A new paradigm for the treatment of infectious disease is through the modulation of innate immune responses. In this capacity, host defense peptides (HDPs) and synthetic Toll-like receptor 9 (TLR9) ligands have the greatest demonstrated potentials. From the perspective of TLR9, a model is proposed in which TLR9 activation is mediated specifically by CpG-containing ligands while sensitivity of the receptor is modulated by the absolute concentration of nucleic acids in a sequence-independent fashion. Alternatively, a methodology for the characterization of HDPs is described that permits discrimination and quantification of the distinct, but related, behaviors of direct antimicrobial activity and PhoQ ligand potential and provides a rational basis for peptide selection with greater therapeutic potential and minimized potential for initiation of bacterial resistance. The work presented here considers mechanisms for the improvement of these treatments through optimization (in the case of CpGs) or alternatively minimization (in the case of HDPs) of the interactions of these ligands with sensory receptors.

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