Liquid-crystalline ordering of antimicrobial peptide–DNA complexes controls TLR9 activation
Schmidt, Nathan W
Wong, Gerard CL
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Schmidt, N. W., Jin, F., Lande, R., Curk, T., Xian, W., Lee, C., Frasca, L., et al. (2015). Liquid-crystalline ordering of antimicrobial peptide–DNA complexes controls TLR9 activation. Nature Materials, 14 696-700. https://doi.org/10.1038/nmat4298
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.
This work is supported by NSF grants DMR1411329 and DMR1106106, EU grants ARG-ERC-COLSTRUCTION 227758 and ITN-COMPLOIDS 234810, by the Herchel Smith Fund, and by the Slovenian Research Agency through Grant P1-0055, and the Swiss National Science Foundation (FN 310030-144072). X-ray research was conducted at Stanford Synchrotron Radiation Lightsource, SLAC National Laboratory, supported by the US DOE Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515, the Advanced Light Source, supported by the US DOE Office of Basic Energy Sciences under Contract No. DE-AC02-05CH11231, and at the UCLA CNSI.
EC FP7 MC ITN (234810)
European Research Council (227758)
External DOI: https://doi.org/10.1038/nmat4298
This record's URL: https://www.repository.cam.ac.uk/handle/1810/248895