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primary topic: Activation of innate immunity by ribonucleic acids

Activation of innate immunity by ribonucleic acids
type: Article
abstract: RNA provides a stimulus for innate immunity either by activating the endosomal Toll-like receptors (TLRs) 3, 7 and 8 or by triggering cytosolic RNA sensors of the RIG-I-like family (RLRs) or the NALP3-containing inflammasome. RNA recognition results in the secretion of type-I interferons or proinflammatory cytokines. Recognition of RNA is supposed to occur due to the presence of non-self structures, such as the abundance of nucleotide modifications, guanosine-uridine-rich sequences, double-stranded conformation or the presence of a terminal 5’-triphosphate. However, the exact structural requirements for RNA recognition are still largely unknown. Within this work the functional and structural interplay between RNA and different receptors within cells of the innate immune system was analyzed. In detail, bacterial RNA, synthetic siRNA and in vitro transcribed RNA was characterized. It can be shown that TLR7 is the responsible receptor for the recognition of siRNA in plasmacytoid dendritic cells resulting in induction of type-I interferons which mediate unwanted off-target effects. Besides a minor sequence-dependent influence, introduction of nucleotide modifications identified the 2’-position of the ribose to be crucial for TLR7-mediated immunorecognition. Further, hyperchromicity assays and structure prediction give strong evidence that stimulating RNA adopts a duplex structure. These findings suggest that immunorecognition takes place within the minor groove of a given RNA duplex, thus revealing a possible mechanism of receptor ligand interaction. Confirming this notion, the introduction of different nucleotide modifications altering major groove recognition showed no effect on immunorecognition. Of note, incorporation of thymidine substitutions was demonstrated to reduce immunostimulation without any effect on gene knockdown. These results identify modifications that dissect unwanted immunostimulation from RNA interference in siRNA, thus paving the way for more prec…
date: 2009
status: published
author list: authors
type: EPrint
type: DoctoralThesisEPrint
is part of: repository
has document: Activation of innate immunity by ribonucleic acids (PDF)
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subject: 570 Biowissenschaften, Biologie

Activation of innate immunity by ribonucleic acids (PDF)
type: Document
has file: Doktorarbeit_Finale.pdf
has part: Doktorarbeit_Finale.pdf

Florian Eberle
type: Person
given name: Florian
family name: Eberle

Activation of innate immunity by ribonucleic acids (Other)
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Activation of innate immunity by ribonucleic acids (Other)
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primary topic: Activation of innate immunity by ribonucleic acids

570 Biowissenschaften, Biologie
type: Concept
preferred label: 570 Life sciences @en