Design Rules for Immunomodulation by Host-Defense Peptides

ORAL

Abstract

Some alpha-helices can form complexes with double-stranded DNA (dsDNA) and potently activate innate immunity via Toll-like receptor 9 (TLR9). In lupus and psoriasis, electrostatic complexes between the antimicrobial peptide (AMP) LL37 and dsDNA can hyperactivate TLR9 in plasmacytoid dendritic cells (pDCs), triggering production of type-I interferons (IFNs) and exacerbating inflammation. However, most alpha-helical motifs do not exhibit this activity. Recent work showed that dsDNA complexes that are proinflammatory via the TLR9 pathway have inter-DNA lattice spacings that match the steric size of TLR9, so that spatially-organized parallel DNA ligands can amplify recruitment and multivalent binding to clustered arrays of TLR9. We examine the self-assembled structures of immunocomplexes formed between dsDNA and alpha-helical AMPs using a combination of high resolution synchrotron small angle X-ray scattering (SAXS) and computer simulations. By correlating these measured structures to their induced immunological activity in pDCs and macrophages, we deduce some fundamental structural rules for alpha-helices that are proinflammatory via the TLR9 pathway.

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Presenters

  • Ernest Lee

    Department of Bioengineering, University of California - Los Angeles, Bioengineering, University of California, Los Angeles

Authors

  • Ernest Lee

    Department of Bioengineering, University of California - Los Angeles, Bioengineering, University of California, Los Angeles

  • Changsheng Zhang

    Biomedical Engineering, The University of Texas at Austin

  • Jeremy Di Domizio

    Dermatology, Lausanne University Hospital CHUV

  • Fan Jin

    Polymer Science and Engineering, Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Soft Matter Chemistry, University of Science and Tech

  • Will Connell

    Bioengineering, University of California, Los Angeles

  • Mandy Hung

    Bioengineering, University of California, Los Angeles

  • Nicolas Malkoff

    Bioengineering, University of California, Los Angeles

  • Veronica Veksler

    Bioengineering, University of California, Los Angeles

  • Michel Gilliet

    Dermatology, Lausanne University Hospital CHUV

  • Pengyu Ren

    Biomedical Engineering, The University of Texas at Austin

  • Gerard Wong

    Department of Bioengineering, University of California - Los Angeles, Univ of California - Los Angeles, Bioengineering, University of California, Los Angeles, Bioengineering, Chemistry, CNSI, UCLA