Nono Justin Komguep, Lutz Manfred B, Brehm Klaus
University of Würzburg, Institute for Hygiene and Microbiology, Würzburg, Germany.
University of Würzburg, Institute of Virology and Immunobiology, Würzburg, Germany.
PLoS Negl Trop Dis. 2014 Jan 2;8(1):e2632. doi: 10.1371/journal.pntd.0002632. eCollection 2014.
Alveolar echinococcosis (AE), caused by the metacestode of the tapeworm Echinococcus multilocularis, is a lethal zoonosis associated with host immunomodulation. T helper cells are instrumental to control the disease in the host. Whereas Th1 cells can restrict parasite proliferation, Th2 immune responses are associated with parasite proliferation. Although the early phase of host colonization by E. multilocularis is dominated by a potentially parasitocidal Th1 immune response, the molecular basis of this response is unknown.
We describe EmTIP, an E. multilocularis homologue of the human T-cell immunomodulatory protein, TIP. By immunohistochemistry we show EmTIP localization to the intercellular space within parasite larvae. Immunoprecipitation and Western blot experiments revealed the presence of EmTIP in the excretory/secretory (E/S) products of parasite primary cell cultures, representing the early developing metacestode, but not in those of mature metacestode vesicles. Using an in vitro T-cell stimulation assay, we found that primary cell E/S products promoted interferon (IFN)-γ release by murine CD4+ T-cells, whereas metacestode E/S products did not. IFN-γ release by T-cells exposed to parasite products was abrogated by an anti-EmTIP antibody. When recombinantly expressed, EmTIP promoted IFN-γ release by CD4+ T-cells in vitro. After incubation with anti-EmTIP antibody, primary cells showed an impaired ability to proliferate and to form metacestode vesicles in vitro.
We provide for the first time a possible explanation for the early Th1 response observed during E. multilocularis infections. Our data indicate that parasite primary cells release a T-cell immunomodulatory protein, EmTIP, capable of promoting IFN-γ release by CD4+ T-cells, which is probably driving or supporting the onset of the early Th1 response during AE. The impairment of primary cell proliferation and the inhibition of metacestode vesicle formation by anti-EmTIP antibodies suggest that this factor fulfills an important role in early E. multilocularis development within the intermediate host.
泡型包虫病（AE）由多房棘球绦虫的中绦期幼虫引起，是一种与宿主免疫调节相关的致命性人畜共患病。辅助性T细胞在宿主控制该病中发挥重要作用。Th1细胞可限制寄生虫增殖，而Th2免疫反应则与寄生虫增殖相关。尽管多房棘球绦虫在宿主定植的早期阶段以具有潜在杀寄生虫作用的Th1免疫反应为主，但这种反应的分子基础尚不清楚。
我们描述了EmTIP，它是人类T细胞免疫调节蛋白TIP的多房棘球绦虫同源物。通过免疫组织化学，我们显示EmTIP定位于寄生虫幼虫的细胞间隙。免疫沉淀和蛋白质印迹实验表明，EmTIP存在于寄生虫原代细胞培养物的排泄/分泌（E/S）产物中，代表早期发育的中绦期幼虫，但不存在于成熟中绦期囊泡的E/S产物中。使用体外T细胞刺激试验，我们发现原代细胞E/S产物可促进小鼠CD4+T细胞释放干扰素（IFN）-γ，但中绦期幼虫E/S产物则不能。抗EmTIP抗体可消除暴露于寄生虫产物的T细胞释放的IFN-γ。重组表达时，EmTIP在体外可促进CD4+T细胞释放IFN-γ。与抗EmTIP抗体孵育后，原代细胞在体外的增殖能力和形成中绦期囊泡的能力受损。
我们首次为多房棘球绦虫感染期间观察到早期Th1反应提供了一种可能的解释。我们的数据表明，寄生虫原代细胞释放一种T细胞免疫调节蛋白EmTIP，它能够促进CD4+T细胞释放IFN-γ，这可能驱动或支持AE期间早期Th1反应的发生。抗EmTIP抗体对原代细胞增殖的损害以及对中绦期囊泡形成的抑制表明，该因子在中间宿主体内多房棘球绦虫的早期发育中发挥重要作用。
