Type I Interferons Increase Host Susceptibility to Trypanosoma cruzi Infection

Abstract

Trypanosoma cruzi, the protozoan parasite that causes human Chagas' disease, induces a type I interferon (IFN) (IFN-␣/␤) response during acute experimental infection in mice and in isolated primary cell types. To examine the potential impact of the type I IFN response in shaping outcomes in experimental T. cruzi infection, groups of wild-type (WT) and type I IFN receptor-deficient (IFNAR ؊/؊ ) 129sv/ev mice were infected with two different T. cruzi strains under lethal and sublethal conditions and several parameters were measured during the acute stage of infection. The results demonstrate that type I IFNs are not required for early host protection against T. cruzi. In contrast, under conditions of lethal T. cruzi challenge, WT mice succumbed to infection whereas IFNAR ؊/؊ mice were ultimately able to control parasite growth and survive. T. cruzi clearance in and survival of IFNAR ؊/؊ mice were accompanied by higher levels of IFN-␥ production by isolated splenocytes in response to parasite antigen. The suppression of IFN-␥ in splenocytes from WT mice was independent of IL-10 levels. While the impact of type I IFNs on the production of IFN-␥ and other cytokines/chemokines remains to be fully determined in the context of T. cruzi infection, our data suggest that, under conditions of high parasite burden, type I IFNs negatively impact IFN-␥ production, initiating a detrimental cycle that contributes to the ultimate failure to control infection. These findings are consistent with a growing theme in the microbial pathogenesis field in which type I IFNs can be detrimental to the host in a variety of nonviral pathogen infection models.

Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis

“…*P < 0.05, **P < 0.01, ***P < 0.001. leishmaniasis. Despite the fact that type I IFNs are mainly known for their antiviral role, increasing evidence attests to the involvement of type I IFNs in bacterial and parasitic infection (24)(25)(26)(27)29). Our findings are consistent with earlier reports suggestive of a disease-exacerbatory role for type I interferons in New World Leishmania species (33)(34)(35).…”

“…Type I interferons (type I IFNs) are mainly known for their antiviral activity, and IFN therapy is currently used to treat several viral infections, including hepatitis B and C and herpes virus (21)(22)(23). The role of type I IFNs in bacterial and parasitic infection is less clear, as they are known to protect mice from Plasmodium falciparum infection, but on the other hand, can promote infection pathology with Listeria monocytogenes, Toxoplasma, and Trypanosoma (24)(25)(26)(27). During parasite infection, type I IFNs show more variable effects, being either protective or detrimental for the host, depending on the dose, timing of administration, and the parasite species (28,29).…”

Contribution of cytokines to pathology and protection in virus infection

“…Indeed, indications that IFNαβ may interfere with antibacterial responses came from Listeria models where IFNαβ deficient mice were shown to be more resistant to infection [37--39]. The same observation was made recently in infection with the parasite Trypanosoma cruzi [40]. Similarly, infection with Mycobacterium tuberculosis is more severe when mice are pre--treated with poly I:C, and this effect has been shown to be IFNαβ--mediated [41].…”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…Recently, Chessler et al (143) reported that Ifnar1 2/2 mice show improved survival following lethal T. cruzi challenge, which is associated with a reduction in IFN-g expression in the splenocytes of WT mice compared with Ifnar1 2/2 animals; this suggests that inhibition of IFN-g production or signaling might be one of the mechanisms by which type I IFNs enhance host susceptibility to the infection (143). Indeed, Lopez et al (144) found that mice deficient in a negative regulator of type I IFN signaling were unable to control infection because of significantly reduced IFN-g induction.…”