Lindsey Brown1,2, Daniel Deredge3, Patrick Wintrode3, Thomas Miethke4, Stefanie Vogel, Kari Ann Shirey5, Greg A. Snyder1,2,5 The Toll-like and Interleukin-1/18 families of receptors mediate immune signaling in response to pathogen, cytokines and self-antigens. Dys-regulation of host based Toll/IL-1 receptor (TIR) signaling is involved in numerous human pathologies involving inflammation, autoimmunity and cancer. We propose a host-based molecular approach via regulationb of innate immune TIR signaling: (1) will allow for protection against multiple pathogens (bacteria and viral) at the same time; (2) Is decoupled from receptor-pathogen interactions and therefore requires no a priori knowledge of the microbe or host -ligand interaction, and (3) provides a novel and broad development platform for controlling inflammation and disease. Accordingly we have previously solved the crystal structures of several TIRs and characterized their molecular interactions with subversive microbial TIR protein mimics using, hydrogen deuterium exchange mass spectrometry (HDX-MS), X-ray crystallography and NMR. Our molecular studies of host and microbial TIR domains identify atomic interactions and druggable sites, which have lead to development of novel small molecule and peptide compounds that selectively inhibit intracellular TIR signaling pathways in vivo and in vitro. As a proof of concept for this host-focused therapeutic approach targeting of intracellular TIR signaling, preliminary data show the pre-clinically approved small molecule inhibitor TAK-242 protects WT C57BL/6 mice against ALI and lethality using the mouse-adapted strain of influenza, A/PR8/8/34 (PR8). TAK-242 targets the TIR domain of TLR4. We are now evaluating TIR inhibitors in models of cancer. Our long-term goal in this host-centered structure-function approach is regulation of acute and chronic inflammation resulting from pathogen infection, immune dysfunction and disease.