Novel immunomodulators from hard ticks selectively reprogramme human dendritic cell responses.

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 b...

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Autores principales:	Stephen G Preston, Juraj Majtán, Chrisoula Kouremenou, Oliwia Rysnik, Lena F Burger, Alejandro Cabezas Cruz, Maylin Chiong Guzman, Miles A Nunn, Guido C Paesen, Patricia A Nuttall, Jonathan M Austyn
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/ea88a881ed4142ee867040cb6714a178
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spelling	oai:doaj.org-article:ea88a881ed4142ee867040cb6714a1782021-11-18T06:05:28ZNovel immunomodulators from hard ticks selectively reprogramme human dendritic cell responses.1553-73661553-737410.1371/journal.ppat.1003450https://doaj.org/article/ea88a881ed4142ee867040cb6714a1782013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23825947/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Hard 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.Stephen G PrestonJuraj MajtánChrisoula KouremenouOliwia RysnikLena F BurgerAlejandro Cabezas CruzMaylin Chiong GuzmanMiles A NunnGuido C PaesenPatricia A NuttallJonathan M AustynPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 9, Iss 6, p e1003450 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Stephen G Preston Juraj Majtán Chrisoula Kouremenou Oliwia Rysnik Lena F Burger Alejandro Cabezas Cruz Maylin Chiong Guzman Miles A Nunn Guido C Paesen Patricia A Nuttall Jonathan M Austyn Novel immunomodulators from hard ticks selectively reprogramme human dendritic cell responses.
description	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.
format	article
author	Stephen G Preston Juraj Majtán Chrisoula Kouremenou Oliwia Rysnik Lena F Burger Alejandro Cabezas Cruz Maylin Chiong Guzman Miles A Nunn Guido C Paesen Patricia A Nuttall Jonathan M Austyn
author_facet	Stephen G Preston Juraj Majtán Chrisoula Kouremenou Oliwia Rysnik Lena F Burger Alejandro Cabezas Cruz Maylin Chiong Guzman Miles A Nunn Guido C Paesen Patricia A Nuttall Jonathan M Austyn
author_sort	Stephen G Preston
title	Novel immunomodulators from hard ticks selectively reprogramme human dendritic cell responses.
title_short	Novel immunomodulators from hard ticks selectively reprogramme human dendritic cell responses.
title_full	Novel immunomodulators from hard ticks selectively reprogramme human dendritic cell responses.
title_fullStr	Novel immunomodulators from hard ticks selectively reprogramme human dendritic cell responses.
title_full_unstemmed	Novel immunomodulators from hard ticks selectively reprogramme human dendritic cell responses.
title_sort	novel immunomodulators from hard ticks selectively reprogramme human dendritic cell responses.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/ea88a881ed4142ee867040cb6714a178
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Novel immunomodulators from hard ticks selectively reprogramme human dendritic cell responses.

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