by endogenous PG and secondarily by NO. Inhibition of their synthesis partially restored the ability to produce high levels of TNF-h to macrophages upon stimulation by LPS. Neither endogenous IL-10 nor TGF-i seem to be involved in the negative regulation of TNF-h production.
Infection and Immunity, 1999
Trypanosoma cruzi replicates in nucleated cells and is susceptible to being killed by gamma interferon-activated macrophages through a mechanism dependent upon NO biosynthesis. In the present study, the role of platelet-activating factor (PAF) in the induction of NO synthesis and in the activation of the trypanocidal activity of macrophages was investigated. In vitro, PAF induced NO secretion by T. cruzi -infected macrophages and the secreted NO inhibited intracellular parasite growth. The addition of a PAF antagonist, WEB 2170, inhibited both NO biosynthesis and trypanocidal activity. The inducible NO synthase/ l -arginine pathway mediated trypanocidal activity, since it was inhibited by treatment with l - N -monomethyl arginine ( l -NMMA), an l -arginine analog. PAF-mediated NO production in infected macrophages appears to be dependent on tumor necrosis alpha (TNF-α) production, since the addition of a neutralizing anti-TNF-α monoclonal antibody mAb inhibited NO synthesis. To test...
The Journal of Infectious Diseases, 2001
Trypanosoma brucei gambiense, a causative agent of sleeping sickness, induced a dose-dependent production of tumor necrosis factor (TNF)-a by human macrophages in vitro. TNFa was also induced in the Mono Mac 6 cell line, which indicates a direct effect of parasite components on macrophages. Parasite-soluble factors were also potent inducers of TNF-a. The addition of anti-TNF-a to cocultures of macrophages and parasites increased the number of trypanosomes and their life span, whereas irrelevant antibodies had no effect. TNF-a may have a direct role (i.e., direct trypanolytic activity) and/or an indirect one, such as TNFa-mediated induction of cytotoxic molecules. A direct dose-dependent lytic effect of TNF-a on purified parasites was observed. This lytic effect was inhibited by anti-TNF-a. These data suggest that, as in experimental trypanosomiasis, TNF-a is involved in parasite growth control in human African trypanosomiasis.
1998
Trypanosoma cruzi target molecules that might regulate the host immune responses have not yet been fully identified. In the present study, we demonstrate that the parasite-released molecule (Tc52) was able to synergize with IFN-␥ to stimulate nitric oxide production by macrophages. This synergistic effect was also observed at the level of inducible nitric oxide synthase gene expression. Furthermore, Tc52 was also shown to induce gene expression for IL-1␣, IL-12, and IL-10. Moreover, the combination of Tc52 and IFN-␥ down-regulates IL-1␣ and IL-10 gene expression, but not IL-12. Isotype profiles and Tc52 or anti-CD3-induced T cell proliferation were also analyzed, indicating that active immunization with Tc52 partially relieves the immunosuppression observed during the acute phase of the disease. Moreover, under conditions of experimental infection, the Tc52 appears immunologically silent, failing to elicit Ab response and lymphocyte proliferation during the initial acute phase infection. Following active immunization, Tc52 was capable of stimulating T cell proliferation and Ab production with a predominance of IgG1, IgG2a, IgG2b, IgG3, and to a lesser extent IgA. Taken together, these results demonstrate that T. cruzi Tc52-released Ag could be involved in the immunoregulatory processes. The immune response against Tc52 that appears late in the T. cruzi infection may play a role in the modulation of its biological function(s).
International Journal for Parasitology, 2007
Innate and adaptive immunity collaborate in the protection of intracellular pathogens including Trypanosoma cruzi infection. However, the parasite molecules that regulate the host immune response have not been fully identified. We previously demonstrated that the immunisation of C57BL/6 mice with cruzipain, an immunogenic T. cruzi glycoprotein, induced a strong specific T-cell response. In this study, we demonstrated that active immunisation with cruzipain was able to stimulate nitric oxide (NO) production by splenocytes. Immune cells also showed increased inducible nitric oxide synthase protein and mRNA expression. Spleen adherent cells secreted high levels of IFN-c and IL-12. Microbicidal activity in vitro was mainly mediated by reactive nitrogen intermediaries and IFN-c, as demonstrated by the inhibitory effects of NO synthase inhibitor or by IFN-c neutralisation. Specific T-cells were essential for NO, IFN-c and TNF-a production. Furthermore, we reported that cruzipain enhanced CD80 and major histocompatibility complex-II molecule surface expression on F4/80+ spleen cells. Interestingly, we also showed that cruzipain up-regulated toll like receptor-2 expression, not only in F4/80+ but also in total spleen cells which may be involved in the effector immune response. Our findings suggest that a single parasite antigen such as cruzipain, through adaptive immune cells and cytokines, can modulate the macrophage response not only as antigen presenting cells, but also as effector cells displaying enhanced microbicidal activity with reactive nitrogen intermediary participation. This may represent a mechanism that contributes to the immunoregulatory process during Chagas disease. Ó
The Journal of Infectious Diseases, 2009
interferon g, and cell contact. Furthermore, rTSIF could down-regulate type 2-oriented immune responses. Therefore, trypanosome-suppressive immunomodulating factor (TSIF) may represent a new parasite molecule with the potential to modulate the host immune network, whereby it could contribute to the inflammatory response required to control parasite growth and to the pathogenicity of African trypanosomiasis, including immunosuppression. TSIF knock-down trypanosomes died within 2 days, indicating that TSIF may be essential for parasite biology.
PLoS ONE, 2014
Neutrophils are involved in the initial steps of most responses to pathogens and are essential components of the innate immune response. Due to the ability to produce and release various soluble mediators, neutrophils may participate in the regulation of the inflammatory response. Little is known about the role of neutrophils during protozoan infections including infection by Trypanosoma cruzi. In the present study we investigated the importance of inflammatory neutrophils on macrophage activation and T. cruzi replication in vitro, in cells obtained from BALB/c mice and C57Bl/6 mice. Co-cultures of BALB/c apoptotic or live neutrophils with infected peritoneal macrophages resulted in increased replication of the parasites and in the production of TGF-b and PGE 2 . The treatment with anti-TGF-b neutralizing antibody and COX inhibitor blocked the parasite replication in vitro. On the other hand, co-cultures of T. cruzi infected macrophages with live neutrophils isolated from C57BL/6 mice resulted in decreased number of trypomastigotes in culture and increased production of TNF-a and NO. The addition of anti-TNF-a neutralizing antibody or elastase inhibitor resulted in the abolishment of macrophage microbicidal effect and increased parasite replication. Addition of elastase to infected macrophages reduced the replication of the parasites, and on the other hand, addition of a selective inhibitor of iNOS increased parasite growth, suggesting the role of NO in this system. Our findings reveal that neutrophils may regulate T. cruzi experimental infection and determine susceptibility and resistance to infection.