Department of Immunology and Infectious Diseases, Harvard School of Public Health, Building I, Rm. 817, 665 Huntington Avenue, Boston, MA 02115, USA.
Infect Immun. 2011 May;79(5):2112-9. doi: 10.1128/IAI.01176-10. Epub 2011 Mar 14.
Trypanosoma cruzi, the protozoan parasite that causes human Chagas' disease, induces a type I interferon (IFN) (IFN-α/β) 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-γ production by isolated splenocytes in response to parasite antigen. The suppression of IFN-γ in splenocytes from WT mice was independent of IL-10 levels. While the impact of type I IFNs on the production of IFN-γ 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-γ 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.
克氏锥虫，引起人类恰加斯病的原生动物寄生虫，在小鼠急性实验感染和分离的原代细胞类型中诱导 I 型干扰素（IFN）（IFN-α/β）反应。为了研究 I 型 IFN 反应在塑造实验性克氏锥虫感染结局中的潜在影响，野生型（WT）和 I 型 IFN 受体缺陷（IFNAR（-/-））129sv/ev 小鼠的几组分别在致死和亚致死条件下感染了两种不同的克氏锥虫株，并在感染的急性阶段测量了几个参数。结果表明，I 型 IFNs 对于宿主早期免受克氏锥虫的保护并非必需。相反，在致命的克氏锥虫挑战条件下，WT 小鼠死于感染，而 IFNAR（-/-）小鼠最终能够控制寄生虫的生长并存活。IFNAR（-/-）小鼠中克氏锥虫的清除和存活伴随着寄生虫抗原刺激下分离的脾细胞中 IFN-γ产生水平升高。WT 小鼠脾细胞中 IFN-γ的抑制独立于 IL-10 水平。虽然 I 型 IFNs 对克氏锥虫感染背景下 IFN-γ和其他细胞因子/趋化因子的产生的影响仍有待充分确定，但我们的数据表明，在寄生虫负荷高的情况下，I 型 IFNs 对 IFN-γ的产生产生负面影响，启动了一个有害的循环，导致最终无法控制感染。这些发现与微生物发病机制领域的一个不断发展的主题一致，即在各种非病毒病原体感染模型中，I 型 IFNs 对宿主可能有害。
