PDF(Pubmed)
Abstract：
Lymphatic filariasis (LF) is a mosquito-borne disease caused by filarial nematodes including Brugia malayi. Over 860 million people worldwide are infected or at risk of infection in 72 endemic countries. The absence of a protective vaccine means that current control strategies rely on mass drug administration programs that utilize inadequate drugs that cannot effectively kill adult parasites, thus established infections are incurable. Progress to address deficiencies in the approach to LF control is hindered by a poor mechanistic understanding of host-parasite interactions, including mechanisms of host immunomodulation by the parasite, a critical adaptation for establishing and maintaining infections. The canonical type 2 host response to helminth infection characterized by anti-inflammatory and regulatory immune phenotypes is modified by filarial nematodes during chronic LF. Current efforts at identifying parasite-derived factors driving this modification focus on parasite excretory-secretory products (ESP), including extracellular vesicles (EVs). We have previously profiled the cargo of B. malayi EVs and identified B. malayi galectin-1 and galectin-2 as among the most abundant EV proteins. In this study we further investigated the function of these proteins. Sequence analysis of the parasite galectins revealed highest homology to mammalian galectin-9 and functional characterization identified similar substrate affinities consistent with this designation. Immunological assays showed that Bma-LEC-2 is a bioactive protein that can polarize macrophages to an alternatively activated phenotype and selectively induce apoptosis in Th1 cells. Our data shows that an abundantly secreted parasite galectin is immunomodulatory and induces phenotypes consistent with the modified type 2 response characteristic of chronic LF infection.
摘要：
淋巴丝虫病（LF）是一种蚊子传播的疾病，由包括马来西亚Brugia的丝虫线虫引起。在72个流行国家，全球有超过8.6亿人被感染或有感染风险。缺乏保护性疫苗意味着当前的控制策略依赖于大规模的药物管理计划，这些计划利用的药物不足，无法有效杀死成年寄生虫。因此确定的感染是无法治愈的。对宿主-寄生虫相互作用的机械理解较差，阻碍了解决LF控制方法缺陷的进展。包括寄生虫的宿主免疫调节机制，建立和维持感染的关键适应。在慢性LF期间，丝状线虫修饰了以抗炎和调节性免疫表型为特征的典型2型宿主对蠕虫感染的反应。目前在确定寄生虫衍生因素驱动这种修饰的努力集中在寄生虫排泄分泌产物（ESP），包括细胞外囊泡(EV)。我们以前已经对马来西亚B.EV的货物进行了分析，并将马来西亚B.galectin-1和galectin-2确定为最丰富的EV蛋白之一。在这项研究中，我们进一步研究了这些蛋白质的功能。寄生虫半乳糖凝集素的序列分析显示与哺乳动物半乳糖凝集素-9的同源性最高，并且功能表征鉴定出与该名称一致的相似底物亲和力。免疫测定显示Bma-LEC-2是一种生物活性蛋白，可以使巨噬细胞极化为选择性激活的表型，并选择性诱导Th1细胞凋亡。我们的数据表明，大量分泌的寄生虫半乳糖凝集素具有免疫调节作用，并诱导与慢性LF感染的修饰的2型反应特征一致的表型。
