For decades, a “one bug, one drug” approach has characterized development of vaccines or treatments for specific infectious diseases. We propose a different approach based on the development of novel treatment of infectious diseases by capitalizing on common host innate immune responses that are triggered during infection by influenza and other priority pathogens. Influenza virus infects up to 5 million people yearly worldwide, killing as many as ~500,000. Our strong experimental evidence demonstrates that the potent TLR4 antagonist, Eritoran (Eisai, Inc.), as well as multiple other TLR4 antagonists, significantly decreased both acute lung injury (ALI) and mortality when administered therapeutically to influenza-infected mice. Eritoran not only blocks influenza-mediated release of host-derived ”danger-associated molecular patterns” (DAMPs), but also blunted DAMP-mediated TLR4 signaling in macrophages that normally results in a “cytokine storm.” While we have elucidated several novel mechanisms by which influenza mediates ALI and lethality that are counteracted by Eritoran therapy (e.g., release of host-derived DAMPS that signal through TLR4; increased tight-junction permeability leading to pulmonary edema; a role for IL-1α/β in lethality), our understanding of the overall innate immune signaling pathways that control influenza-induced ALI and Eritoran-mediated protection remains incomplete, necessitating further investigation to develop a highly efficacious host-directed therapy. Therefore, Specific Aim 1 will focus on the identification of innate immune mechanisms that underlie both influenza sensitivity and Eritoran-mediated protection. We will take advantage of genetically modified mouse strains to dissect the signaling pathways engaged. Whether TLR4 must be expressed on stromal and/or myeloid cells, the role of virus-induced epithelial cell necroptosis in DAMP release, mechanisms by which non-TLR4 PRRs contribute to influenza resistance/susceptibility, and the possibility that TLR2/TLR4 dimerization is required for the host response to influenza will be evaluated as novel potential mechanisms that can be exploited to enhance therapeutic efficacy. In Specific Aim 2, the therapeutic benefit of a novel IKKβ inhibitor, E6070 (Eisai, Inc.), against influenza, alone or in the presence of current anti-influenza antiviral therapies, will be tested in cotton rats (CR), a second rodent species that permits analysis of ALI in response to infection by non-adapted human influenza isolates. Aim 2 will also compare Eritoran and E6070 in CR in a model of secondary staphylococcal (MRSA) pneumonia following influenza infection. Lastly, we will assess the relative effectiveness of Eritoran and E6070 for the ability to block ALI caused by other clinically important or biothreat pathogens associated with ALI in humans (e.g., Francisella tularensis, Streptococcus pneumoniae, Klebsiella pneumoniae, SARS-CoV and MERS-CoV), first in mice, and, if effective, in CR. Th...