Experimental African trypanosomiasis: IFN‐γ mediates early mortality

Abstract

In this study, we demonstrate that Kupffer cells in the livers of highly susceptible BALB/c mice infected with Trypanosoma congolense were loaded with trypanosomal antigen and appeared highly activated. This was associated with an enlarged capillary bed in the livers and decreased blood pressure of these mice towards the terminal stage. Blocking of murine IL‐10 receptor (IL‐10R)in vivo shortened the survival time of highly susceptible T. congolense‐infected BALB/c mice. Anti‐IL‐10R treatment decreased the survival of relatively resistant T. congolense‐infected C57BL/6 mice dramatically. Blocking of the IL‐10R also significantly shortened the survival time of mice infected with T. brucei. The acute death of trypanosome‐infected mice treated with anti‐IL‐10R antibodies in vivo was associated with focal liver necrosis, with significantly increased plasma levels of IL‐6, IL‐10, IL‐12p40 and IFN‐γ and enhanced synthesis of IL‐6, IL‐12p40 and IFN‐γ by spleen cell cultures. Anti‐IL‐10R‐induced death of T. congolense‐infected C57BL/6 mice could be prevented by administration of a neutralizing antibody specific forIFN‐γ. We conclude that phagocytosis of a critical number of trypanosomes by Kupffer cells leads to a systemic inflammatory response syndrome and, depending on the degree of Kupffer cell activation, is followed by death that is mediated by IFN‐γ. The role of trypanosome‐pulsed macrophages, T cells and genetic influences is discussed in a synopsis.

Quantitative Differences in Immune Responses in Mouse Strains that Differ in their Susceptibility to Trypanosoma brucei brucei Infection

“…Thus, during African trypanosomosis, hypersecretion of IFN-, with a concomitant suppression of IL-10, results in profound increase in the IFN-/IL-10 ratio, macrophage hyperactivation with excessive TNF-and NO production and a susceptible phenotype [10]. In agreement with previous reports [11,15,16], IL-10 could play an important role in trypanotolerance by means of checking the levels of IFN- production during the course of infection.…”

“…This study further suggests that the production of various immune molecules during trypanosomosis is under tight control. Thus, there seems to be a certain range within which pro-inflammatory and associated molecules are protective, above which they become harmful to the host, possibly through host-tissue damage [11,15], and below which they fail to induce an effective parasite control, leading to massive parasitosis [3,11]. Of note, the IFN-/IL-10 balance appears to be critical [11].…”

“…However, Uzonna et al [19,20] correlated this cytokine with susceptibility to T. congolense infection while TNF- and IL-12 were associated with resistance. Yet other studies have linked IFN- and TNF- via macrophage hyperactivation and nitric oxide (NO) production [15,16], as well as IL-10 via immunodepression [21], with the pathogenesis of African trypanosomosis. Type-2 cytokines such as IL-4 and IL-10 have also been linked with resistance during African trypanosomosis [9,16].…”

Regulatory T Cells Prevent Control of Experimental African Trypanosomiasis

“…The complexity of the host-parasite relationship is demonstrated by multiple effects of IFN-␥ as well as IL-10 in African trypanosomiasis. IFN-␥ is mediating mortality in susceptible BALB/c mice infected with T. congolense (12,37) and immunopathology in infected, relatively resistant C57BL/6 mice (34) but is also required for survival (25). IL-10 down-regulates production of IFN-␥ and the immunopathology in trypanosome-infected mice (12,34,38) but also suppresses protective immune responses (39).…”

“…infection with 10 3 T. congolense clone 13 (TC13), whereas relatively resistant C57BL/6 mice survive for Ͼ100 days, a survival associated with cycles of parasitemia and expression of new VSGs (11). We have shown that the early mortality in highly susceptible BALB/c mice infected with T. congolense or T. brucei is caused by an excessive activation of the macrophage system, associated with an excessive production of IFN-␥ and a systemic inflammatory response syndrome (12)(13)(14).…”