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Liquid-crystalline ordering of antimicrobial peptide–DNA complexes controls TLR9 activation

Nathan W. Schmidt,        Fan Jin,        Roberto Lande,        Tine Curk,        Wujing Xian,        Calvin Lee,        Loredana Frasca,        Daan Frenkel,        Jure Dobnikar,        Michel Gilliet        & Gerard C. L. Wong

Double-stranded DNA (dsDNA) can trigger the production of type I interferon (IFN) in plasmacytoid dendritic cells (pDCs) by binding to endosomal Toll-like receptor-9 (TLR9; refs 1, 2, 3, 4, 5). It is also known that the formation of DNA–antimicrobial peptide complexes can lead to autoimmune diseases via amplification of pDC activation1, 2. Here, by combining X-ray scattering, computer simulations, microscopy and measurements of pDC IFN production, we demonstrate that a broad range of antimicrobial peptides and other cationic molecules cause similar effects, and elucidate the criteria for amplification. TLR9 activation depends on both the inter-DNA spacing and the multiplicity of parallel DNA ligands in the self-assembled liquid-crystalline complex. Complexes with a grill-like arrangement of DNA at the optimum spacing can interlock with multiple TLR9 like a zipper, leading to multivalent electrostatic interactions that drastically amplify binding and thereby the immune response. Our results suggest that TLR9 activation and thus TLR9-mediated immune responses can be modulated deterministically.

http://www.nature.com/nmat/journ ... 8.html#contrib-auth