Inflammation plays a crucial role in both acute pneumonitis and chronic pulmonary fibrosis induced by irradiation. Immune intervention represents a viable approach to alleviate damages associated with radiation-induced injury. However to devise a successful strategy, it is necessary to understand the roles of key innate immune receptors and sensors during radiation. This understanding is required to for the rational selection of appropriate immune modulators for treating radiation-associated damages. During the last grant period, one of our goals was to focus on key immunologic regulators and their role in radiation-induced damage. These regulators included (a) MyD88 (myeloid differentiation factor 88), the common adaptor molecule for Toll-like receptors (TLR) and (b) NLRP3, a member of the NBD-LRR (NLR) gene family that is now recognized as a key component of the inflammasome complex that controls caspase-1, IL-1 and IL-18. The TLR and NLR pathways respectively are considered by some as extracellular and intracellular pattern recognition sensors important in the control of innate immunity and inflammation. In contrast to our initial expectation that MyD88 and NLRP3 would exacerbate inflammation, we and other labs have increasingly found that during tissue injury, both molecules serve as homeostatic factors important for tissue repair. In specific, we found that MyD88 and NLRP3 protect against injury sustained upon radiation damage in the lung, and both gene products are critical for minimizing fibrosis and restoring lung function. This is consistent with reports showing that flagellin, a TLR5 agonist, can protect against pulmonary radiation. These data suggest a paradigm shift in how we should view MyD88 and NLRP3 in the context of pulmonary radiation and suggest that both pathways are beneficial in attenuating the damage caused by radiation injury. Hence therapeutic agents that can activate these pathways might protect against radiation damage. Furthermore, since the TLR and NLR pathways are also required for protect host response during infection, these two molecules might protect against a dual exposure to radiation and infectious microbes associated with pandemic and opportunistic infections. Accordingly the Aims are: (1) to assess the use of non-flagellin TLR and NLR agonists as deliverable therapeutics for pulmonary radiation-induced injury; (2) to assess the mechanisms by which MyD88 and NLRP3 serve as protective factors during pulmonary radiation; and (3) to determine the roles of MyD88 and NLRP3 during dual exposure to radiation and infectious agents of immense public health impact, influenza virus and K. pneumoniae.