title: Toll-like receptor-dependent activation of several human blood cell types by protamine-condensed mRNA.
abstract: We reported that RNA condensed on protamine is protected from RNase-mediated degradation and can be used for vaccination. Here, we show that such complexes are also danger signals that activate mouse cells through a MyD88-dependent pathway. Moreover, mRNA-protamine complexes stimulate human blood cells. They strongly activate DC and monocytes, leading to TNF-alpha and IFN-alpha secretion. In addition, protamine-RNA complexes directly activate B cells, NK cells and granulocytes. The detailed analysis of the activated cell types, the study of the cytokines released from PBMC cultured with protamine-RNA complexes and recently published results suggest that TLR-7 and TLR-8 may be involved in the recognition of protamine-stabilized RNA. Our data indicate that protamine-stabilized RNA, which may be similar to RNA condensed in the nucleocapsids of RNA viruses, is a strong danger signal. Thus, similarly to plasmid DNA, protamine-RNA combines antigen production and non-specific immunostimulation. The studies presented here explain the capacity of protamine-RNA to act as a vaccine, and pave the way towards the development of safe and efficient mRNA-based immunotherapies.
authors.affiliation: CureVac GmbH, Tübingen, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Scheel
authors.forename: Regina
authors.initials: R
authors.lastname: Teufel
authors.forename: Jochen
authors.initials: J
authors.lastname: Probst
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Carralot
authors.forename: Jens
authors.initials: J
authors.lastname: Geginat
authors.forename: Markus
authors.initials: M
authors.lastname: Radsak
authors.forename: David
authors.initials: D
authors.lastname: Jarrossay
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.forename: Günther
authors.initials: G
authors.lastname: Jung
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Rammensee
authors.forename: Ingmar
authors.initials: I
authors.lastname: Hoerr
authors.forename: Steve
authors.initials: S
authors.lastname: Pascolo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D006098:Granulocytes / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D018375:Neutrophil Activation / Q000276:immunology; D011479:Protamines / Q000276:immunology* / Q000378:metabolism; D012333:RNA, Messenger / Q000276:immunology* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051193:Toll-Like Receptors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D016207:Cytokines; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011479:Protamines; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051193:Toll-Like Receptors