Novel Immunomodulators from Hard Ticks Selectively Reprogramme Human Dendritic Cell Responses

PLoS Pathogens

Miles A. Nunn¹  Jonathan M. Austyn²  Juraj Majtán²  Patricia A. Nuttall³  Chrisoula Kouremenou⁴  Guido C. Paesen⁵  Lena F. Burger⁶  Stephen G. Preston⁷  Alejandro Cabezas Cruz⁷  Oliwia Rysnik⁷  Maylin Chiong Guzman⁸ 

[1] Center for Genetic Engineering and Biotechnology, Animal Biotechnology Division, Havana, Cuba;Department of Zoology, University of Oxford, Oxford, United Kingdom;Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, Oxford, United Kingdom;Institute of Zoology, Slovak Academy of Sciences, Bratislava, Slovakia;NERC Centre for Ecology & Hydrology, Crowmarsh Gifford, Wallingford, Oxfordshire, United Kingdom;Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom;Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom;University of South Bohemia, Faculty of Science and Biology Centre of the ASCR, Institute of Parisitology, České Budějovice, Czech Republic

关键词: T cells;    Sequence alignment;    Cytokines;    Monocytes;    Flow cytometry;    Dendritic cells;    Cytotoxic T cells;    Salivary gl;    s;   

DOI  :  10.1371/journal.ppat.1003450

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY