Ithree Institute, University of Technology Sydney, Sydney, Australia.
FASEB J. 2012 Nov;26(11):4614-27. doi: 10.1096/fj.12-213876. Epub 2012 Aug 7.
We previously reported the identification of a novel family of immunomodulatory proteins, termed helminth defense molecules (HDMs), that are secreted by medically important trematode parasites. Since HDMs share biochemical, structural, and functional characteristics with mammalian cathelicidin-like host defense peptides (HDPs), we proposed that HDMs modulate the immune response via molecular mimicry of host molecules. In the present study, we report the mechanism by which HDMs influence the function of macrophages. We show that the HDM secreted by Fasciola hepatica (FhHDM-1) binds to macrophage plasma membrane lipid rafts via selective interaction with phospholipids and/or cholesterol before being internalized by endocytosis. Following internalization, FhHDM-1 is rapidly processed by lysosomal cathepsin L to release a short C-terminal peptide (containing a conserved amphipathic helix that is a key to HDM function), which then prevents the acidification of the endolysosomal compartments by inhibiting vacuolar ATPase activity. The resulting endolysosomal alkalization impedes macrophage antigen processing and prevents the transport of peptides to the cell surface in conjunction with MHC class II for presentation to CD4(+) T cells. Thus, we have elucidated a novel mechanism by which helminth pathogens alter innate immune cell function to assist their survival in the host.
我们之前报道了一类新型的免疫调节蛋白，称为寄生虫防御分子（HDM），它们由医学上重要的吸虫寄生虫分泌。由于 HDM 在生化、结构和功能上与哺乳动物的抗菌肽（HDP）相似，我们推测 HDM 通过模拟宿主分子来调节免疫反应。在本研究中，我们报告了 HDM 影响巨噬细胞功能的机制。我们表明，来自 Fasciola hepatica 的 HDM（FhHDM-1）通过与磷脂和/或胆固醇选择性相互作用结合到巨噬细胞膜脂筏上，然后通过内吞作用被内化。内化后，FhHDM-1 被溶酶体组织蛋白酶 L 迅速加工，释放出一个短的 C 端肽（含有一个保守的两亲性螺旋，这是 HDM 功能的关键），然后通过抑制液泡型 ATP 酶活性来防止内体酸化。由此产生的内体碱化阻碍了巨噬细胞的抗原加工，并阻止了与 MHC Ⅱ类结合的肽向细胞表面的转运，从而递呈给 CD4(+) T 细胞。因此，我们阐明了一种新的机制，即寄生虫病原体改变先天免疫细胞的功能，以帮助它们在宿主中存活。
