Type I IFNs Stimulate Nitric Oxide Production and Resistance to Trypanosoma cruzi Infection

Abstract

The participation of type I IFNs (IFN-I) in NO production and resistance to Trypanosoma cruzi infection was investigated. Adherent cells obtained from the peritoneal cavity of mice infected by the i.p. route produced NO and IFN-I. Synthesis of NO by these cells was partially inhibited by treatment with anti-IFN-αβ or anti-TNF-α Abs. Compared with susceptible BALB/c mice, peritoneal cells from parasite-infected resistant C57BL/6 mice produced more NO (2-fold), IFN-I (10-fold), and TNF-α (3.5-fold). Later in the infection, IFN-I levels measured in spleen cell (SC) cultures from 8-day infected mice were greater in C57BL/6 than in infected BALB/c mice, and treatment of the cultures with anti-IFN-αβ Ab reduced NO production. IFN-γ or IL-10 production by SCs was not different between the two mouse strains; IL-4 was not detectable. Treatment of C57BL/6 mice with IFN-I reduced parasitemia levels in the acute phase of infection. Mice deprived of the IFN-αβR gene developed 3-fold higher parasitemia levels in the acute phase in comparison with control 129Sv mice. Production of NO by peritoneal macrophages and SCs was reduced in mice that lacked signaling by IFN-αβ, whereas parasitism of macrophages was heavier than in control wild-type mice. We conclude that IFN-I costimulate NO synthesis early in T. cruzi infection, which contributes to a better control of the parasitemia in resistant mice.

Type I Interferons Increase Host Susceptibility to Trypanosoma cruzi Infection

“…Second, IFNAR Ϫ/Ϫ mice exhibit a strong advantage over WT mice in their ability to survive T. cruzi infection, which emerges under conditions of lethal parasite challenge. These findings clarify the discordant conclusions of earlier studies, which reported different outcomes for the involvement of type I IFNs in experimental acute T. cruzi infection (12,22,51). Specifically, in the study in which type I IFN-dependent signaling was associated with increased host susceptibility to T. cruzi infection, a lethal dose of parasites was used (51).…”

“…T. cruzi triggers a type I interferon response in a variety of primary cell types in vitro and in vivo in a parasite strain-dependent manner (10,13). The role of type I IFNs in experimental T. cruzi infection is presently unclear given inconsistent outcomes observed in type I IFN receptor knockout (IFNAR Ϫ/Ϫ ) mice (12,22,51). Given the phenotypic diversity exhibited by different T. cruzi strains (4,16,17), we posited that the variable outcomes reported previously might reflect differences in parasite strain and/or infecting dose.…”

“…Despite observations that T. cruzi elicits a prominent type I IFN response early in infection (10,13,52), it is presently unclear if type I IFNs play a role in innate resistance to T. cruzi (12,22,51). The goal of the present study was to determine whether type I IFN-dependent signaling plays a role in innate host resistance to T. cruzi infection.…”

“…Cytokines produced during acute infection, such as interleukin-12 (IL-12), tumor necrosis factor alpha (TNF-␣), and gamma interferon (IFN-␥), as well as nitric oxide, play critical roles in controlling T. cruzi infection in the acute stage of infection (33). In addition, T. cruzi triggers a TLR-independent type I IFN response (9) in isolated cells and in murine models of acute infection (10,12,21,22,51,52).…”

Papel das células TCD4⁺FoxP3⁺ (T_reguladoras) na fase aguda da infecção murina pelo <i>Trypanosoma cruzi</i>.

“…Esta cepa induz altos níveis de parasitemia e mortalidade na maioria das linhagens de camundongos (Sardinha et al, 2006). No entanto, os camundongos da linhagem C57BL/6 são relativamente resistentes (Costa et al, 2006;Graefe et al, 2006) e conseguem sobreviver a inóculos de até 1000 tripomastigotas. Nas primeiras semanas de infecção por parasitas desta cepa de T. cruzi observa-se um quadro de miocardiopatia aguda.…”