Novel immunomodulators from hard ticks selectively reprogramme human dendritic cell responses.
Novel immunomodulators from hard ticks selectively reprogramme human dendritic cell responses.
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DOI：
10.1371/journal.ppat.1003450
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Austyn JM
中科院分区：
文献类型：
--
作者：
Preston SG;Majtán J;Kouremenou C;Rysnik O;Burger LF;Cabezas Cruz A;Chiong Guzman M;Nunn MA;Paesen GC;Nuttall PA;Austyn JM
硬蜱破坏其脊椎动物宿主的免疫反应，以便比其他吸血外寄生虫更长时间地进食;这可能是它们传播可能是任何节肢动物媒介中最大多样性的病原体的原因之一。蜱诱导的免疫调节是由唾液成分介导的，其中一些中和先天免疫的元素或抑制适应性免疫的发展。由于树突状细胞（DC）触发并帮助调节适应性免疫，因此它们是免疫调节的理想靶点。然而，先前描述的蜱唾液的免疫活性成分在其细胞和分子靶点中是高度混杂的，或者对DC的作用有限。在这里，我们解决的问题，是否最大的和全球最重要的一组蜱（硬蜱transstriates）产生唾液分子，专门调节DC的活动。本研究利用层析法从无斑扇头蜱中分离出一种唾液腺蛋白（Japanin）。克隆了Japanin基因，并在杆状病毒表达系统中表达了重组蛋白。我们发现，Japanin在体外特异性地重新编程DC对各种刺激的反应，从根本上改变它们的共刺激和共抑制跨膜分子的表达（通过流式细胞术测量）以及它们的促炎、抗炎和T细胞极化细胞因子的分泌（通过Luminex多重测定评估）;它还抑制DC从单核细胞分化。序列比对和酶促去糖基化显示Japanin是17.7 kDa的N-糖基化脂质运载蛋白。通过分子克隆和数据库检索，我们已经确定了一组同源蛋白在R。apaculatus和相关物种，其中三个我们已经表达并显示具有DC-调节活性。所有数据都是使用从至少四个人献血者产生的DC获得的，并进行了严格的统计分析。我们的研究结果表明，寄生虫诱导的适应性免疫的颠覆，这也可能有利于病原体的传播一个以前未知的机制。树突状细胞（DC）是脊椎动物免疫系统的特化细胞。DC可以感知不同类型的传染源和寄生虫，并触发和帮助调节消除它们所需的特定类型的免疫力。我们已经发现，最大和全球最重要的硬蜱群体在其唾液中产生一个独特的蛋白质家族，该蛋白质家族选择性地靶向DC，从根本上改变了原本会诱导强大免疫反应的功能;这些蛋白质还阻止DC从前体细胞发育。这些唾液分子的产生可能有助于解释这些硬蜱与其他吸血寄生虫相比的两个非常不寻常的特征：它们能够在相当长的时间内（7天或更长时间）连续喂养脊椎动物宿主而不会引发潜在的破坏性免疫反应，以及它们传播可能是任何类型的无脊椎动物中最多种类的病原体的能力。
Hard ticks subvert the immune responses of their vertebrate hosts in order to feed for much longer periods than other blood-feeding ectoparasites; this may be one reason why they transmit perhaps the greatest diversity of pathogens of any arthropod vector. Tick-induced immunomodulation is mediated by salivary components, some of which neutralise elements of innate immunity or inhibit the development of adaptive immunity. As dendritic cells (DC) trigger and help to regulate adaptive immunity, they are an ideal target for immunomodulation. However, previously described immunoactive components of tick saliva are either highly promiscuous in their cellular and molecular targets or have limited effects on DC. Here we address the question of whether the largest and globally most important group of ticks (the ixodid metastriates) produce salivary molecules that specifically modulate DC activity. We used chromatography to isolate a salivary gland protein (Japanin) from Rhipicephalus appendiculatus ticks. Japanin was cloned, and recombinant protein was produced in a baculoviral expression system. We found that Japanin specifically reprogrammes DC responses to a wide variety of stimuli in vitro, radically altering their expression of co-stimulatory and co-inhibitory transmembrane molecules (measured by flow cytometry) and their secretion of pro-inflammatory, anti-inflammatory and T cell polarising cytokines (assessed by Luminex multiplex assays); it also inhibits the differentiation of DC from monocytes. Sequence alignments and enzymatic deglycosylation revealed Japanin to be a 17.7 kDa, N-glycosylated lipocalin. Using molecular cloning and database searches, we have identified a group of homologous proteins in R. appendiculatus and related species, three of which we have expressed and shown to possess DC-modulatory activity. All data were obtained using DC generated from at least four human blood donors, with rigorous statistical analysis. Our results suggest a previously unknown mechanism for parasite-induced subversion of adaptive immunity, one which may also facilitate pathogen transmission. Dendritic cells (DC) are specialised cells of the vertebrate immune system. DC can sense different types of infectious agents and parasites, and both trigger and help regulate the specific types of immunity needed to eliminate them. We have discovered that the largest and globally most important group of hard ticks produce a unique family of proteins in their saliva that selectively targets DC, radically altering functions that would otherwise induce robust immune responses; these proteins also prevent DC developing from precursor cells. The production of these salivary molecules may help to explain two highly unusual features of these hard ticks compared with other blood-feeding parasites: their ability to feed continuously on their vertebrate hosts for considerable lengths of time (7 days or more) without eliciting potentially damaging immune responses, and their capacity to transmit possibly the greatest variety of pathogens of any type of invertebrate.
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影响因子：
5.4
作者：
Figueiredo, Amanda B.;Serafim, Tiago D.;Afonso, Luis C. C.
通讯作者：
Afonso, Luis C. C.
影响因子：
4.3
作者：
da Silva, Henrique Borges;Caetano, Susana S.;Tadokoro, Carlos E.
通讯作者：
Tadokoro, Carlos E.
DOI：
10.1084/jem.20090847
发表时间：
2009-12-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Francisco LM;Salinas VH;Brown KE;Vanguri VK;Freeman GJ;Kuchroo VK;Sharpe AH
通讯作者：
Sharpe AH
影响因子：
32.4
作者：
Butte, Manish J.;Keir, Mary E.;Freeman, Gordon J.
通讯作者：
Freeman, Gordon J.
影响因子：
32.4
作者：
Anguita, J;Ramamoorthi, N;Fikrig, E
通讯作者：
Fikrig, E