T lymphocyte-dependent IL-10 down-regulates a cytokine storm driven by Toxoplasma gondii GRA24.

IF 5.1 1区 生物学 Q1 MICROBIOLOGY mBio Pub Date : 2024-11-13 Epub Date: 2024-10-23 DOI:10.1128/mbio.01455-24
Claire M Doherty, Paige R Patterson, Julie A Emeanuwa, Jessica Belmares Ortega, Barbara A Fox, David J Bzik, Eric Y Denkers
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Abstract

As a model organism in the study of immunity to infection, Toxoplasma gondii has been instrumental in establishing key principles of host anti-microbial defense and its regulation. Here, we employed an attenuated uracil auxotroph strain of Type I Toxoplasma designated OMP to further untangle the early immune response to this parasitic pathogen. Experiments using αβ T cell-deficient Tcrb-/- mice unexpectedly revealed that an intact αβ T lymphocyte compartment was essential to survive infection with OMP. Subsequent antibody depletion and knockout mouse experiments demonstrated contributions from CD4+ T cells and most predominantly CD8+ T cells in resistance. Using transgenic knockout mice, we found only a partial requirement for IFN-γ and a lack of requirement for Toll-like receptor (TLR) adaptor MyD88 in resistance. In contrast to other studies on Toxoplasma, the ability to survive OMP infection did not require IL-12p40. Surprisingly, T cell-dependent IL-10 was found to be critical for survival, and deficiency of this cytokine triggered an abnormally high systemic inflammatory response. We also found that parasite molecule GRA24, a dense granule protein that triggers TLR-independent IL-12 production, acts as a virulence factor contributing to death of OMP-infected Tcrb-/- and IL-10-/- mice. Furthermore, resistance against OMP was restored in Tcrb-/- mice via monoclonal depletion of IL-12p40, suggesting that GRA24-induced IL-12 underlies the fatal immunopathology observed. Collectively, our studies provide insight into a novel and rapidly arising T lymphocyte-dependent anti-inflammatory response to T. gondii which operates independently of MyD88 and IL-12 and that depends on the function of parasite-dense granule protein GRA24.IMPORTANCEAs a model infectious microbe and an important human pathogen, the apicomplexan Toxoplasma gondii has provided many important insights into innate and adaptive immunity to infection. We show here that a low virulence uracil auxotrophic Toxoplasma strain emerges as a virulent parasite in the absence of an intact T cell compartment. Both CD4+ and CD8+ T lymphocytes are required for optimal protection, in line with previous findings in other models of Toxoplasma infection. Nevertheless, several novel aspects of the response were identified in our study. Protection occurs independently of IL-12 and MyD88 and only partially requires IFN-γ. This is noteworthy particularly because the cytokines IL-12 and IFN-γ have previously been regarded as essential for protective immunity to T. gondii. Instead, we identified the anti-inflammatory effects of T cell-dependent IL-10 as the critical factor enabling host survival. The parasite dense granule protein GRA24, a host-directed mitogen-activated protein kinase activator, was identified as a major virulence factor in T cell-deficient hosts. Collectively, our results provide new and unexpected insights into host resistance to Toxoplasma.

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依赖于 T 淋巴细胞的 IL-10 可下调由弓形虫 GRA24 驱动的细胞因子风暴。
作为研究感染免疫的模式生物,弓形虫在建立宿主抗微生物防御及其调控的关键原则方面发挥了重要作用。在这里,我们采用了被命名为 OMP 的 I 型弓形虫尿嘧啶辅助减毒株,以进一步解开这种寄生病原体的早期免疫反应。使用αβ T细胞缺陷的Tcrb-/-小鼠进行的实验意外地发现,完整的αβ T淋巴细胞区系是在感染OMP后存活的必要条件。随后的抗体耗竭和基因敲除小鼠实验表明,CD4+ T 细胞和最主要的 CD8+ T 细胞对抵抗力有贡献。通过使用转基因基因敲除小鼠,我们发现在抗药性中只需要部分 IFN-γ,而不需要 Toll 样受体(TLR)适配体 MyD88。与其他有关弓形虫的研究不同,OMP 感染的存活能力并不需要 IL-12p40。令人惊讶的是,我们发现依赖于 T 细胞的 IL-10 对存活至关重要,缺乏这种细胞因子会引发异常高的全身炎症反应。我们还发现,寄生虫分子 GRA24 是一种致密颗粒蛋白,它能触发不依赖于 TLR 的 IL-12 的产生,是导致感染了 OMP 的 Tcrb-/- 和 IL-10-/- 小鼠死亡的毒力因子。此外,Tcrb-/-小鼠通过单克隆去除IL-12p40可恢复对OMP的抵抗力,这表明GRA24诱导的IL-12是观察到的致命免疫病理学的基础。总之,我们的研究深入揭示了一种新的、快速产生的依赖于 T 淋巴细胞的对弓形虫的抗炎反应,这种反应独立于 MyD88 和 IL-12 而运行,并且依赖于寄生虫致密颗粒蛋白 GRA24 的功能。重要意义弓形虫作为一种模式传染性微生物和重要的人类病原体,为先天性和适应性免疫感染提供了许多重要的见解。我们在此表明,在没有完整的 T 细胞区系的情况下,低毒性尿嘧啶辅助营养性弓形虫菌株会成为一种毒性寄生虫。CD4+ 和 CD8+ T 淋巴细胞都是最佳保护所必需的,这与之前在其他弓形虫感染模型中的发现一致。然而,我们的研究发现了反应的几个新方面。保护作用的产生与 IL-12 和 MyD88 无关,仅部分需要 IFN-γ。这一点尤其值得注意,因为细胞因子IL-12和IFN-γ以前一直被认为是对淋球菌产生保护性免疫的必要条件。相反,我们发现依赖于 T 细胞的 IL-10 的抗炎作用是使宿主存活的关键因素。寄生虫致密颗粒蛋白 GRA24 是宿主定向的丝裂原活化蛋白激酶激活剂,被确定为 T 细胞缺陷宿主的主要毒力因子。总之,我们的研究结果为了解宿主对弓形虫的抵抗力提供了意想不到的新见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
mBio
mBio MICROBIOLOGY-
CiteScore
10.50
自引率
3.10%
发文量
762
审稿时长
1 months
期刊介绍: mBio® is ASM''s first broad-scope, online-only, open access journal. mBio offers streamlined review and publication of the best research in microbiology and allied fields.
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