Tumor necrosis factor alpha mediates resistance to Trypanosoma cruzi infection in mice by inducing nitric oxide production in infected gamma interferon-activated macrophages

Abstract

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.

Role of the IFNG +874T/A polymorphism in Chagas disease in a Colombian population

“…Control of Chagas infection requires both humoral and cell-mediated immunity directed by a type 1 cytokine response (Kumar and Tarleton, 1998). Endogenous IFN-g and TNFa play critical roles in the control of the infection through a mechanism including release of free radicals (Silva et al, 1995).…”

CCR5 Plays a Critical Role in the Development of Myocarditis and Host Protection in Mice Infected withTrypanosoma cruzi

“…It is now clear that IFN-g-and TNF-a-activated macrophages control of the replication of T. cruzi in various hosts [20]. The mechanism by which macrophages are able to kill intracellular parasites has been shown to be dependent on NO [8][9][10][11][12][13]20], although a recent study using T. cruzi strains Tulahuen and Brazil suggested that inducible NO synthase (iNOS) is not required to control parasite replication in vivo [21]. However, much less is known about the mechanisms governing the migration of leukocytes to sites of tissue infection, especially to hearts of infected hosts.…”

“…Thus, infection with T. cruzi was accompanied by a parasite-associated increase in the expression of CCR5 and migration of T cells to infected tissues, in which several CCR5-acting chemokines are produced. The increased expression of CCR5 could be due to the production of IFN-g [28,29], TNF-a [8,30], interleukin (IL)-10 [7,31], and/or IL-12 [30,32,33] that occurs after the addition of trypomastigote forms of T. cruzi to cultures of splenocytes or after the infection of mice. Indeed, CCR5 expression is positively regulated by these cytokines [34][35][36][37].…”

“…Control of the infection is eventually achieved. Several studies have reported an essential role for CD4 + [1-3] and CD8 + [3, 4] T cells and for interferon (IFN)-g and tumor necrosis factor (TNF)-a [5][6][7][8] in the control of acute infection. However, it is still not known how these types of cells migrate to sites of tissue infection and interact with inflam-…”

Production of hydrogen peroxide by peripheral blood monocytes and specific macrophages during experimental infection with Trypanosoma cruzi in vivo

“…The ultrastructural features of the macrophage activation such as increase in size, surface rufflings and amount of cytoplasmic organelles are recognized as an accurate indication of high phagocytic and microbicidal activities of these cells both in humans and experimental models (Anosa et al, 1997;El Shewemi et al, 1996;Takemura et al, 1989), including Chagas' disease (Melo and Machado, 2001;Melo et al, 2003). On the other hand, biochemical changes, as the ability of secreting hydrogen peroxide (Nathan, 1982;Nogueira and Cohn, 1978;Reed et al, 1987), tumor necrosis factor-alpha (Silva et al, 1995), nitric oxide (Vespa et al, 1994;Petray et al, 1995;Rodrigues et al, 2000) and interleukin-12 (Antunez and Cardoni, 2000) have been considered important markers of macrophage activity.…”